Business Report 20 ANNUAL REPORT 20 Idorsia – Reaching out for more The purpose of Idorsia is to discover, develop and commercialize innovative medicines to help more patients.
We have more ideas, we see more opportunities and we want to transform the horizon of therapeutic options. More science – For a better future
4 Further parts of the Idorsia Annual Report 2020 Contents
Be prepared Financial for more Report 20 ANNUAL REPORT 20 Curious to learn more? Reach out to us. 6 Idorsia today Investor Relations Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91 4123 Allschwil Switzerland
Phone +41 58 844 10 10 [email protected] © Idorsia Pharmaceuticals Ltd 2020 www.idorsia.com 8 Milestones in 2020 Idorsia – 10 Letter from the Chairman of the Board Reaching out 12 Letter from the Chief Executive Officer 16 Our strategic priorities Be prepared Governance for more Report 2 for more 22 Q&A with the Chief Commercial Officer 20 ANNUAL REPORT 20 Curious to learn more? Reach out to us.
Investor Relations Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91 4123 Allschwil Switzerland
Phone +41 58 844 10 10 [email protected] © Idorsia Pharmaceuticals Ltd 2020 www.idorsia.com 30 Q&A with the Chief Scientific Officer 36 Clinical development pipeline
Be prepared Compensation 38 Daridorexant for insomnia for more Report 46 Aprocitentan for resistant hypertension 20 ANNUAL REPORT 20 52 Clazosentan for cerebral vasospasm Curious to learn more? Reach out to us.
Investor Relations Idorsia Pharmaceuticals Ltd Hegenheimermattweg 91 4123 Allschwil Switzerland
Phone +41 58 844 10 10 58 Lucerastat for Fabry disease [email protected] © Idorsia Pharmaceuticals Ltd 2020 www.idorsia.com Our Research & 64 Selatogrel for acute myocardial infarction 70 Cenerimod for systemic lupus erythematosus 26 Development 76 Partnerships
Contents navigation Our 80 Working at Idorsia > Contents 78 People 88 The Idorsia Executive Committee
Idorsia – Reaching out for more Our 91 Compliance, ethics and quality Our Research & 96 Sustainability reporting strategy Development 90 Responsibilities
Our People
Our Responsibilities
5 >900 Highly qualified professionals 12 Compounds in the pipeline, with six in late-stage development
Strong balance sheet >550 State-of-the-art laboratory workspaces
6 More science – Bursting with ideas
Idorsia is a high-potential biopharmaceutical Idorsia’s key numbers (non-GAAP* results) company, with an experienced team of over in CHF millions, except EPS (CHF) and 2020 2019 900 highly qualified professionals, a full R&D number of shares (millions) pipeline, state-of-the-art facilities, and a Revenues 72 24 strong balance sheet – the ideal constellation Operating expenses (444) (470) Operating income (loss) (372) (446) for bringing successful medicines to the Net income (loss) (392) (448) market. Basic EPS (2.75) (3.41) Basic weighted average number of shares 142.8 131.2 We began our operations after demerging from Actelion Diluted EPS (2.75) (3.41) following its acquisition by Johnson & Johnson in 2017. At that Diluted weighted average number of shares 142.8 131.2 time, approximately 650 talented and engaged employees were transferred to Idorsia, together with the discovery pipeline and * Idorsia measures, reports and issues guidance on non-GAAP operating performance. Idorsia believes that these non-GAAP financial measurements more accurately reflect early-stage clinical assets. the underlying business performance and therefore provide useful supplementary information for investors. These non-GAAP measures are reported in addition to, not Contents Idorsia is specialized in the discovery and development of small as a substitute for, US GAAP financial performance. The full financial statements can navigation be found in the 2020 Financial Report. molecules, with the aim of transforming the horizon of therapeutic Contents options. We have a broad, diversified and balanced development pipeline, covering multiple therapeutic areas. Our clinical pipeline “2020 was an outstanding year for Idorsia. We will invest during > Idorsia – Reaching out comprises 12 assets, 6 of which are in late-stage development. While 2021 to ensure commercial success of daridorexant in the US and for more we do not yet have any marketed products, we expect to see two clazosentan in Japan, both anticipated to launch in 2022, following product launches in major markets in the first half of 2022, subject market authorization. As a result, our spend will increase in 2021, Our Research & to regulatory approval. With this in mind, we have built a commercial with US GAAP operating expenses of around CHF 685 million and Development organization to bring our products to patients. non-GAAP operating expenses of around CHF 640 million, both Our measures include an inventory build of around CHF 35 million and People Idorsia is headed by Chief Executive Officer Jean-Paul Clozel; he and exclude unforeseen events.” Chief Scientific Officer Martine Clozel (who co-founded Actelion) Our André Muller Responsibilities now hold almost 30 % of Idorsia’s shares. Executive Vice President, Chief Financial Officer
7 Milestones in 2020
Idorsia started the year with 12 compounds in development – 4 in the final stage before filing for May 2020 Successful offering of marketing authorization. 2020 has been an incredible 11 million new shares year for Idorsia – positive Phase 3 results, preparation secured CHF 330 million of funding to prepare for the of our first new drug application, and market launch of daridorexant and preparation for our first products. to develop our diversified pipeline 2020
March 2020 April 2020 May 2020 July 2020 Janssen submitted a new Positive results in the Neurocrine Biosciences Positive results of the drug application to the first Phase 3 study entered into a license second Phase 3 study US FDA and a marketing of daridorexant, agreement for the with daridorexant in authorization application to demonstrating improved development and insomnia, confirming and the EMA for ponesimod for overall sleep and daytime commercialization of reinforcing the efficacy the treatment of adults with functioning of patients Idorsia’s novel T-type and safety profile from relapsing multiple sclerosis* with insomnia calcium channel blocker the first pivotal study
* Idorsia and Janssen have a revenue-sharing agreement in respect of ponesimod
8 August 2020 Daridorexant Phase 3 October 2020 July 2020 results in insomnia Successful capital increase January 2021 US commercial operations presented at SLEEP 2020 – secured CHF 535 million New drug application established, with the world’s largest meeting of funding to prepare for for daridorexant leadership team in place devoted entirely to clinical the launch of daridorexant submitted to the US to prepare for the launch sleep medicine, and sleep and to develop our FDA for the treatment of daridorexant and circadian research diversified pipeline of insomnia
August 2020 September 2020 November 2020 Idorsia Japan confirmed Syneos Health selected as Positive results in the daridorexant dose commercialization partner Japanese registration response in Japanese to build the salesforce for program for clazosentan, Contents patients with insomnia – the launch of daridorexant demonstrating a reduction navigation preparations for a local in the US in vasospasm-related Contents registration program morbidity and all-cause underway mortality > Idorsia – Reaching out for more
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9 The purpose of Idorsia is to discover, develop and commercialize innovative medicines to help more patients.
Mathieu Simon Despite the devastation all around us, I am Chairman of the Board very proud and excited to report that Idorsia has not only weathered the storm this year, but gone from strength to strength.
Thanks to the investments made during Idorsia’s first few years, our technology platforms are state-of-the-art and scalable. As a result, when the call went out for office-based staff to work from home Dear Shareholders and for those who need to work on-site It is my great honor to write to you as to be protected, our workforce was able Chairman of your company for the first to transition seamlessly. Our laboratory- time. I am only sorry that we have not yet based staff willingly turned up every day, had the opportunity to interact personally. motivated to move the company forward. Our virtual Annual General Meeting was just one of the many disruptions caused by The resilience and determination of our the COVID-19 pandemic – a crisis which has workforce contributed to an incredibly impacted every area of our lives in 2020, successful year: the company has delivered bringing misery and hardship to countless on every one of the ambitious goals set by millions. In our industry, COVID-19 has the management and Board at the end of upended supply chains and clinical trial 2019. Jean-Paul Clozel’s update on these timelines, threatening longer waiting times achievements (see the CEO’s letter) makes for much-needed treatments. for very enjoyable reading. As you reflect
10 “Our workforce’s resilience and determination contributed to an incredibly successful year.”
Mathieu Simon Chairman of the Board
on these successes, please bear in mind that science and quality, together with a strong Of course, if Idorsia is to become it is very unusual for a clinical pipeline to governance framework, means that the sustainable, we now need to bring our advance so positively. For a young company company has sound foundations on which to products to market and start generating to have so many innovative compounds – at build its success. revenue. The capital market funding we a late stage of development, and in a wide were able to access this year will take us a variety of therapeutic areas – progressing as As a Board, we are committed to long way towards this goal. Thank you for planned is, in itself, an impressive feat. For transparency on the topics that are your confidence in Idorsia – and stay tuned two of those compounds to achieve positive important to you. This year, we initiated for the continued success of this dynamic results and move towards regulatory a dialogue to identify and prioritize what company on the verge of great things! submissions, in parallel, is outstanding. matters most to you, and these lines of Accordingly, as you will see, the Board communication will remain open. I look Sincerely, Contents has recognized this performance through forward to developing our reporting on navigation Idorsia’s employee reward system. these important non-financial measures, in Contents line with the company’s development. As Chairman, I am well aware that positive > Idorsia – Reaching out results alone are not enough to ensure One result of the company’s willingness for more sustainable success. With several newcomers to engage is the growth of our analyst to the Board, we have undertaken a critical base during 2020: 14 analysts are now Mathieu Simon Our Research & review of the company to make sure that covering Idorsia, reflecting the great Chairman of the Board Development all the appropriate checks and balances interest in Idorsia’s equity story. I personally Our are in place. For me, this is another of the believe that independent stock research People beauties of Idorsia: while the company is is important in guiding investors and Our only a few years old, it has a rich heritage highlighting opportunities for long-term Responsibilities of over 20 years in pharma. A solid focus on value creation.
11 Developing Idorsia into a leading biopharmaceutical company, with a strong scientific core.
Jean-Paul Clozel Dear Shareholders This year, the public has gained a new Chief Executive Officer I want to begin by recognizing that, while appreciation of the efforts of all frontline Idorsia has had a very successful year, 2020 healthcare workers, and also of the mission was extremely difficult for many people. No that drives everyone in the pharma world – doubt some of you will have been seriously finding medicines to prevent or treat illness. affected by the COVID-19 pandemic, and to Let us hope that the vaccines developed in you I extend my sincere sympathy. record time can help the world return to some semblance of normality. I myself am very proud to be a member of this industry, and to see how our efforts in research are helping patients.
In spite of the pandemic, the company has made great strides this year. Our employees achieved every one of the ambitious key goals set for 2020 – and much else besides. Their performance was simply phenomenal. In the development of new medicines, hard work does not always guarantee good results, which makes it all the more rewarding when our efforts are crowned with success.
12 “I am very proud of all that has been accomplished at Idorsia in 2020.”
Jean-Paul Clozel Chief Executive Officer
Revolutionizing the field of insomnia For the millions of people suffering from Perseverance finally paying off Our review of the progress made in 2020 insomnia, daridorexant is an absolute Our efforts to design the perfect DORA must start with the outstanding results gamechanger, whose excellent benefit and began in our labs as long ago as 1998, achieved with daridorexant. The Phase 3 safety profile will encourage patients to seek but our work with clazosentan goes back registration program demonstrated treatment. even further. This year, the Japanese statistically significant and clinically studies of clazosentan for patients meaningful improvements in sleep It is important to recognize that these suffering cerebral vasospasm following maintenance, sleep onset, total sleep gratifying results were no accident. They aneurysmal subarachnoid hemorrhage also time and daytime functioning, which were are a direct result of our efforts to design a demonstrated excellent efficacy results, sustained over time. Daridorexant was well dual orexin receptor antagonist (DORA) with without any unexpected safety findings (for tolerated, with a favorable safety profile in the properties required to deliver all the more information on clazosentan, see pages Contents adult and elderly patients. benefits of a good night’s sleep. For more 52 to 57). I am truly delighted to finally have navigation details, I invite you to read the interview the evidence that clazosentan can improve Contents Particularly important, as well as efficacy with Martine Clozel on page 30. outcomes for these patients – often young during the night, are the effects seen adults with so much life left to live. These > Idorsia – Reaching out during the day. While a negative impact on The team responsible worked tirelessly results give the commercial team even more for more daytime functioning is part of the definition to evaluate the huge amount of data to get their teeth into. The impressive data of insomnia, not one of the treatments generated and to present the results has renewed the enthusiasm of the whole Our Research & currently available have rigorously assessed appropriately for regulatory agencies. A REACT team to complete the global study Development their effect on this key aspect of the new drug application was submitted to the of clazosentan as soon as possible, so that Our condition. Here, in fact, most therapies FDA in January 2021, and the submission to patients around the world can benefit. People have a negative impact – especially first the European authorities will follow shortly. Our thing in the morning, when patients may In anticipation of regulatory approval, the Responsibilities feel hangover effects of their medication. commercial team is now working flat out to prepare for the launch. 13 More to come from the pipeline As well as the conclusion of studies, 2021 Taking our innovation to the patient Thanks to the development group’s speedy will also see the initiation of a very exciting Work on building our commercial capabilities response to the COVID-19 pandemic, our study. Under a Special Protocol Assessment began in 2019, and we continued to fill key ongoing late-stage studies were able to (SPA) agreed with the FDA in 2020, a 14,000 strategic roles on the global team in 2020. continue, and risk mitigation procedures patient Phase 3 study will be commenced We also established our US commercial were agreed with global health authorities. with selatogrel – a drug-device product organization, securing premises and – most for patients with suspected heart attack. importantly – a leadership team. This is a Recruitment for both the CARE study The investigation of selatogrel has been very exciting development for Idorsia, and I (cenerimod) and the MODIFY study designated as a “fast-track” development am proud to have such an experienced and (lucerastat) was affected, but following program, indicating the FDA’s interest in this talented group of professionals on board. some adjustments, in consultation with innovative approach. Patients themselves health authorities, patient enrollment was will play a crucial role in the preparations Following the positive results achieved with adapted. Accordingly, we should see the for this study, as they need to be trained daridorexant, a tremendous amount of results of CARE and be able to plan for to identify symptoms and self-administer work has been done to prepare for the US Phase 3 development of cenerimod by the treatment. The potential implications for launch of this product in 2022 – not least, end of 2021, and the results of MODIFY – future heart attack patients are enormous, engaging Syneos Health as the ideal partner the Phase 3 registration study for lucerastat and I look forward to sharing more details in to reach the large US primary care market. – should also be available in the second half due course. In addition, after the excellent results with of 2021. clazosentan, the Japanese team is also gearing up for our first product launch in In addition, again despite the impact of the Japan. pandemic, recruitment for the PRECISION (aprocitentan) study accelerated, with randomization now expected to be completed by mid-2021.
Major shareholders (as of December 31, 2020) Key share data (as of December 31, 2020)
Jean-Paul and Martine Clozel 29.15 % Shares outstanding 166.5 million Rudolf Maag 5.40% Closing share price CHF 25.52 FMR LLC 3.51 % Market capitalization CHF 4.2 billion Artisan Partners 3 .07% 52-week high CHF 33.88 52-week low CHF 18.69 YTD price change CHF -4.42 (-14.76 %) Idorsia Ltd is part of the following indices: SPI, SPIEX, SXSLI, SXI Life Sciences, SXI Bio+Medtech, and SSIRT. Annual average daily 603,126 shares volume Idorsia is traded under the following symbols: Free float 109.0 million shares Reuters IDIA.S / Bloomberg IDIA:SW
14 With two product launches in preparation, pharmacology studies. On the preclinical I am very proud of all that has been we have also been building our global supply front, four compounds were selected as accomplished at Idorsia in 2020. 2021 will be chain function, to ensure consistent supplies preclinical candidates. These advances in our an extremely exciting year for our growing of our innovative medicines to patients. discovery efforts made during lockdown are company, and I look forward to keeping you More information on our preparations a testament to our researchers’ commitment updated on our progress throughout the can be found in the interview with Chief and dedication. year. I would also like to thank you for your Commercial Officer Simon Jose on page 22. confidence in Idorsia. Financing our future Ongoing innovation Through a series of financing activities Warmest regards, We have always had a long-term focus in 2020, we have secured additional for Idorsia, setting ourselves the goal of funding of more than CHF 865 million. becoming a fully-fledged biopharmaceutical Our strengthened balance sheet with company, innovating from bench to CHF 1.2 billion liquidity will take us through bedside. As our late-stage pipeline starts to the next inflection points – namely, key to bear fruit, it is essential that we keep clinical data from late-stage assets and the the pipeline supplied with fresh innovation launch of our first product, daridorexant. Jean-Paul Clozel for sustainable success. As our Chairman As you may be aware, Martine and I have CEO emphasized, work in our laboratories participated in each of the capital increases, continued unabated in 2020, and there is believing more than ever in Idorsia and in much to show for it. Progress was made the value that can be created for patients, with our early-stage clinical pipeline, and we employees and shareholders alike. advanced a new CNS compound into clinical
Contents navigation Share price development (in CHF)
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> Idorsia – 34 Reaching out for more 29 24 Our Research & Development 19
Our 14 People Jan-20 Apr-20 Jul-20 Oct-20 Our Responsibilities
15 Our strategic priorities
We will develop Idorsia into one of Europe’s leading biopharmaceutical companies, with a strong scientific core. We have identified five key strategic priorities to ensure the company’s success in the medium term.
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16 More energy – Growing and delivering
Build a world-class 2 commercial organization
Bring Idorsia to 3 sustainable profitability Deliver at least three 1 products to market
Contents Fuel our pipeline navigation 4 with new discoveries Contents
> Idorsia – Reaching out for more
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Our Utilize state-of-the-art People 5 technologies to drive innovation Our Responsibilities
17 Deliver at least three products to market
We believe that our development compounds have 1 the potential to significantly change treatment in their target diseases, resulting in medicines with substantial commercial potential.
We have a diversified and balanced With our scientific, data-driven approach clinical development pipeline, covering helping to mitigate risk at each step, we multiple therapeutic areas, including CNS, aim to bring at least three products to cardiovascular and immunological disorders, the market in the medium term. Our late- as well as orphan diseases. stage pipeline is described in detail in the “Research & Development” section of this The pipeline comprises 12 compounds, report (from page 26). including 6 in late-stage development. The development of an innovative compound Contents into a future therapy is a complex navigation undertaking, which inevitably involves an Contents element of risk.
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18 Build a world-class commercial organization
In order to bring pioneering therapies to patients 2 and to maximize the value of our innovations, we plan to continue building and integrating our global commercial organization.
We will take a simple, efficient approach We have established commercial operations to preparing product launches, utilizing in the US and Japan, with experienced shared, best-in-class platforms and ways of leadership teams and strategic locations. working that enable fast decision-making We have also established a robust and lean and cost-effective growth. We will focus global supply chain function to ensure on transforming treatment in underserved consistent supplies of our innovative markets, such as insomnia, and building medicines to patients. new markets, such as cerebral vasospasm, using scientific and medical evidence to Contents engage effectively with experts in the field navigation and with payors. We plan to remain flexible Contents and nimble in the way we commercialize our portfolio, building the core capabilities > Idorsia – Reaching out required to successfully launch our products, for more while also being prepared to enter into partnerships where we need support to Our Research & reach a primary care market. Development
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19 Bring Idorsia to Fuel our pipeline sustainable profitability with new discoveries
We are building Idorsia with a While building up our 3 long-term focus and ambitious 4 commercial operations and aspirations. By advancing our developing our late-stage development pipeline and clinical pipeline so as to commercial readiness, we aim bring innovative therapies to to bring Idorsia to sustainable patients, we also continue to profitability as soon as possible. discover new compounds.
We believe that we have the potential to generate In addition to several drug candidates in significant revenues from product sales, once the first the early stages of clinical and preclinical of our development compounds has received regulatory development, we must continue with our approval. discovery efforts, to maintain a steady supply of innovative compounds to our Contents To maximize the medical value of our discoveries and pipeline. We aim to create a pipeline with a navigation to provide a source of liquidity in the short to medium sales potential of at least CHF 5 billion. Contents term, we have entered into several collaborative partnerships with pharmaceutical companies. These Achieving this is dependent on a company- > Idorsia – Reaching out include development, commercialization and revenue- wide effort, so we must attract, retain and for more sharing agreements, under which we are eligible to develop a talented and engaged workforce. receive milestone payments based on the progress of the We want our employees to feel proud of Our Research & development compound in question. their work, and of the company they work Development for. We provide a supportive and stimulating Our Furthermore, with several unencumbered assets in environment for high-performing People clinical development, additional contract revenue from teams, recognizing and rewarding their Our partnerships and/or out-licensing remains an option for us. contributions. Responsibilities
20 Utilize state-of-the-art technologies to drive innovation
As we wish to remain at the cutting edge of science, 5 it is vital that we consider innovative approaches and utilize state-of-the-art technologies at each stage of the process, from bench to bedside.
We integrate computational tools and digital technologies at various stages of the drug discovery, development and commercialization process, so as to maximize our potential and bring breakthrough medicines to patients.
We look for creative ways to harness advances in technology to focus on novel Contents targets and use new drug development navigation methods. All functions of the drug discovery, Contents clinical and pharmaceutical development processes are streamlined to assist in the > Idorsia – Reaching out delivery of tailored, high-quality medicines. for more
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21 Gearing up to launch
Simon Jose, Idorsia’s Chief Commercial Officer, leads our commercial operations From compounds to at the region and country levels as well as global product strategy, medical affairs and supply chain. Simon and his team bring deep commercialization experience in successfully launching new products across a wide range of therapeutic “We are confident that, with such a areas and geographies. wealth of evidence, we can make this unique, non-sedating sleep
Contents medication a huge success, and navigation we are excited by the opportunity Contents to lead the transformation and > Idorsia – Reaching out modernization of the sleep market.” for more Simon Jose Chief Commercial Officer Our Research & Development
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22 What are you doing now to As you build Idorsia’s commercial organization, prepare for a successful what are you most excited about? Q US launch of daridorexant?
I’m very excited about the unique opportunity we have at Idorsia to build a We’ve made enormous progress in A commercial organization from the ground up and bring to market multiple A building our US team in 2020. Under innovative products in areas ranging from insomnia to aSAH. Given the remarkable the leadership of Patty Torr, President breadth and depth of our late-stage pipeline, we have the potential to transform of Idorsia US, we have established our treatment in multiple disease areas and in doing so create a sustainable mid-sized US headquarters in Radnor, a suburb Q pharma company based on innovation. of Philadelphia, and brought on board a talented and experienced leadership We are now moving full speed ahead to prepare to launch two very different team that is already making strides in products in the first half of 2022 in two major markets – daridorexant in the US and preparing the US market for the launch of clazosentan in Japan. It’s this type of challenge we’re excited about, and we’ve made daridorexant. huge progress in 2020. As announced in August 2020, we have finalized an innovative, revenue-driven agreement with Syneos Health to launch As you focus on successful launches for these products, daridorexant in the US and reach the primary Q what are the must-win priorities for your team? care market that accounts for the majority of insomnia prescriptions. In addition, the team is preparing our plans to engage with There is no doubt that the launch We will continue to engage with the medical the medical community, payors and patients, A of daridorexant is the number one community and other key stakeholders who play a critical role in seeking solutions Contents focus for us – and will remain so over the to advance the science of sleep and raise for their insomnia. navigation next few years. Our ambition is to lead the awareness about the burden of insomnia Contents transformation and modernization of the on patients’ daily lives and the need for new The US team has also prioritized fulfilling sleep market, and leadership requires a safe and effective treatment options. governance requirements for US operations, > Idorsia – Reaching out long-term commitment. With over 20 years’ including staffing key enabling functions and for more experience researching sleep, and orexins I’m confident that we have the right forming a Compliance Committee to ensure in particular, we have built deep scientific ingredients to lead in sleep – a differentiated appropriate oversight of our medical and Our Research & expertise in sleep and insomnia, and have product profile, strong commitment from commercial activities. Development developed daridorexant, a product born our leadership, and deep scientific expertise. Our out of that science. (See the interview with For Idorsia, changing sleep will be at the People Martine Clozel on page 30.) heart of what we do for years to come. Our Responsibilities
23 Turning to the second launch you’re preparing for, how is a Swiss company – Q with a big US launch in the works – going to be successful in Japan?
While it’s true that these markets aSAH. The incidence of aSAH in Japan is “It is so fulfilling to work on A are very different, I believe we at least twice as high as in other countries a product which has the are well positioned for success. It starts around the world. This well-understood and with an innovative asset, clazosentan, and significant medical need, together with the potential to prevent the the impressive data from our Japanese excellent efficacy and safety data, gives us devastating outcomes faced registration program, announced in confidence that we can successfully launch November 2020. Next, we have the strong clazosentan in Japan. by patients with cerebral leadership of Satoshi Tanaka, President vasospasm.” of Idorsia Japan, and his established team It is so fulfilling to work on a product with deep expertise in aSAH and cerebral which has the potential to prevent the Simon Jose vasospasm. The team is already developing devastating outcomes faced by patients with Chief Commercial Officer a focused launch plan, establishing our local cerebral vasospasm. Clazosentan could be commercial infrastructure and engaging a gamechanger for aSAH patients and their with the neurosurgeons and other intensive treatment teams. & care specialists who treat patients with Q Do you have any plans for product launches in Europe?
Contents navigation Yes, absolutely! We have already appointed Jean-Yves Chatelan to head up Region Contents A Europe and Canada, and we plan for daridorexant to be Idorsia’s first European launch. As in the US market, Europe also has a high prevalence of insomnia and significant > Idorsia – Reaching out unmet need for new safe and effective treatments. As a result, we believe that there is for more an exciting opportunity for daridorexant in Europe. What’s more, we would be the first company to bring a dual orexin receptor antagonist (DORA) to insomnia patients in Europe. Our Research & Of course, there is a very different payor environment in Europe, and different approaches Development to insomnia treatment across countries, so we will need well-thought-out, country-specific Our strategies. This will be job number one for our new Head of Europe and Canada commercial People operations. Our Responsibilities
24 With experienced and empowered country-based teams, what role does the global Q commercial organization play?
As a lean and cost-conscious biopharma, we need to keep the right balance between global and A market-based resources. The way I see it, the global team leads the development of the overall product strategies, including the medical affairs, marketing, and market access components, by working with our scientists and clinical experts. Together with major markets, particularly the US, they shape the product strategy to align it with the deep scientific understanding we have built during the discovery and development phases.
The global product strategy then gives the countries a head start – which they can then adapt to meet the particular needs of their markets. For example, the global team provides patient insights, global branding, real-world evidence, common systems, and efficient and compliant decision-making processes. The countries are responsible for customer relationships and local execution of the strategy. With my team’s extensive experience in launching products at both the global and market levels, we know that this is the optimal set-up to help the countries move quickly without getting in their way. A Can you give us a preview of your plans for the commercial Q organization in 2021?
COVID-19 has highlighted the importance and challenges of ensuring product supply. How are you preparing Idorsia’s supply chain to support There is no question of our priorities Q the up-coming launches? A for 2021. We will be laser-focused on our two important launches expected Contents in the first half of 2022. Given the size and navigation One of our 2020 company goals was that include Sales & Operations Planning complexity of the US primary care market, Contents A to establish a robust global supply (S&OP), sourcing, logistics, procurement, preparing for a flawless daridorexant launch chain function and I'm pleased with the quality control and systems. Given the long will be our number one priority, followed > Idorsia – Reaching out progress we have made building this core lead times for drug substance production, closely by ramping up for the clazosentan for more capability. ramping up our supply chain for commercial launch in Japan. launch will require investments in 2021; Our Research & Our supply strategy relies on contract however, this is critical to ensure that we Not so long ago, Idorsia was founded with Development manufacturing organizations (CMOs) will be ready to meet the anticipated high the purpose of bringing more innovative Our to manufacture our products, while our demand for daridorexant and clazosentan at medicines to patients, and we are on the People internal team leads a range of activities the time of launch. cusp of doing just that. There is now so Our much to be optimistic about as we head into Responsibilities this final pre-launch phase!
25 Our Research & Development
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26 More knowledge – Powered by science
At Idorsia, our drug discovery focuses on families of proteins, which are characterized by the way they work.
We strive to identify innovative programs to perform hundreds of thousands of involving proteins which have not been measurements, it needs to be automated, targeted up to now, to discover drugs with using robotic equipment. novel mechanisms of action. But there are two sides to the discovery The drug discovery process starts with process – a target and a compound. an idea from our scientists. We scour the literature to see what others have not yet Compounds are substances which, we hope, discovered, to generate ideas and then will modify the activity of a target involved translate them into a concept which can lead in a pathological process and can then be “We need creativity to be to new treatments for patients. developed into a drug for patients. Contents navigation innovative, so we need a Our work in the lab begins with the target. At Idorsia, we maintain a library consisting Contents brilliant idea and a deep This may be a particular protein which, when of hundreds of thousands of different its activity is modulated, can normalize compounds. To begin our hunt for drugs, Idorsia – understanding of the Reaching out a biological process in the body – with we test the entire library of compounds on for more disease, to translate it into a beneficial effect for patients. To see the target, in the hope that one of them whether we can affect the protein’s activity, will modify the activity of the protein. This > Our Research & a molecular mechanism, we first need to be able to measure it. process is called high-throughput screening; Development and to try to find a drug to if it’s a simple assay, we can test the whole Our We produce, or “express”, the target in large library within a matter of weeks. At this People treat that disease.” quantities and measure its natural activity stage, the goal is to identify compounds Our John Gatfield in assays. The assay needs to be sensitive, which exhibit some activity. Responsibilities Associate Director, Principal Scientist accurate and highly reliable. Plus, in order
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28 The project team then analyzes these For example, our electrophysiologists specialists take a compound which has been compounds to decide which of them is screen drugs for side effects by monitoring optimized by the chemists and ask how it the most promising starting point for electrical activity in the heart or brain. Here, can best be delivered to the patient. One optimization using the art of medicinal electrical communication depends on ion way to protect the compound, for example, chemistry. channels in the cell membrane; if a drug is to package it in a capsule; alternatively, it blocks some of these ion channels, it can may be better to develop an injectable form. Obviously, huge amounts of data are have serious adverse effects. generated, and powerful IT tools are Once reproducible processes to produce required to extract the knowledge we need. Small-scale testing for initial assays requires large quantities of the active compound and To really understand the data, we visualize it only milligram quantities; for subsequent the formulated drug product are elaborated, and study the relationship between chemical testing, however, much more material is our technical project teams manage the structures and biological properties. needed. This is where our process research production of the drug with partner teams come into the picture. They are companies. They secure the drug supply for Target and compound fit together like a lock responsible for scaling up from milligram to clinical development and beyond. and a key. The compound can be modified so gram quantities, and finally to the kilogram that it fits better and, ideally, becomes more batch which is used for preclinical testing. For Idorsia, the process which begins with potent. drug discovery and preclinical development It’s no good having a potent compound ends, we hope, with a novel molecule that Medicinal chemistry involves the use of which gets destroyed by the body before it will help patients in diseases with a high chemistry’s tools to design molecules has a chance to do its job. Our formulation unmet medical need. that are potential drugs. We manipulate the molecular structure and then send the compounds back to our biologists or “For me, invention is making something out pharmacologists for testing in an iterative of a daring idea. And I really have the feeling process. With each cycle, the compound is Contents further optimized to finally become a drug. that’s what we are trying to do at Idorsia.” navigation Corinna Grisostomi Contents At first, we seek to enhance the potency Senior Scientist of the compound’s effects on the target Idorsia – Reaching out protein, but as we advance we look at other for more activities which may cause side effects. The aim is to ensure that the compound’s overall > Our Research & properties allow it to become a drug. Development
Our People
Our Responsibilities
29 Better night, better day –
As Idorsia’s Chief Scientific Officer, Martine by design! Clozel has been a driving force behind the discovery and development of daridorexant, our investigational therapy for the treatment of insomnia (for more details, see page 38). But the story of daridorexant began more than 20 years ago – well before the foundation of Idorsia. Martine and a dedicated research group embarked upon the study of orexins almost as soon as Martine Clozel Executive Vice President, orexin was first identified, and that rapidly Contents Chief Scientific Officer led to the science of sleep. This interview navigation reveals how our research and the acquired Contents knowledge of the orexin system enabled Idorsia to find a treatment which, we Idorsia – Reaching out believe, will transform the lives of patients for more suffering from insomnia.
> Our Research & Development
Our People
Our Responsibilities
30 Researchers at Idorsia have a strong track record in rare diseases. Q What was the trigger for your work on insomnia?
The truth is that, at first, we didn’t The receptors for orexins are so-called A know we were studying sleep! We G-protein coupled receptors, a preferred followed where the science led us, which has family of targets for our drug discovery always been our approach to drug discovery. efforts. We had all the technologies we Judging by the results achieved needed to initiate a drug discovery program Q with daridorexant, you obviously Our journey began when I invited Masashi focused on orexin receptors, so we hit the did not give up. What drove you Yanagisawa – the researcher who first ground running. to keep going when other, much discovered endothelin and a “friendly bigger players had joined the race? competitor” in the field of endothelin As soon as we were able to generate research – to the labs we were just building antagonists as tools to block the orexin at Actelion. He told me about a paper he receptors, we discovered that in rats, You must remember that, until this was about to publish in the journal Cell 1, dual orexin receptor antagonists (DORAs) A new class of insomnia medicines was reporting the discovery of a new family of induced sleep. That changed everything. We discovered, no significant progress had been neuropeptides that he was calling orexins. were now in the field of sleep and insomnia. made in the treatment of insomnia for many I was fascinated! years, and patients have suffered from the side effects of the older classes of insomnia How did that work lead you to daridorexant? drugs.
Our initial experience and the evidence of The team’s early work led us to an important conclusion, which remains valid efficacy that we had generated convinced A today, more than 20 years later: the orexin system plays a fundamental role in us that DORA offered an amazing potential Contents arousal and wakefulness and its blockade by a DORA offers the best hope of inducing in insomnia and that we needed to pursue navigation a natural sleep for patients with insomnia. our research and discover a next-generation Contents DORA. The drug discovery group set about characterizing the effects of DORAs on sleep Idorsia – Reaching out and selected a compound for clinical development, which would later be known as for more almorexant. In 2007, we published a paper in Nature Medicine 2, which presented the results of this groundbreaking research – “Promotion of sleep by targeting the orexin > Our Research & system in rats, dogs and humans”. Development
Our Although almorexant trials were stopped because of a particular drug-drug People interaction which could not be overcome, it was the first DORA to be studied in Our humans, and we gained a deep understanding of the orexin system and the science 1. Cell. 1998, 92(4):573–85 Responsibilities of sleep as a result. 2. Nat Med. 2007, 13(2):150–5 31 & What criteria were defined to Q determine the optimal candidate? Q How did you design daridorexant to be a better insomnia treatment?
We needed a compound that would It has not been easy! We synthesized and tested more than 25,000 compounds in A be potent and specific for the two A pursuit of the ideal drug. We narrowed down the candidates through a variety of orexin receptors, both to avoid off-target screening and optimization techniques, filtering out any compounds that did not meet our activity and to support the safety profile high expectations. In particular, we developed a computer model using animal and human required for a compound which could data, including the data for almorexant, to predict the human pharmacokinetic behavior be used by many patients. We wanted that we could expect from our candidates. a molecule which would have a rapid absorption, to help the patient get to We began the development of daridorexant in 2015 and the results have surpassed even sleep quickly, and a duration of action long our high expectations! Daridorexant has demonstrated an improvement in objective and enough to cover a full night’s sleep, but subjective sleep measures – almost one hour more sleep, as reported by the patients! – most importantly short enough to avoid without causing next-morning residual effect, and for the first time daytime functioning is negative hangover effects the next morning. improved. Plus, all this is achieved with an excellent tolerability and safety profile.
The insomnia market is a tough one to crack. Q Why are you so confident that daridorexant will be a game-changer in insomnia?
As a research scientist medical need for patients suffering With Simon Jose and his growing A and physician, I believe in from insomnia. team of experts, we are handing evidence-based medicine, and I our baby into safe hands. Science is look at what the data tell us. The When we were designing also at the core of our commercial results we’ve seen have rewarded daridorexant, we made assumptions team’s work, making them the ideal the drug discovery group for the in the lab about what kind of therapy steward for the next phase of this many additional years of work would have meaningful effects for exciting journey. They will help both A they have put in. Our clinical group patients. What’s so rewarding is that physicians and people suffering designed a development program our patients have now confirmed, from insomnia to understand the which placed the needs of patients not only that daridorexant is benefits that daridorexant brings at the center of the investigation. delivering on the characteristics we – better sleep and better daytime The team developed and validated designed into the drug, but that functioning. tools to establish patient-reported those were the qualities which really outcomes, particularly for daytime mattered to them. functioning, which is a serious
32 Daridorexant optimization process
>25,000 compounds synthesized in the orexin program in 7 years
1 Targets Hits Improved Leads Drug Candidate
300,000 – 400,000 Daridorexant compounds Optimized duration of action (rapid onset, no next-day hangover) Human pharmacokinetic 1361 263 83 12 and pharmacodynamic prediction
Contents navigation
Contents
Idorsia – Reaching out Potent dual OX1 and OX2 Optimal in vivo for more receptor blockade in vitro efficacy
> Our Research & High affinity in receptor No major drug-drug High brain In vivo efficacy tested Development binding and functional assays interaction penetration in rats and dogs In vitro cytochrome Physicochemical properties Our P450 profile and confirmation in vivo People
Our Responsibilities
33 More molecules – For a better future
Following the drug discovery phase, the selected molecule must be comprehensively studied to demonstrate clinical safety and efficacy.
Idorsia aims to deliver new products with the potential to significantly change the treatment options in their target diseases. We want to bring new perspectives to the development of innovative compounds, challenging accepted paradigms to answer the questions that matter most. Our key assets have the potential to transform treatment in the target indications.
“We tailor the target indication to
Contents characteristics of the compound. We navigation always try to find the disease, spectrum Contents of diseases or subset of medical Idorsia – Reaching out conditions where the molecule will for more fit best from an efficacy and safety > Our Research & Development perspective, and where it addresses a medically important need.” Our People Guy Braunstein Executive Vice President, Head of Global Clinical Development Our Responsibilities
34 Regulatory submission
Years 10 to 12 Before a drug can be placed on the market, it must first be approved by local regulatory authorities. A comprehensive dossier is submitted for approval.
Clinical studies
Years 5 to 10 Phase 1 assessment Phase 2 assessment of Phase 3 assessment of Efficacy and safety of tolerability or the safety and efficacy of the safety and efficacy of future drugs side effects in a the compound in a limited of a future medicine, are assessed in small group of number of patients, with the most often compared humans. healthy volunteers. aim of finding the optimal to placebo, in a large dose for large-scale studies. group of patients. Preclinical studies Pharmaceutical development
Years 0 to 5 In parallel research-grade molecules are transformed The effects and toxicity of drugs are through chemical and pharmaceutical development assessed in silico (with computer into pharmaceutical-grade drugs, compliant with health programs), in vitro (in cell cultures), authority guidelines, for administration to patients. and in vivo (in animals).
Patenting the molecule
Year 0 Patents are filed for the most promising compounds. This protection provides 20 years of exclusive commercial use – the clock starts!
Drug discovery phase
Years -5 to 0 A discovery program aims at discovering molecules which need to be progressively optimized for activity against a biological target and for desired physicochemical, pharmacokinetic and other properties. Their pharmacological activity and their safety need to confirm their potential in pathological situations.
The timeline can be influenced by many factors, such as the indication for which a drug is being studied.
35 More in the pipeline – Promising compounds
We have a diversified and balanced clinical development pipeline covering multiple therapeutic areas, including CNS, cardiovascular and immunological disorders, as well as orphan diseases.
“The way we work in research is focused on and built around innovation and core competencies. This has led to a diverse pipeline, addressing different diseases where Contents either no treatment is available or certain navigation patients are resistant to treatment.” Contents Martine Clozel Idorsia – Executive Vice President, Chief Scientific Officer Reaching out for more
> Our Research & Development
Our People
Our Responsibilities
36 Insomnia
Clinical development pipeline Resistant Daridorexant hypertension Dual orexin receptor antagonist management Status: NDA submitted, MAA in Suspected acute preparation myocardial Aprocitentan* infarction Fabry disease Dual endothelin Vasospasm associated receptor with aneurysmal Selatogrel Lucerastat antagonist subarachnoid hemorrhage Status: Phase 3 P2Y12 receptor Glucosylceramide antagonist synthase inhibitor Clazosentan Status: Phase 3 Status: Phase 3 Selective endothelin (ETA) in preparation receptor antagonist Status Global: Phase 3 Status Japan: Filing in preparation
Systemic lupus erythematosus
Cenerimod
S1P1 receptor modulator Status: Phase 2b Binge eating disorder Immunology Rare lysosomal ACT-539313 storage disorders ACT-1004-1239 Selective orexin 1 CXCR7 antagonist receptor antagonist Sinbaglustat Status: Phase 1 Status: Phase 2 GBA2/GCS inhibitor Status: Phase 1 complete Immunology
ACT-1014-6470 Status: Phase 1 Rare pediatric epilepsy CNS
ACT-709478 ACT-541478 Novel T-type calcium channel blocker Immunology Status: Phase 1 Status: Phase 2 ACT-777991 Neurocrine Biosciences has a global license to develop Status: Phase 1 37 and commercialize Idorsia's ACT-709478 * In collaboration with Janssen Biotech, Inc. Status: January 2021 Daridorexant for insomnia
Insomnia is a condition of overactive wake signaling which can have functioning. Idorsia’s research has shown that poor-quality sleep can a profound effect on the lives of patients. Insomnia can be defined affect many aspects of daily life, including the ability to concentrate, as difficulty falling asleep and/or staying asleep, occurring at least mood, and energy levels. three times a week for a minimum of three months. Insomnia is a common problem. The prevalence of insomnia disorder Insomnia as a disorder is quite different from a brief period of poor is approximately 10 %. On this basis, and assuming a US adult sleep, and it can take its toll on both physical and mental health. population of around 250 million, there are approximately 25 million It is a persistent condition with a negative impact on daytime adults in the US who suffer from insomnia.
Contents Cycle of sleep Sleep stages REM = Rapid Eye Movement, NREM = Non-REM navigation Fall asleep One Sleep Cycle Notice how the REM stage grows longer with each sleep cycle Wake Contents
Idorsia – REM REM REM REM REM Reaching out for more Stage 1 (Lightest sleep) NREM NREM > Our Research & Stage 2 Development NREM
Our Stage 3 People (Deepest sleep) NREM NREM
Our Responsibilities 0 1 2 3 4 5 6 7 8 Hours
38 Sleep architecture Sleep is vital for repairing and restoring our Sleep is composed of two different types: body and brain. The pattern or structure non-rapid eye movement (NREM) and rapid of sleep is known as “sleep architecture”. eye movement (REM). Sleep is divided into cycles, lasting around 90 minutes each. On average, we go through four cycles a night.
Insomnia is a common problem. The prevalence of insomnia disorder is approximately
Studies have shown that lack Each night, we wake several of slow wave (stage 3) sleep is times for 1–2 minutes, associated with cognitive and although we do not usually 10 % other health-related issues. remember this.
The pattern of sleep changes as the night progresses. Most deep sleep occurs in the first half of the night, while REM sleep tends to occur mostly in the second half of the night.
“It really annoys me when people say ‘if you were really tired, you would sleep’. If only it were that simple! Unless you have suffered from true NREM is divided into insomnia, you have absolutely no idea three further stages what it’s like.” (1–3).
Patient with insomnia
39 The treatment landscape receptor antagonists were suvorexant and The orexin system The goal of treatments for insomnia is to lemborexant which are available in North Wake and sleep signaling is regulated by improve sleep quality and quantity, as well America and certain Asia Pacific markets. The intricate neural circuitry in the brain. One as daytime functioning, while avoiding most widely used off-label treatment for key component of this process is the orexin adverse events and next-morning residual insomnia in the US is trazodone, a selective system, which helps promote wakefulness. effects. Current recommended treatment serotonin reuptake inhibitor (SSRI) which has of insomnia includes sleep hygiene an off-target sedation effect. There are two forms of orexin neuro- recommendations, cognitive behavioral peptides – small protein-like molecules used therapy and pharmacotherapy. Overall, current agents are perceived to by nerve cells (neurons) to communicate be either somewhat effective on certain with each other in the brain – orexin A and With regard to prescription medications, parameters, but with safety concerns orexin B. Orexin promotes wakefulness patients are treated with products indicated (e.g. next-morning hangover effects, through its receptors OX1R and OX2R. for insomnia as well as off-label treatments. anterograde amnesia, and risk of tolerance Together, these neuropeptides and The on-label treatment category primarily and dependence), or safe but with limited receptors make up the orexin system. The comprises drugs that induce sleep by efficacy in insomnia. In addition, most orexin system stimulates targeted neurons Contents enhancing GABA, the primary inhibitory patients suffer from sleep-onset and in the wake system – leading to the release navigation neurotransmitter in the brain, which works maintenance problems, and existing sleep of several chemicals (dopamine, serotonin, Contents by slowing brain activity in a non-targeted agents do not adequately treat both of histamine, acetylcholine, norepinephrine) manner. There are two main categories of these problems. Furthermore, while a which promote wakefulness. Under normal Idorsia – Reaching out GABA agonists – benzodiazepines, such negative impact on daytime functioning circumstances, orexin levels rise throughout for more as temazepam, and non-benzodiazepines, is part of the definition of insomnia, none the day as wakefulness is promoted and such as zolpidem, zaleplon and eszopiclone. of the treatments currently available have then fall at night. Overactivity of the wake > Our Research & In addition, other approved insomnia rigorously assessed their effect on this key system is an important driver of insomnia. Development medications include the melatonin receptor aspect of the condition. Our agonist ramelteon and the low-dose People tricyclic antidepressant doxepin. The first Our products in the new class of dual orexin Responsibilities
40 The orexin system is crucial for the regulation of wakefulness Orexin stimulates many wake-promoting pathways
Dual orexin receptor antagonists (DORAs) offer an entirely different approach to treating insomnia than previous drug classes: by blocking the activity of orexin, they turn down overactive wakefulness, in contrast to insomnia treatments which act via general CNS sedation. DORAs specifically target the Orexin orexin system by competitively binding with both receptors, thereby reversibly blocking the activity of orexin. Blocking orexin receptors reduces the downstream activity of the wake-promoting neurotransmitters that are overactive in insomnia. As a result, orexin receptor antagonism targets the fundamental mechanism of insomnia. Contents navigation Histamine Contents
Idorsia – Serotonin Reaching out for more Norepinephrine > Our Research & Development
Our Dopamine People
Our Acetylcholine Responsibilities
41 Idorsia’s innovation Idorsia’s research team has been working on Daridorexant is a DORA designed and the science of orexin and orexin receptors developed for the treatment of insomnia. since they were first described in 1998. The The Phase 3 registration program team’s initial work led to the conclusion that demonstrated the efficacy of daridorexant antagonism of the orexin system was the key on objective and subjective sleep to preserving a natural sleep architecture parameters, and showed positive effects on for patients with insomnia. With this as the daytime functioning, with patients reporting target, the team designed a dual antagonist no next-morning sleepiness compared to with a rapid onset of effect and a duration of placebo, no signals suggestive of rebound action sufficient to cover the night but short insomnia compared to baseline sleep enough to avoid any negative next-morning parameters, and no withdrawal symptoms residual activity at optimally effective doses. upon discontinuation of treatment.
Contents navigation
Contents
Idorsia – Reaching out Daridorexant for more
> Our Research & Development
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42 Daridorexant has been shown to be quickly absorbed, with a half- The placebo-controlled studies investigated the effects of three life short enough to avoid next-morning carry-over effects and no doses of daridorexant (10 mg, 25 mg, and 50 mg) on sleep and accumulation over time, as demonstrated by the chart below. daytime functioning parameters, objectively in a sleep lab by polysomnography and subjectively with a daily patient diary at home. The impact of insomnia on patients’ daytime functioning was Pharmacokinetic profile showing fast absorption and optimal measured daily using the sleepiness domain score from the Insomnia half-life (8 h) Daytime Symptoms and Impacts Questionnaire (IDSIQ) – a patient- reported outcome (PRO) instrument validated according to FDA
industry guidance.
More than 800 patients continued treatment in the ongoing 40‑week extension study, which will measure the effects of all mg mg three doses vs placebo, generating data for long-term treatment of insomnia. The Phase 3 registration program demonstrated statistically significant and clinically meaningful improvements in sleep and daytime functioning which were sustained over time. The results showed efficacy during the night and the day, in respect of sleep aridore ant plasma concentration ng m
maintenance, sleep onset, total sleep time and daytime functioning. 1 The nighttime symptoms were improved while preserving the ime hours proportions of sleep stages. The Phase 3 program provided a 25mg and 50mg daridorexant mean PK profiles, single dose, young adults deep understanding of the efficacy and tolerability profile of Mean pharmacokinetic n per group profiles for 25 mg and 50 mg daridorexant, single dose, young adults (n=6 per group) daridorexant. aridore ant C -541468) is investigational, in development and not approved or mar eted in any country Contents navigation The Phase 3 registration program comprised two three-month Contents studies, together with a long-term double-blind extension study. Both pivotal studies are complete, having enrolled around 1,850 Idorsia – Reaching out patients with insomnia at over 160 sites across 18 countries. As for more insomnia often presents later in life, and elderly patients are more susceptible to fragmented sleep, early awakening and daytime > Our Research & sleepiness, around 40 % of the recruited population was aged Development 65 years or older. Our People
Our Responsibilities
43 Summary of the results from the pivotal Phase 3 program
1st pivotal study 2nd pivotal study
Daridorexant 50 mg Daridorexant 25 mg Daridorexant 25 mg Daridorexant 10 mg
1 month 3 months 1 month 3 months 1 month 3 months 1 month 3 months
WASO √ √ √ √ √ √ NS* NS* Primary endpoints LPS √ √ √ √ NS* NS* NS* NS*
sTST √ √ √ √ √ √ NS* NS* Secondary endpoints IDSIQ √ √ NS* NS* NS* NS* NS* NS*
* Not significant – numerical trend WASO: wake after sleep onset; LPS: latency to persistent sleep; sTST: subjective total sleep time; IDSIQ: insomnia daytime symptoms and impacts questionnaire
The highest (50 mg) dose was the most daytime functioning across all IDSIQ at 50 mg. The incidence of somnolence was effective, followed by 25 mg, while the domains. Patients on daridorexant felt more low and did not increase with daridorexant Contents 10 mg dose had only a marginal effect. energetic and less sleepy, and reported 50 mg compared to placebo. The incidence navigation better alertness, cognition and mood. of adverse events of special interest, Contents A key consideration in the treatment considering the potential association of of insomnia is the reversal of daytime Daridorexant was well tolerated and had a orexin deficiency with narcolepsy, was low, Idorsia – Reaching out functioning impairment associated with favorable safety profile in adult and elderly with isolated cases of sleep paralysis or for more sleep difficulties – altered mood, cognition, patients. Adverse reactions reported with a hallucinations in the daridorexant treatment and tiredness. To date, no insomnia frequency of ≥ 2% in daridorexant-treated groups. > Our Research & studies have reported on the effects of patients and greater (≥ 1%) than in placebo- Development pharmacological intervention on daytime treated patients in 3-month efficacy trials Our functioning using an adequately developed were headache, somnolence, fatigue, People and validated PRO instrument. At 50 mg, dizziness, and nausea. There was no excess Our daridorexant produced consistent and of morning sleepiness, as assessed by the Responsibilities meaningful improvements in scores for morning visual analogue scale (VAS), even
44 “I am optimistic that intelligent drug discovery together with our focus on endpoints that matter to patients – not only sleep at night, but also the ability to function during the day – will help us to meet the needs of those who suffer from insomnia.”
Eric Luthi Vice President, Global Marketing Lead Daridorexant Current status These results make daridorexant the first non-broadly sedative sleep medication to demonstrate an improvement in sleep and daytime functioning, as measured by a new, specifically developed and validated instrument, while keeping a favorable safety profile.
The new drug application (NDA) was submitted to the US FDA in January In addition, an interim analysis was 2021. Should market authorization be conducted on the ongoing 40-week received on schedule, this would allow for Contents extension study, once all patients had commercialization and launch in the US in navigation received six months of treatment altogether the first half of 2022. Contents (during the core and extension study). This study – primarily measuring the safety of Idorsia – Reaching out long-term treatment with daridorexant Insomnia for more and allowing an exploratory analysis of the Compound: Daridorexant maintenance of efficacy – did not reveal > Our Research & any new safety findings, either qualitatively Development or quantitatively, while efficacy (in terms Mechanism of action: Our of sleep and daytime functioning) was Dual orexin receptor antagonism People maintained over the longer treatment Status: NDA submitted, Our duration. MAA in preparation Responsibilities
45 Aprocitentan for resistant hypertension
Hypertension (high blood pressure) is one Patients with hypertension can often of the most common cardiovascular risk successfully control their blood pressure million deaths factors, and its prevalence continues to rise. by combining a healthier lifestyle with a year caused According to a recent study, there are more effective medication. However, there are 7. 5 by hypertension than a billion people living with hypertension patients whose blood pressure remains worldwide – a startling number, which high despite receiving at least three has almost doubled in the past 40 years. antihypertensive medications of different Left untreated, hypertension can lead to pharmacological classes, including a diuretic, life-threatening conditions such as stroke, at optimal doses, and they are categorized ischemic heart disease, or kidney disease. in hypertension guidelines and the medical community as having resistant hypertension. Contents The World Health Organization estimates It is this form of hypertension that scientists navigation that hypertension causes 7.5 million deaths a at Idorsia are trying to treat. Contents year – about 12.8 % of all deaths worldwide.
Idorsia – Reaching out Stages of hypertension for more
> Our Research & Optimal Normal/High normal Grade 1 hypertension Grade 2 hypertension Grade 3 hypertension Development
Our Systolic 120 140 160 180 People mmHg (upper #)
Our Diastolic 80 90 100 110 Responsibilities mmHg (lower #)
46 Typical characteristics of patients with resistant hypertension Excessive dietary sodium
Ethnicity (black)
High baseline Target organ damage blood pressure (left ventricular and chronic Aortic hypertrophy, chronic True resistant hypertension stiffening kidney disease) Patients whose blood pressure uncontrolled remains high, despite receiving hypertension at least three antihypertensives of different pharmacological classes, including a diuretic, at optimal doses. It is estimated Female that 10 % of patients treated for gender hypertension can be classified as having true resistant hypertension.
Obesity
“I was given three different Diabetes tablets and it has been a Not resistant hypertension real battle to get my blood Pseudo-resistant hypertension pressure down. My blood due to: Atherosclerotic – White-coat effect (in the vascular disease pressure is never quite what presence of medical staff) it should be, and I find it quite – Non-optimal treatment – Poor adherence to treatment frightening that they can’t – Inappropriate measurement seem to control it.” Older age; Treatable hypertension especially >75 years Patient with resistant hypertension
47 The treatment landscape The endothelin system in hypertension suggests that resistant hypertension may The current pharmacological treatment Endothelin-1 (ET-1) is a potent be endothelin dependent. The endothelin strategy for patients with resistant vasoconstrictor that also induces system certainly plays an important role hypertension is to add on antihypertensive neurohormonal activation, vascular in hypertension, especially in volume‑ and medications, preferably with a mechanism hypertrophy and remodeling, cardiac salt-dependent forms, which are a of action which is not yet used. Although hypertrophy and fibrosis, and endothelial common feature in patients with resistant hypertension is a serious and growing dysfunction. hypertension. By targeting the endothelin problem around the world, it has been over pathway – an as yet untreated pathway 30 years since an antihypertensive drug In hypertension, both ETA and ETB in systemic hypertension – Idorsia could working via a new pathway was last brought receptors mediate ET-1-induced harmful provide a new treatment option for difficult- to the market. effects. Clinical and preclinical evidence to-treat patients.
Developed in partnership with Janssen Biotech, Inc. In December 2017, Idorsia entered into a collaboration agreement with Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, to jointly develop aprocitentan and any of its derivative compounds or products. Both parties have Contents joint development rights over aprocitentan. Idorsia is overseeing navigation the Phase 3 development and regulatory submission for difficult- Contents to-control hypertension. The costs are shared equally between both partners. Janssen will oversee the Phase 3 development and Idorsia – Reaching out submission for any additional indications and will have the sole for more worldwide commercialization rights.
> Our Research & Development
Our People
Our Responsibilities
48 “I believe that resistant hypertension is only resistant to treatment because the endothelin system, which is clearly involved in hypertension, is yet to be tackled.”
Martine Clozel Executive Vice President, Chief Scientific Officer
Aprocitentan
Idorsia’s innovation effect, while aprocitentan induced a left ventricular hypertrophy. In contrast, Aprocitentan is a once-a-day, potent significant blood pressure reduction. treatment with aprocitentan dose-
dual (ETA and ETB) endothelin receptor In addition to hypertension, increased dependently improved renal hemodynamics Contents antagonist, which is being investigated endothelin also drives inflammation and and decreased cardiac hypertrophy, navigation for the treatment of difficult-to-control fibrosis, and hypertrophy and proliferation in demonstrating a reduction in end-organ Contents hypertension. certain vascular and cardiac cells. Particularly damage – specifically in the kidneys and the in resistant hypertension, this can lead to heart. Idorsia – Reaching out In animal models of hypertension, end-organ damage. Furthermore, increased for more aprocitentan has demonstrated a synergistic endothelin also drives aldosterone secretion In humans, the clinical pharmacology profile effect on blood pressure reduction when and salt retention, which also contributes to suggests that there is a low propensity for > Our Research & given with antihypertensive drugs that elevated blood pressure and, again, can lead drug–drug interaction, which is particularly Development target the renin–angiotensin–aldosterone to end-organ damage. important for patients who typically are Our system (RAAS). In a second animal model, being treated for several other problems. People mimicking resistant hypertension, where rats In the model of resistant hypertension, Our develop hypertension with low renin levels, untreated rats develop hypertension, Responsibilities RAAS blockers have less antihypertensive increased renal vascular resistance and
49 In a Phase 2 dose-response study, patients no additional effect at 50 mg. The effect of with hypertension received monotherapy aprocitentan was shown to cover a 24-hour with four doses of aprocitentan or placebo period. (lisinopril was used as a positive control) for eight weeks, using a randomized, double- The overall incidence of adverse events “There is an urgent public health blind study design. A total of 490 eligible observed in the aprocitentan groups need for additional therapies acting patients were randomized, with 430 patients (ranging from 22.0 % to 40.2 %) was successfully completing the double-blind similar to that seen in the placebo group on pathways different from those treatment period. Blood pressure was (36.6 %). Overall, the most common currently used, in line with the measured carefully with an unattended events were hypertension, headache and automated office blood pressure device. The nasopharyngitis. underlying disease mechanism.” results are shown in the charts below. No changes in heart rate were observed for any The data from the preclinical and clinical Professor John Chalmers, MD Senior Director of The George Institute for Global Health dose of aprocitentan. There was a clear dose program gave Idorsia the confidence and Professor of Medicine at the University of New South Wales, Sydney response on both diastolic and systolic blood to embark on the large Phase 3 study, pressure, with clinically relevant effects PRECISION, in patients with resistant observed at 10 mg, 25 mg, and 50 mg, with hypertension.
Aprocitentan dose-dependently decreased blood pressure in hypertensive patients
Systolic lood Pressure Diastolic lood Pressure
g Contents g navigation mm mm
P P
Contents n n i i
e e n n i
i l l e e
Idorsia – s s a a b b
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for more r r f f e e g g n n
a > Our Research & a h h c c
n Development n a a e e Our People 5 10 5 50 0 5 10 5 50 0
Our Placebo procitentan dose mg Lisinopril mg Placebo procitentan dose mg Lisinopril mg Responsibilities
50 “If successful, the PRECISION study Current status should provide all the information PRECISION is a Phase 3 study to demonstrate the antihypertensive effect required for filing with regulatory of aprocitentan when added to standard authorities to bring a therapy to care in patients with resistant hypertension. Idorsia, in consultation with regulatory patients who have exhausted many agencies, designed a single, placebo- other options.” controlled study which efficiently addresses both the short-term efficacy of aprocitentan Frédéric Naud and the durability of its effects in long-term Senior Director, Life Cycle Leader for aprocitentan treatment. The study aims to randomize 600 patients at approximately 180 sites in around 20 countries, and results are targeted for the first half of 2022.
The evidence built to date gives the company confidence that aprocitentan has the potential to revolutionize the treatment of difficult-to-control hypertension by targeting the endothelin pathway for the Contents first time. navigation
Contents
Idorsia – Reaching out Resistant hypertension for more management Compound: Aprocitentan > Our Research & Development Mechanism of action: Our Dual endothelin receptor People antagonism Our Status: Phase 3 Responsibilities
51 Clazosentan for cerebral vasospasm
Aneurysmal subarachnoid hemorrhage the brain, and about one third of patients (aSAH) is a rare condition involving sudden consequently experience worsening of their life-threatening bleeding occurring in the neurological condition. Cerebral vasospasm subarachnoid space. It is caused by the is one of the leading secondary causes of rupture of an aneurysm – a weak, bulging disability and death in patients with aSAH. spot on the wall of a cerebral artery. Emergency surgical repair (endovascular Approximately 50 % of the overall aSAH coiling or microsurgical clipping) is required population present with thick, diffuse blood to stop the hemorrhage. clots characterized by a large amount of subarachnoid blood on the admission CT The incidence of aSAH is estimated to be scan. These patients have a significantly Contents between 6 and 9 per 100,000 per year higher risk of experiencing cerebral navigation worldwide. Notably, aSAH is a significant vasospasm. Contents problem in Japan, with an incidence at least twice as high as in many other countries of The treatment landscape Idorsia – Reaching out the world. Today, patients with vasospasm are typically for more treated with hemodynamic therapy (the The bleeding and the release of a administration of fluids and agents to > Our Research & vasoconstrictor (endothelin) by the increase blood pressure) or a more invasive Development neighboring vascular endothelium can neurovascular intervention, such as balloon Our lead to cerebral vasospasm (constriction angioplasty or intra-arterial administration People of arteries in the brain), usually occurring of vasodilators. Our between 4 and 14 days after aneurysm Responsibilities securing. This diminishes blood flow to
52 “It is very frustrating to see our Long-term consequences of Numbness or weakness of the face, arm or leg, especially on one side of the body, patients survive the initial trauma of vasospasm or in more severe cases, paralysis Necrosis or death of an area of the brain hemorrhage and seemingly the brain can lead to a variety of make a recovery, only for the long-term effects, depending on the brain area involved, and vasospasm to take hold and cause can affect all aspects of the patient’s life: significant long-term damage.” Dizziness – Physical deficits E. Francois Aldrich, MB, ChB – Cognitive deficits Professor of Neurosurgery, Director of Cerebrovascular Surgery, – Social and emotional impact University of Maryland Mood change, agitation
Symptoms Blurred or of cerebral Worsening double vision vasospasm of headache
Difficulty speaking or Confusion being unable to speak
Loss of consciousness
The endothelin system in cerebral vasospasm Cerebral vasospasm is caused by the An understanding of the role played by release of vasoactive mediators after aSAH. endothelin in cerebral vasospasm prompted Estimated global prevalence of aSAH: Endothelin is one of the most powerful, our scientists to investigate a compound long-acting vasoactive mediators, causing which blocks the effects of endothelin as constriction of blood vessels. Patients with a potential way of preventing or reversing 6 - 9 per 100,000 cerebral vasospasm show high levels of vasospasm in the future. endothelin in the cerebrospinal fluid.
53 Idorsia’s innovation This was followed by two Phase 3 studies, However, an exploratory analysis of the Clazosentan is a fast-acting, selective CONSCIOUS-2 and CONSCIOUS-3, to data collected in CONSCIOUS-3 showed
endothelin A (ETA) receptor antagonist, assess the effect of clazosentan on the that a higher dose of clazosentan (15 mg/h), being developed as an intravenous infusion incidence of cerebral vasospasm-related administered by continuous intravenous for the prevention of vasospasm-related morbidity and all-cause mortality. In 2010, infusion, significantly reduced cerebral delayed cerebral ischemia in patients CONSCIOUS-2 showed that the 5 mg/h dose vasospasm-related morbidity and all- following aSAH. of clazosentan, administered by continuous cause mortality, with a 44 % relative risk intravenous infusion, did not allow a reduction (p=0.0074). The 15 mg/h dose Several studies have built our understanding statistically significant treatment effect to also significantly reduced the incidence of of the role of clazosentan in preventing be observed, resulting in the premature delayed ischemic neurological deficit, with or reversing cerebral vasospasm. In 2006, termination of CONSCIOUS-3. a 54 % relative risk reduction (p=0.0038). In results were reported for clazosentan in addition, clazosentan reduced the need for the prevention of angiographic vasospasm rescue therapy for vasospasm. Clazosentan in patients with aSAH. The Phase 2 dose- did not improve long-term clinical outcome. finding study, CONSCIOUS-1, demonstrated dose-dependent prevention of vasospasm. More recently, a pilot study evaluating the early effect of clazosentan on reversing established cerebral vasospasm in large proximal cerebral artery segments at 3 hours post initiation suggested that, with early administration, clazosentan has the potential to improve large-vessel vasospasm.
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54 “Clinical studies have built a deep understanding of the role of clazosentan in preventing or reversing cerebral vasospasm. We are confident that we can now show that clazosentan can prevent vasospasm-related clinical deterioration in those patients most at risk of developing cerebral vasospasm.”
Angelina Marr Director, Senior Clinical Project Scientist for clazosentan In a post-hoc analysis of the effect of The studies confirmed the well-documented clazosentan on reversing established safety profile of clazosentan, which has now cerebral vasospasm in the entire cerebral been administered to approx. 2000 patients vasculature (including smaller distal vessel around the world. The side effects of segments and the cerebellar arteries), a clazosentan are managed based on clear clearly visible improvement was observed in protocol guidelines: hypotension can be vessel diameter at 3 and 24 hours. mitigated using blood pressure control with vasopressors in the ICU, while lung complications (such as pulmonary edema) can be managed by aiming to maintain euvolemia by avoiding excessive fluid administration.
All this evidence, together with the registration program in Japan (described below), suggests that clazosentan has the potential to prevent vasospasm-related delayed cerebral ischemia and to reduce the need for invasive neurovascular intervention. As a result, Idorsia has initiated REACT, a Phase 3 study.
55 “We have worked on the role of endothelin in aSAH for more than 25 years. We had a very clear goal – to help patients following aSAH, who are often young adults and whose lives can be devastated by the terrible consequences of cerebral vasospasm. We are now well on the way to bringing a much-needed therapy to these patients.”
Jean-Paul Clozel Chief Executive Officer
Current status: Global registration Clazosentan has been granted orphan drug In November 2020, Idorsia announced program designation in Europe (2003) and the US positive top-line results from the Japanese REACT is a Phase 3 study to investigate the (2006), leading to regulatory exclusivity registration program investigating efficacy and safety of clazosentan for the protection of 10 and 7 years, respectively. clazosentan in adult Japanese patients prevention of clinical deterioration due post-aSAH. The program consisted of two to vasospasm-related delayed cerebral Japanese registration program studies assessing the efficacy and safety of ischemia in adult patients following aSAH. A Phase 2 study in Japanese and Korean clazosentan in reducing vasospasm-related Contents The Phase 3 study incorporates the learnings patients showed that 10 mg/h clazosentan morbidity and all-cause mortality events. The navigation from the clazosentan program to identify administered by continuous intravenous two studies followed the same study design, Contents patients at high risk of vasospasm and infusion significantly reduced vasospasm and with one enrolling 221 patients whose delayed cerebral ischemia, the optimal vasospasm-related morbidity and mortality aneurysm was secured by surgical clipping Idorsia – Reaching out dose, the best measure to demonstrate events. On that basis, a registration program and the other enrolling 221 patients whose for more efficacy, and an optimized set of patient was initiated with clazosentan in Japan in aneurysm was secured by endovascular management guidelines to ensure patient May 2016. coiling. > Our Research & safety. The study aims to randomize Development approximately 400 patients – treated either In Japan, clazosentan has regulatory data Our with microsurgical clipping or endovascular protection after approval, leading to eight People coiling – at around 95 sites across 15 years’ exclusivity. Our countries, and results are targeted for the Responsibilities second half of 2022.
56 Responsibilities Our People Our Development > Contents navigation Contents 57 Our Research & for more Reaching out Idorsia –
in theseregistration studies.Treatment- There wereno unexpectedsafetyfindings studies. additional pooledanalysis of datafromboth Further analysisisongoing,including (p<0.05) inapre-plannedpooled analysis. clazosentan onthisendpointwassignificant mortality inbothstudies.Theeffectof reduction ofall-causemorbidityand above. Clazosentan showedanumerical 6 weeks post-aSAH, asshowninthecharts morbidity andall-causemortalitywithin occurrence ofcerebralvasospasm-related significant (p<0.01)reductioninthe Both studiesdemonstratedastatistically cerebral vasospasm. one ofthefollowing:Alldeath Cerebral vasospasm-relatedmorbidityandall-causemortalitywasblindlyadjudicatedbyanindependentcommitteedefined atleast Incidence ofvasospasm-relatedmorbidityandall-causemortality Top-line results from theJapaneseregistration program Event rate ( %) 15 25 35 10 20 30 40 5 0 Coiling Placebo (n=111) 28.8 / New cerebralinfarctionduetovasospasm p=0.0055 (n=103) mg /h 10 Clazosentan 13.6 should marketing authorization bereceived. and launchinJapanthe first halfof2022, would inturnallowforcommercialization (PMDA) inthecomingmonths.This Agency Pharmaceuticals andMedical Devices drug applicationwiththeJapanese Idorsia Japanplanstofileanew edema). pulmonary anemia, pleuraleffusion,brainand (i.e., hyponatremia, hypoalbuminemia, and signsofhemodilutionorfluidretention of >2%comparedtoplacebo) werevomiting of theclazosentan group(withadifference emergent adverseeventsoccurringin>5%
Event rate ( %) 25 30 35 40 10 15 20 0 5 Clipping / Delayed ischemicneurologicdeficit(DIND) dueto Placebo (n=106) 39.6 p=0.0001 Status Japan: Filinginpreparation Status Global:Phase3 receptor antagonism Selective endothelin(ET Mechanism ofaction: Compound: Clazosentan associated withaSAH Cerebral vasospasm (n=105) mg /h 10 Clazosentan 16.2
A ) Lucerastat for Fabry disease
Fabry disease is a rare, life-threatening, lysosomal storage disorder, caused by mutations in the GLA gene, leading to a deficiency or dysfunction of alpha- galactosidase A (alpha-Gal A), an enzyme that normally breaks down a fatty substance known as globotriaosylceramide (Gb3) in the cells of the body. Over time, this may result in a build-up of Gb3 deposits throughout the body, particularly in the kidneys, heart and nervous system.
The symptoms range from neuropathic pain (primarily in the hands and feet) and gastrointestinal, skin and eye problems, to hypertension, progressive kidney damage, cardiomyopathy and stroke. Since most symptoms are non-specific, Fabry disease is often undetected or misdiagnosed. As the disease is progressive, Contents early diagnosis is essential to manage the symptoms as soon as possible and navigation reduce the risk of developing serious complications. Contents New therapeutic options are needed to treat the underlying mechanism of the Idorsia – Reaching out disease and provide symptomatic relief. for more
> Our Research & Development “Pain is a genuine and pressing unmet need of the Fabry patient population. Pain remains a significant burden for many patients – even for some of Our People those who are already being treated with enzyme replacement therapy.”
Our Dr Derralynn Hughes Responsibilities DPhil, FRCP, FRCPath, coordinating investigator of the European studies
58 “The sensations that I get – it feels Clinical manifestations of Fabry disease like my hands are on fire. It feels like – More frequent / severe in men – Gradually progressing in severity from childhood to adulthood there’s a thousand needles poking at – Major impact on quality of life my hands and feet… If I was to get – Slow progressive damage to vital organs over decades – Premature death out of bed and I was to walk, it would Brain Ears feel like I’m walking on hot coals with Strokes, transient Hearing loss, tinnitus ischemic attacks and vertigo needles jabbing into my feet.” and dizziness
Patient with Fabry disease Eyes Heart Changes in the Cardiomyopathy with appearance arrhythmia, valvular of the eyes dysfunction, ischemia, left heart failure
Kidneys Gastrointestinal tract Cysts, reduced Abdominal pain, diarrhea, kidney function, constipation and nausea progressive kidney failure
Neuropathic pain Skin Pain resulting from Dark red spots or damage to or dysfunction rashes, burning / tingling of the nervous system sensations, sensitivity to temperature and profuse sweating
The diagnosed prevalence of Fabry disease in 2018 was approximately Fabry patient survey Idorsia conducted an international survey conducted a separate study to define (with 367 patients) to gain a better neuropathic pain in Fabry patients. The understanding of the symptoms and needs results informed the development of a of patients with Fabry disease, from their Fabry-specific pain questionnaire, in which 7,500 patients own perspective. The findings indicate neuropathic pain was defined as a type that Fabry patients experience significant of pain which feels like burning, shock or in the US and the EU-5 (i.e., France, neuropathic pain (in terms of intensity, shooting, stabbing, tingling and/or pins and Germany, Italy, Spain and the UK). frequency and location), which has a large needles in the hands and feet. impact on their quality of life. Idorsia then 59 The Gb3 cycle and therapeutic increases plasma concentrations of alpha- load in patients with Fabry disease. Since approaches Gal A, or by chaperone therapy, which this mechanism is independent of alpha-Gal The normal biosynthesis and degradation improves the function of mutated enzymes A deficiency or dysfunction, it should not of Gb3 is shown schematically in the (in patients with amenable mutations). be limited to specific mutations of the GLA Figure below. In patients with Fabry These approaches attempt to reduce the gene. disease, deficiency or dysfunction of the continued accumulation of Gb3. enzyme alpha-Gal A leads to abnormal accumulation of Gb3, which in turn causes In contrast, lucerastat, an oral inhibitor of the symptoms of Fabry disease. Current glucosylceramide synthase (GCS), reduces treatments focus on replacing or supporting the substrate which forms Gb3. Substrate alpha-Gal A – either through infusion of reduction therapy (SRT) decreases the recombinant enzyme, which temporarily build-up and subsequently reduces the Gb3
The Gb3 cycle
Symptoms of Fabry Disease Normal synthesis & Dysfunction of α-GalA Current treatments Lucerastat targets the degradation Fabry Disease temporarily replace α-GalA production of Gb3 by or support α-GalA inhibiting the enzyme GCS (where possible) Biosynthesis Degradation Biosynthesis Degradation Biosynthesis Degradation Biosynthesis Degradation of Gb3 of Gb3 of Gb3 of Gb3 of Gb3 of Gb3 of Gb3 of Gb3 Gb3 Gb3 Gb3 Gb3
Contents GlcCer GlcCer GlcCer GlcCer navigation Replace: Enzyme Contents Replacement Inhibit: Dysfunction Therapy Lucerastat Idorsia – GCS α-GalA GCS α-GalA GCS α-GalA GCS α-GalA Reaching out Support: for more Chaperone Therapy > Our Research & Development Cer Sph Cer Cer Sph Cer
Our People
Our Responsibilities Abbreviations: α-GalA, α-galactosidase A; Cer, ceramide; Gb3, globotriaosylceramide; GCS, glucosylceramide synthase; GlcCer, glucosylceramide; Sph, sphingosine
60 “By reducing the production of the lipids that cannot be broken down due to Fabry disease, we believe that lucerastat can change the course of the disease for these patients.”
Luba Trokan Director, Clinical Project Physician for lucerastat
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61 Idorsia’s innovation In an exploratory study in patients with Lucerastat is an oral inhibitor of Fabry disease, treatment with lucerastat in glucosylceramide synthase, offering a addition to enzyme replacement therapy potential new treatment approach for induced a marked decrease in plasma levels all patients living with Fabry disease, of metabolic substrates associated with the irrespective of mutation type. development of the disease. The biomarker chart on page 63 shows the reduction in Preclinical studies have shown that biomarker in the treatment group (n=10) vs lucerastat is an orally available, highly controls (n=4). soluble small molecule with rapid and complete absorption. As a small molecule, it is widely distributed to most tissues, including the central nervous system, kidney and heart.
In an animal model of Fabry disease, treatment with lucerastat reduced Gb3 Lucerastat levels and related biomarkers in dorsal root ganglia, the kidneys and the heart, as shown by the animal model charts on page 63. This demonstrates that lucerastat has the potential to reduce Gb3 levels in key target organs and, therefore, to show clinical efficacy in Fabry disease.
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62 Current status Reduction of Gb3 levels in tissues from an animal model of Fabry disease Lucerastat for Fabry disease has received orphan drug designation in the US and the Dorsal root ganglia Kidneys Heart EU, and is under review in Japan.
p<0.05* 2,000 25 p<0.05* p<0.05* 12 NS NS MODIFY is a Phase 3 study to determine the efficacy and safety of lucerastat oral 10 20 1,500 monotherapy in adult patients with Fabry 8 disease. The study aims to determine the 15 1,000 6 effects of treatment on neuropathic pain mg wet weight) / 10 over a 6-month period, as measured by 4 500 Idorsia’s Fabry disease neuropathic pain 5 2 instrument (developed in accordance with n=5 n=5 n=5 n=6 n=6 n=6 n=6 n=6 n=6 n=6 Gb3 (pmol 0 0 0 health authority guidance). At the end Control Lucerastat Control Lucerastat Control Lucerastat Control Lucerastat Control Lucerastat of the double-blind period, patients will Females Males Females Males have the option of entering an open-label * ANOVA with Bonferroni's multiple testing correction extension study to determine long-term safety and to explore long-term efficacy and disease-modifying potential, as measured by Mean % biomarker reduction from baseline at week 12 in patients with Fabry disease estimated glomerular filtration rate (eGFR), Plasma Gb3 Urinary Gb3 GlcCer LacCer Plasma LysoGb3 left ventricular mass index and biomarkers (n=10) (n=10) (n=10) (n=10) (n=10) of Fabry disease. Enrollment in the study 0 % concluded at the end of 2020, with more than 100 patients being randomized to -10 % lucerastat or placebo in a 2:1 ratio. Results Contents of this study are therefore expected in the navigation -20 % -55 %* -52.5 %** -49.0 %* -32.7 %* -5.4 %^ second half of 2021. Contents -30 %
Idorsia – -40 % Reaching out Fabry disease for more -50 % Compound: Lucerastat
Control (n=4) > Our Research & -60 % Development -6.9 % -8.6 % -6.5 % -3.9 % 2.7 % Mechanism of action: Our Glucosylceramide synthase People *P<0.0001, **statistical significance not calculated, ^non-significant inhibition Our Status: Phase 3 Responsibilities The study also indicated that lucerastat is well tolerated in patients with Fabry disease.
63 Selatogrel for acute myocardial infarction
About AMI An AMI, or heart attack, is a life-threatening condition that occurs when blood flow to the heart muscle (myocardium) is suddenly decreased or completely cut off. It is usually caused by a blood clot or blockage in one or more of the coronary vessels supplying blood to the heart muscle. An AMI requires immediate treatment and medical attention, as any delay in intervention can result in irreversible damage to the heart muscle. According to the Centers for Disease Control and Prevention, each year more than 800,000 persons living in the US will suffer a heart attack.
Contents Although the management of AMI has improved in recent decades, navigation morbidity and mortality associated with AMI remain high, with the Contents majority of early deaths occurring prior to hospital admission. As a result, early action is crucial for survival; however, there are no Idorsia – Reaching out treatment options available for the critical time from onset of AMI for more symptoms to first medical contact. The need for an early intervention Each year more than has been highlighted by the guidelines of the European Society of > Our Research & Cardiology, which identified the prehospital phase as the most critical Development for high-risk patients and reiterated that efforts must be made to Our reduce the delay in initiation of treatment in order to reduce death. People 800,000
Our people living in the US Responsibilities will suffer a heart attack.
64 Heart attack can occur in: What causes a heart attack? All ages. All ethnicities. All genders. A heart attack occurs when there is a sudden If a plaque ruptures, it triggers the formation interruption of the blood supply to some of a blood clot at the same site (coronary of deaths in part of the heart muscle. thrombosis). This can lead to partial – or in 1/3 developed nations extreme cases complete – obstruction of the can be attributed to A heart attack usually occurs in patients coronary artery (coronary occlusion). Both heart attack with coronary heart disease (CHD), coronary thrombosis and coronary occlusion where coronary arteries are narrowed obstruct the blood flow in the coronary due to the build-up of fat, cholesterol arteries, starving the heart muscle of oxygen and other substances (known as plaque (a process known as myocardial ischemia). or atheroma). This process of build-up is of deaths caused by cardiovascular called atherosclerosis. The development of 80 % disease are due to heart attack atherosclerosis can progress over decades and stroke and often has no symptoms – this explains why around half of the people experiencing 1st heart Recurring a heart attack have no warning signs attack heart beforehand. 800,000 attack people living in the US have a heart attack each year Plaque
72 Atherosclerosis Average age at first heart attack – risk Plaque increases with 66 age Thrombus
women die of heart Partial coronary attack worldwide occlusion 3.3m every year
Women tend to underestimate Plaque Thrombus the risk of heart attacks Full coronary occlusion 65 Recognizing the symptoms – Chest pain – Heaviness in the chest – Pain or discomfort in the chest: this – Chest discomfort – Burning in the chest can include heaviness, pressure, burning, – Chest pressure – A feeling like a band around the tightness or a feeling of having a band – Chest tightness chest or a weight on the chest around the chest or a weight on the chest. – These symptoms can spread to the left arm or both arms, to the upper back, to Common heart the neck or jaw or gums. attack symptoms – The chest symptoms can also be associated with shortness of breath, feeling the need to take in more air, feeling lightheaded, breaking out in a cold The left arm or sweat, or feeling sick. both arms – Unexpected or unexplained nausea, vomiting or indigestion.
Chest pain can Between the Symptoms of Unexpected radiate to: shoulders heart attack or unexplained indigestion, nausea or vomiting
The chest symptoms The neck or Contents can also be jaws or gums navigation Breaking out associated with: Contents in cold sweat
Idorsia – Reaching out for more
> Our Research & Feeling Development lightheaded Our Feeling the need People to take more air, Our shortness of breath Responsibilities
66 P2Y12 receptor antagonism Idorsia’s innovation Platelet adhesion, activation and Selatogrel is a potent, fast-acting, reversible
aggregation play a pivotal role in and highly selective P2Y12 receptor atherothrombosis. An essential element antagonist, being developed for the in the platelet activation process is the treatment of AMI in patients with a history interaction of adenosine diphosphate of AMI. It is intended to be self-administered
(ADP) with the platelet P2Y12 receptor. This subcutaneously via a drug delivery system platelet activation and aggregation can be (auto-injector). This novel, self-administered
The treatment landscape inhibited by antagonizing the platelet P2Y12 emergency agent has the potential to Dual antiplatelet therapy – the combination receptor. This prevents the binding of ADP protect heart muscle in the very early phase
of aspirin and a P2Y12 receptor antagonist – to the receptor, which reduces platelet of an AMI, in the crucial time between is a cornerstone of the treatment of patients aggregation and the reaction of platelets to symptom onset and first medical attention, with acute coronary syndromes (ACS) stimuli of thrombus aggregation. so as to prevent severe clinical outcomes. and of those undergoing percutaneous
coronary intervention (PCI). Oral P2Y12 P2Y12 receptor antagonists have been used receptor antagonists are indicated for in the treatment of millions of patients acute treatment as well as long-term globally, and the safety and efficacy profiles secondary prophylaxis of confirmed AMI. are well established. However, until now,
An intravenous P2Y12 receptor antagonist is the method of administration or the delayed intended for specialized use in an acute and onset of effect means that currently hospital setting in patients undergoing PCI available treatments do not have the desired who have not been pretreated with an oral profile to cover the critical time from onset
P2Y12 receptor antagonist. of AMI symptoms to first medical contact.
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67 Two Phase 2 studies in patients with chronic coronary syndromes and AMI, respectively, have met their pharmacodynamic objectives of significantly inhibiting platelet aggregation. Subcutaneous administration of selatogrel 8 mg and 16 mg has demonstrated a rapid onset of action, within 15 minutes, with the height of its effect extending over four to eight hours, depending on the dose. Selatogrel was safe and well tolerated in both studies, and there were no treatment-emergent serious “With our integrated drug delivery device, bleeds. The chart below shows the rapid inhibition of the potential to self-administer selatogrel platelet aggregation following subcutaneous injection: in the critical time period immediately following onset of suspected AMI Selatogrel has a rapid effect following subcutaneous symptoms could be revolutionary for injection patients.” lace o 300 Sebastien Roux Selatogrel mg Senior Director, Medical Expert Cardiovascular Therapeutic Area Selatogrel mg
200
Contents 100 navigation
Contents Platelet reactivity unit (PRU) value
0 Idorsia – Reaching out ime post in ection hours for more
> Our Research & In late 2019, Idorsia entered into a global agreement Development with Antares Pharma, Inc., to develop a novel drug- Our device product combining selatogrel with the Antares People QuickShot® auto-injector for subcutaneous delivery. Our Responsibilities
68 Current status In consultation with health authorities, The drug-device product is being tested in Idorsia is preparing a large, international usability and reliability studies tailored for Phase 3 study, involving approximately emergency use, to ensure safe and effective 14,000 patients, to evaluate the efficacy and use can be demonstrated in preparation for safety of self-administered subcutaneous a Phase 3 study. injection of selatogrel for the treatment of suspected AMI in patients with a history of AMI. Participating patients will be trained on when and how to self-inject treatment. “Every patient will play a central role Initiation of the registration study is by understanding the symptoms of AMI, targeted for the first half of 2021. A Special Protocol Assessment has been agreed with taking the decision to self-inject, and the FDA. This indicates the FDA’s approval calling for emergency medical care.” of the adequacy and acceptability of specific critical elements of overall protocol design Corine Bernaud (e.g., entry criteria, dose selection, endpoints Director, Clinical Project Physician and planned analyses) for a study intended to support a future marketing application.
In December 2020, the FDA designated the investigation of selatogrel for the treatment of suspected AMI as a “fast-track” development program. This designation is intended to promote communication and collaboration between the FDA and pharmaceutical Contents companies for drugs that treat serious navigation conditions and fill an unmet medical need. Contents
Idorsia – Reaching out Acute Myocardial Infarction for more Compound: Selatogrel
> Our Research & Development Mechanism of action: Our Selective P2Y12 receptor People antagonist Our Status: Phase 3 in preparation Responsibilities
69 Cenerimod for systemic lupus erythematosus
“There is a stigma attached to lupus. I always talk about my illness and explain it to people first; I tell them it’s an autoimmune disease, but it’s not contagious and I can’t pass it on to them.”
Patient Systemic lupus erythematosus (SLE), to manage the symptoms of lupus, initiate the most common form of lupus, is an treatment to reduce the risk of long-term Contents autoimmune disease, which means that complications, and enable those affected navigation the body’s immune system malfunctions to access wider support (e.g. local patient Contents and attacks the body’s own tissues. Some groups). autoimmune diseases affect just one organ, Idorsia – Reaching out but in the case of lupus, all parts of the body It is estimated that 1.5 million Americans, for more can be affected. and at least 5 million people worldwide, have a form of lupus, and that 90 % of > Our Research & As a result, symptoms vary widely and are people living with lupus are women, with Development often similar to other conditions, which most developing the disease between Our need to be ruled out before a diagnosis the ages of 15 and 44. There is a higher People can be made. Lupus therefore often goes prevalence of lupus among people of Our undetected or misdiagnosed for long Asian and Afro-Caribbean origin than in Responsibilities periods. Yet early diagnosis is important Caucasians.
70 Normal immune Autoimmune In SLE, the body’s immune system As any part of the body can be affected by response response malfunctions and attacks the body’s own SLE, the condition can manifest itself in a tissues, which can affect the skin, joints, gut, multitude of ways. blood cells, lungs and other organs.
Blood and circulation: Fatigue Joint and muscle swollen glands, poor pain circulation in the Foreign threat Immune system fingers and toes, invades forms antibodies anemia against its own body cells Nervous system: Skin: rashes, headaches, depression sensitivity to light and seizures
Symptoms Antibodies Antibodies of lupus attack and attack the remove body’s own invading threat cells
Liver and spleen Fever enlarged and/or night sweats
Antibodies Antibodies Scalp and Weight continue to remain in the mucosa changes protect body body causing Kidney inflamation and problems tissue damage
71 The treatment landscape The choice of treatment depends on how There is no cure for SLE, and a significant the patient with SLE presents; which part of need exists for safe and effective therapies. their body is affected and the severity of the Most people with SLE are prescribed a condition at the time. combination of different medications to manage their symptoms, improve their The only FDA-approved treatments quality of life and reduce the risk of more for SLE are acetylsalicylic acid (aspirin), serious complications. hydroxychloroquine (an antimalarial), corticosteroids and belimumab. Some other immunosuppressive therapies are used off- label.
“The presence of autoreactive T cells and B cells and the subsequent production of autoantibodies is key to the inflammation and organ damage seen in lupus. By acting on both cell types and at a fundamental stage in the autoimmune response, cenerimod has the potential to Contents navigation alter the course of the disease.”
Contents Beate Sehorz Senior Director, New Product Strategy Idorsia – Reaching out for more
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72 By binding to S1P1 receptors, a receptor modulator can trigger the internalization of those receptors. This effectively blinds T and B lymphocytes to the S1P gradient, thereby holding them in the lymph nodes and reducing circulating autoreactive T and B cells in the blood and thus in the tissues.
As a consequence of this reduction, it is hypothesized that a reduction in autoantibodies and immune cytokines – Cenerimod markers of the underlying disease processes – would also be seen, ultimately reducing inflammation and tissue damage, key contributors to the disease.
S1P1 receptor antagonism Idorsia’s innovation While the cause of SLE is not fully known, Cenerimod, the result of 20 years of T and B lymphocytes are considered the research in Idorsia’s labs, is a highly selective
key immune system cells playing a role in S1P1 receptor modulator, given as an oral the development of SLE. In individuals with once-daily tablet. Cenerimod potentially SLE, both T and B cells become overactive. offers a novel approach for the treatment The main consequence of this increased of SLE, a disease with a significant impact on activity is the production of autoantibodies patients and limited treatment options. (antibodies that recognize and destroy the Contents body’s own cells), leading to inflammation In a mouse model of SLE, mice typically navigation and organ damage. develop an aggressive version of a lupus- Contents like disease, with increased inflammation, T and B lymphocytes have a cell surface autoantibodies and immune cytokines, Idorsia – Reaching out receptor called sphingosine-1-phosphate resulting in damage to the kidney and death. for more receptor 1 (S1P1). These receptors enable T When treated with cenerimod, an increase in and B lymphocytes to detect the signaling survival was observed. This was underpinned > Our Research & molecule S1P – sphingosine 1 phosphate by improved kidney structure and function, Development – which is responsible for lymphocyte as well as marked decreases in important key Our trafficking from the lymph nodes to the markers of disease. People blood. Our Responsibilities
73 The effect of cenerimod on lymphocyte Cenerimod induced a dose-dependent reduction of total lymphocyte count in patients trafficking was confirmed in humans when with SLE administration of cenerimod induced a dose-dependent, sustained and reversible reduction in circulating lymphocyte counts. Absolute change in Placebo n 1 total lymphocyte 0.5 mg n 1 count (109/L) from In a Phase 2 proof-of-concept study baseline to EOT 1 mg n 10 investigating the effect of cenerimod on – mg n 1 circulating lymphocytes, disease activity, mg n safety and pharmacokinetics in SLE patients, cenerimod dose-dependently reduced total lymphocyte count from baseline to – end of treatment (p<0.001). In addition, the antibody-producing B cells, which are elevated in patients with SLE and critical to P 0.001 for dose response the disease process, were markedly reduced by cenerimod. Placebo
Cenerimod dose mg The study provided promising data, with an early indication of efficacy being numerical Dashed line represents the 95% CI reductions in mSLEDAI-2K (one of the Analysis set: Modified Pharmacodynamic Set measures of disease activity) and in anti- EOT, end of treatment - Week 12 double-stranded DNA antibodies. This is very encouraging, especially considering that the result was seen after only 12 weeks of Contents treatment. navigation
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74 In December 2017, the FDA designated Cenerimod induced numerical reductions in modified SLEDAI-2K in patients with SLE the investigation of cenerimod for the treatment of SLE as a “fast-track” Mean mSLEDAI-2K development program. This designation score ± SE is intended to promote communication and collaboration between the FDA and pharmaceutical companies for drugs that treat serious conditions and fill an unmet medical need.
Placebo n 1 0.5 mg n 1 1 mg n 10 mg n 1 mg n
0 aseline O O
Analysis Set: Modified Pharmacodynamic Set modified SLEDAI-2K, Systemic Lupus Erythematosus Disease Activity Index-2000 modified to exclude leukopenia; EOT, end of treatment; EOS, end of study
Contents navigation Cenerimod was well tolerated at all dose four different dose levels; to determine Contents levels. The occurrence of adverse events was the appropriate dose, patient population similar in all five treatment groups. and endpoints for further development in Idorsia – Reaching out SLE; and to evaluate the effects on quality Systemic lupus erythematosus for more Current status of life and fatigue, using patient-reported Compound: Cenerimod CARE is a multiple-dose efficacy and safety outcome instruments, as well as the effects > Our Research & study with cenerimod for the treatment of on SLE biomarkers. Randomization will be Development adult patients with moderately to severely completed by the end of February 2021, Our active, autoantibody-positive SLE. The with at least 350 patients enrolled. The Mechanism of action: People aims of the study are to assess the safety results are targeted for the second half of S1P1 receptor modulation Our and efficacy of cenerimod treatment at 2021. Status: Phase 2b Responsibilities
75 More cooperation – Maximizing the value of innovation
For Idorsia, sophisticated partnerships are a way of gaining strategic access to technologies or products and fully exploiting our discovery engine and clinical pipeline. In general, we seek suitable external project partners to maximize the value of internal innovation.
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76 Actelion Pharmaceuticals Neurocrine In 2017, Idorsia and Actelion Pharmaceuticals, one of the Janssen In 2020, Idorsia entered into a global license agreement with Pharmaceutical Companies of Johnson & Johnson, entered into a Neurocrine Biosciences for the development and commercialization revenue-sharing agreement in respect of ponesimod. of ACT-709478, Idorsia’s potent, selective, orally active and brain- www.investor.jnj.com penetrating T-type calcium channel blocker, for the treatment of a rare pediatric epilepsy, and a research collaboration to discover, Antares Pharma identify and develop additional novel T-type calcium channel In 2019, Idorsia entered into a global agreement with Antares blockers. Pharma to develop a novel drug-device product combining www.neurocrine.com selatogrel – Idorsia’s potent, fast-acting, reversible and highly
selective P2Y12 receptor antagonist – with the Antares subcutaneous Roche QuickShot® auto-injector. In 2017, Idorsia entered into a research collaboration that provides www.antarespharma.com Roche with an exclusive option right to develop and market first-in- class compounds for a promising new approach in the field of cancer Janssen Biotech immunotherapy. In 2017, Idorsia entered into a collaboration agreement with Janssen www.roche.com Biotech, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, to jointly develop aprocitentan and any of its derivative Santhera compounds or products. Janssen Biotech has sole commercialization In 2020, Idorsia’s license, collaborative development and rights worldwide. commercialization agreement with ReveraGen BioPharma in www.janssen.com respect of vamorolone was transferred in its entirety to Santhera Pharmaceuticals, with the latter replacing Idorsia as a party to the Mochida agreement. In 2019, Idorsia and Mochida Pharmaceutical entered into an www.santhera.com exclusive license agreement for the supply, co-development and co- Contents marketing of daridorexant, Idorsia’s dual orexin receptor antagonist Syneos Health navigation (DORA), for insomnia and related disorders in Japan. In 2020, Idorsia and Syneos Health entered into an innovative Contents www.mochida.co.jp commercial partnership to build the salesforce for the US launch of daridorexant, Idorsia’s new dual orexin receptor antagonist, being Idorsia – Reaching out investigated for the treatment of insomnia. for more www.syneoshealth.com
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77 Our People
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78 More power – For scientific thinking
Simply put – our success depends on our people! This is why we want to recruit, engage and One common goal develop talented people who are passionate about working together and applying science to bring benefits to patients. 42 % 58 % female male
38 nationalities Contents Highly navigation qualified Contents professionals
Idorsia – Reaching out >900 for more employees
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79 More diversity – Creating opportunities
Advancing our R&D pipeline and preparing for commercialization requires the company to grow its talent base. As a result, we created more than 90 new positions worldwide in 2020.
As a growing company, it is important that we attract, retain and advance top talent from all backgrounds and cultures. During the recruitment process, we seek to attract a diverse pool of candidates, focusing on the skill set they offer and matching their competencies to the behaviors we expect our people to live by daily and to the key qualifications required to fulfill the role.
Our people are committed to making Contents Idorsia one of Europe’s leading navigation biopharmaceutical companies, while at the Contents same time developing both personally and professionally. Idorsia – Reaching out for more “I’m very glad to have joined Idorsia at this
Our Research & stage of our journey. I’ve found a highly Development productive environment where people enjoy > Our People their work – it’s a very exciting place to be.”
Our Fenna Gloggner Responsibilities Director, Global Customer Insights
80 At Idorsia, we harness the power of difference to achieve business success: our employees come from diverse cultural backgrounds, representing 38 nationalities. 12 % Rest of the world
4 % 5 % 13 % 4 % 4 % United States Japan Germany United Kingdom Italy
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Our Research & Development > Our 34 % People France Our 24 % Responsibilities Switzerland
81 More science – Bursting with ideas
Our people work every day with creativity and passion to find new treatments and make them available to patients with serious diseases – from bench to bedside.
We aim to create an inspiring working environment and provide equal opportunities for all our employees. We do not tolerate discrimination of any kind.
In 2020, we conducted a gender equal pay analysis, which encouragingly revealed that there are no relevant differences in pay between men and women at the Swiss Headquarters of Idorsia. The required Contents standard regression analysis – validated by navigation external auditors – of the effect of gender Contents on base salary, and on base salary including annual bonus, showed a non-significant Idorsia – Reaching out difference of -0.34% and -0.49% in favor of for more men, respectively, which is well within the 5% tolerance threshold specified by the Our Research & Federal Office for Gender Equality. For more Development information please refer to the gender equal > Our pay analysis description in the Compensation People Report 2020. Our Responsibilities
82 More potential – Expanding opportunities
Our future as a company depends on a workplace that enables employees to achieve their full potential – both at work and outside the office. We believe that a culture fostering employees’ development and growth is essential to our success. We take an integrated approach to rewards and talent management, designed to build an organization of highly engaged and enthusiastic professionals.
To support our people in achieving their full program in 2018 to help managers become in the center of our daily activities. We also potential, we provide a range of internal great leaders. regularly organize internal campaigns to and external learning and development raise awareness of common diseases that programs. We emphasize results-oriented This year, we launched a global virtual could affect our employees, such as breast coaching, encourage internal mentorship, program that offers employees a possibility cancer, testicular cancer and mental health Contents offer a variety of training programs, and fully to learn from other colleagues. The main issues. navigation support language learning. purpose of this program is to encourage Contents cross-functional learning for all employees Idorsia also provides financial assistance worldwide – for example, an expert in IT Idorsia – “Idorsia offers a unique Reaching out to employees who wish to advance their learning about the drug discovery process. for more education through an accredited university possibility of personal and or business school. We also run disease awareness campaigns Our Research & for our employees. Since Idorsia’s professional growth as we Development We regularly assess our talent to identify foundation in 2017, we have hosted several work together to develop > Our high performance and provide support for on-site events where employees could People those who display potential for further experience and discover diseases which we and transform the company."
Our growth. For employees taking on additional are actively researching, such as lupus and Pier Paolo Lo Valvo Responsibilities responsibilities, we launched a leadership Fabry disease, to help us keep the patient Director, Global Integrated Talent Management
83 More experience – Driving innovation
At Idorsia, we have tools in place to recognize extraordinary achievements and emphasize the importance of working in teams.
Our simple and transparent reward and In addition to our stock-based programs, we recognition philosophy is based on engaging recognize individual long-term engagement everyone in an entrepreneurial approach to with Idorsia, through a special “Anniversary long-term value creation. Vacation” (4 weeks’ fully paid sabbatical leave) when employees reach their 10th, Idorsia’s approach to performance and 20th and 30th anniversary of employment recognition provides a simple and effective with Idorsia. Disconnecting from work for way to align individual and team efforts an extended period to pursue personal with Idorsia’s strategic priorities, as well as interests leaves employees energized and encouraging excellent performance and ready to immerse themselves when they sharing the results that we achieve together. return. Contents navigation
Contents “It’s very exciting to be able to discover Idorsia – Reaching out innovative new treatments and really help for more patients, while at the same time contributing Our Research & Development to the growth and value generation > Our of our company." People Naomi Tidten Our Director, Team Leader Computer-Aided Drug Design Responsibilities
84 48 % 1% Generation X Generation Z (1965 – 1979) (2000 – 2012) 39 % female 43 % female 61 % male 57 % male
Contents navigation 1940 1950 1960 1970 1980 1990 2000 2010
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Idorsia – Reaching out for more 10 % 41% Our Research & Development Baby boomers Generation Y (1943 – 1964) (1980 – 1999) > Our 30 % female 49 % female People 70 % male 51 % male
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85 More ambitions – Courageous and energetic
It is not just what we achieve, but how we get there. To support this, management has identified model behaviors which will help us to implement our strategy, shaping Idorsia’s learn corporate culture.
team up be pragmatic advance invent
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86 To reach our ambitious goals, we advance We team up to harness the power of our with energy and drive. We take full collective passion and sense of fun. We ownership and accountability to find work collaboratively, sharing information solutions and outpace the competition. and exchanging ideas, listening to and supporting each other. Whatever the challenge, we are agile and pragmatic in implementing initiatives We are curious, open-minded, and we learn without compromising the quality of our continuously. We are encouraged to expand work. our knowledge, skills and self-awareness, while looking for ways to apply what we’ve To seize more opportunities, we invent learned. Contents with creativity and imagination. Our work navigation is science- and data-driven, and we remain Contents open to new approaches in all aspects of what we do. “We create a meaningful and Idorsia – Reaching out enjoyable environment for people for more to do their best work.” Our Research & Development Alex Khatuntsev Senior Vice President, Head of Global Human Resources > Our People
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87 More opportunities – Expanding the horizon
Since its foundation, Idorsia has added more than 250 professionals to its ranks. This rapid growth reflects the rapid advancement of our pipeline and ongoing preparations to bring our drugs to patients.
Initially, it was important to bolster the Global Information Services team. As so much of our work depends on smooth-running IT systems, we have made considerable efforts to establish a state-of-the- art environment, supporting all activities. Our proactive efforts towards state-of-the art technology over the past few years proved to be Contents even more important in 2020, when navigation we relied so heavily on technology Contents to allow the company to function throughout the COVID-19 pandemic Idorsia – Reaching out without missing a beat. for more
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> Our People The Idorsia Simon Jose Martine Clozel Guy Braunstein Our Executive Committee Executive Vice President, Executive Vice President, Executive Vice President, Responsibilities Chief Commercial Officer Chief Scientific Officer Head of Global Clinical Development
88 “This is a very exciting time for Idorsia. I am very proud that such experienced and talented people have decided to join our company.”
Jean-Paul Clozel Chief Executive Officer Expansion was also required to ensure the development, manufacturing and control of high-quality drug products, needed first for clinical development and ultimately, of course, for our commercial launches.
We started to build our commercial capabilities in 2019, and this year, our Chief Commercial Officer hired further people to fill key strategic roles, such as the Head of Global Medical Affairs, Antonio Olivieri, Head of Global Supply Chain, Olivier Nalinne, President of Idorsia Europe and Canada, Jean-Yves Chatelan, and the President of our US commercial organization, Patty Torr. Since joining Idorsia in March 2020, Patty has already filled all key positions for her leadership team in the US.
We have formed a talented and diverse leadership team to commercialize and realize the potential of our deep and broad pipeline. The team members each have exceptional experience of the pharma world, in their respective functional areas, as well as a strong entrepreneurial mindset. This combination will be critical to our success as we move a step closer to commercializing our first product in the US.
The Idorsia André C. Muller Jean-Paul Clozel Executive Committee Executive Vice President, Chief Executive Officer Chief Financial Officer
89 Our Responsibilities
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90 More drive – For a better future
Idorsia’s goal is to discover, develop and commercialize innovative medicines to help more patients. We believe that delivering on this mission is our core responsibility to our stakeholders and society in general. We also believe that it is possible to achieve this in an economically, socially and environmentally responsible manner.
Although we are, on paper, a young The EFPIA and Idorsia are fully committed to and guidelines covering the breadth of its company, we have already established a complying with the highest ethical standards business areas. Access to these documents robust governance framework, with a broad under EFPIA and National Codes. is ensured for all employees via an electronic range of supporting policies, standard quality management system. Policies which operating procedures and guidelines, such To ensure that our employees understand are relevant to other stakeholders are as our Code of Business Conduct, driving a how important it is to work in a compliant, available on our corporate website and can culture of integrity. ethical and transparent manner, Idorsia be accessed below. Contents has implemented a number of policies navigation Idorsia is proud to be working in a highly Contents regulated industry, with codes of conduct, guidelines and regulations designed to Idorsia – Reaching out protect patients, healthcare professionals for more and the reputation of the industry. We are Code of Anti- Communi- Scientific Global Whistle- a member of the European Federation of Business Corruption cation Publi- Principles blower Conduct & Anti- cations for Protection Our Research & Pharmaceutical Industries and Associations Development Bribery Healthcare (EFPIA). Our People
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91 Sound corporate governance and high The Idorsia Code of Business Conduct is at Anti-Corruption & Anti-Bribery standards of ethical behavior are essential the foundation of our corporate culture Full compliance with applicable laws in all to the company’s success, as well as in and defines the core principles and ethical the regions where Idorsia operates is crucial maintaining the trust and confidence of standards by which we create value in our to our success. Idorsia’s position is clearly our stakeholders. Corporate governance at company. It is the responsibility of every stated in its Anti-Corruption and Anti-Bribery Idorsia is designed to promote the long- Idorsia employee to be familiar with and Policy: We take a zero-tolerance approach to term interests of our shareholders, maintain to comply with our Code. We are proactive bribery and corruption and are committed internal checks and balances, strengthen in establishing policies and practices that to acting professionally in all our business management accountability and foster support strong corporate governance and dealings and relationships wherever we responsible decision‑making. transparency. These policies and practices operate. are continually reviewed and enhanced as Our Legal & Compliance function seeks appropriate. We implement and enforce effective to drive a culture of integrity, with the systems to counter bribery. We will uphold following priorities: Employees of Idorsia and its worldwide all laws relevant to countering bribery and affiliates are responsible for always corruption in all the jurisdictions in which we – communicate clearly to employees demonstrating honesty, integrity and operate. All Idorsia employees are required – focus on key compliance risk areas respect in their work activities, obeying to undergo training on this policy. – improve compliance behavior through applicable laws and regulations, and training and support adhering to Idorsia policies and procedures. Labor & Human Rights – ensure that employees can raise concerns Idorsia is committed to a work environment Idorsia respects the rights of its employees and that these are properly addressed that encourages honest discussion of issues as set out in the Universal Declaration of – ensure fair and objective investigations of and concerns about legal compliance, Human Rights, and we fully comply with potential policy breaches company policy, and business conduct. all relevant laws, rules and regulations Employees who learn of, or suspect, a legal, governing labor, employment and the An example of best practice in governance ethical or policy violation must raise it with employment relationship in all the countries Contents is our Code of Business Conduct, which their supervisor, the Corporate Compliance where we operate. navigation underpins our commitment to integrity and Office, or through the Global Compliance Contents sets out fundamental rules for interacting Helpline. Idorsia does not permit sanctions We respect the right of all employees to join with others as we drive our business against anyone who, in good faith, raises a legally recognized employee association, Idorsia – Reaching out forward. Supporting policies, standard issues, concerns or allegations of compliance and we comply with all laws relating to for more operating procedures and guidelines violations or unethical conduct. Idorsia will employee representation. We strive to provide more detail on how our high-level investigate all allegations of misconduct maintain an open dialogue with all our Our Research & commitments are to be applied in practice. and, where appropriate, take disciplinary employees and their representatives. Development and corrective action, up to and including Our All Idorsia employees have undergone termination of employment. People mandatory training to ensure compliance > Our with the Code. Responsibilities
92 Due to the nature of our business and the and tolerability profile of products and, Clinical Trials Transparency location of our operations, the risk of child once approved for use, the products will Clinical trials are essential to the or forced labor is minimal. We do, however, continuously be monitored through the development of innovative medicines. We remain vigilant for unexpected issues that use of post-marketing surveillance and are committed to the highest standards may arise – not only in our own operations spontaneous reports from prescribers and of quality and ethical conduct in all our but also in relation to our procurement patients. It is the responsibility of all Idorsia clinical research. Our trials are performed practices. employees to promptly report any adverse in accordance with internationally accepted drug experiences that they become aware guidelines, and protocols are evaluated Privacy & Data Security of that could be associated with an Idorsia by independent review boards and ethics Idorsia understands the importance of product to the company’s Global Drug Safety committees prior to study initiation. We protecting personal information and Department. are also dedicated to improving public applying the highest ethical and regulatory health through responsible clinical trial standards. We are committed to respecting Idorsia is also committed to quality in the data transparency which – while complying our stakeholders’ privacy and safeguarding manufacturing, packaging and testing of its with applicable regulations – respects their personal information. Idorsia’s data products. To ensure patient safety, it strives our proprietary information and patients’ protection policy covers all personal data on to meet or exceed applicable regulatory privacy. study participants, healthcare professionals, authority requirements for current Good customers, suppliers and employees. Manufacturing, Clinical and Laboratory Practices (cGXPs). Idorsia is required to To ensure the integrity and privacy of compile and maintain numerous records and personal and health-related information to file reports and applications with various provided to us, we use state-of-the-art government agencies. Idorsia requires that information security programs, focusing all employees who prepare information, on protection of sensitive information and records or submissions for governmental detection of unauthorized access. agencies, or who otherwise deal with Contents such agencies, do so diligently, accurately, navigation Safety & quality of products completely and with absolute integrity. Contents Patient safety, through the optimal performance and quality of products, is Idorsia – Reaching out fundamental to our company’s mission. for more Idorsia takes seriously its commitment to ensure that our products have and maintain Our Research & an acceptable risk-benefit profile when used Development in accordance with the product labeling Our and good medical practice. The company People performs extensive and robust non-clinical > Our and clinical testing to identify the safety Responsibilities
93 With regard to access to medicines outside Refinement – Alleviate or minimize impacts Health, safety and the environment of a clinical study setting, Idorsia will use a to animals by reducing potentially painful or Idorsia recognizes that excellence in health set of criteria to determine whether access invasive procedures, whenever possible. and safety performance is integral to an to Idorsia’s Discretionary Compassionate Reduction – Use the absolute minimum efficient and successful business, particularly Use Program can be provided to the patient, number of animals required to obtain valid in the field of drug discovery. To this end, including available clinical data supporting results in each study. we have developed environmental, health an anticipated acceptable risk-benefit Replacement – Always look for alternative, and safety policies and procedures which profile for the proposed use, as well as non-animal-based research methods where employees are obliged to comply with. any potential implications for the overall possible. Employees must also attend required clinical development of the medicine training and perform their jobs in a manner and the possible supply of the requested The number of animals used in drug that promotes a safe and healthy workplace investigational drug. development has dropped dramatically over while also preserving and protecting the the past three decades as a result of industry environment. This has never been more Research ethics initiatives of this kind. Idorsia has a strong applicable than in 2020, as the company We strive to maintain the highest ethical, policy on the care, welfare and treatment of pursued its goals in the context of a global scientific and clinical standards in all our animals, and we conduct regular audits to pandemic. research activities, and to comply with all make sure that our expectations are being national and international standards. Idorsia met, whether the studies are conducted in- regularly reviews its research policies to house or outsourced. align them with its strategic objectives and with the evolving values and goals of In addition, we ensure that the use and care stakeholders. of all laboratory animals meets or exceeds relevant local, national and international Regulatory authorities around the world regulations. Our programs and facilities are require pharmaceutical companies to test subject to unannounced regulatory review Contents all new drugs before they are launched, and and inspections. For sponsored work at navigation there is no alternative to including some contract research organizations, our animal Contents animal testing as part of this process. This welfare oversight activities include regular is essential both for scientific reasons and on-site evaluations by our veterinary staff. Idorsia – Reaching out to safeguard the volunteers and patients Idorsia will never use great apes (gorillas, for more who take part in subsequent clinical trials. chimpanzees, orangutans and bonobos) in As a fundamental principle, we support the its research. Our Research & “three Rs” in relation to animal testing: Development
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94 Supply chain management Idorsia is committed to complying with all applicable laws and regulations in terms of managing our supply chain. In 2020, an internal audit was conducted by an external consultancy to review and assess supplier due diligence, bidding, selection and monitoring, as well as the vendor master data and supplier performance evaluation processes and controls. We are pleased to report that no significant issues were detected.
Transparent communication Idorsia’s goal is to be a company known for its open communication by proactively providing a regular flow of relevant information, thereby avoiding rumors, suspicion and mistrust resulting from concealment of information. Our communication is based on facts from evidence and confirmed data. We provide all information in a timely and consistent fashion and treat all stakeholders equally when considering their information needs. Contents Our goal is to provide simultaneous, navigation targeted dissemination of information and Contents news relating to Idorsia. Moreover, in 2020, we reached out to many representatives Idorsia – Reaching out of our stakeholder groups to better for more understand the topics that are important to them. More information on our approach Our Research & to non-financial, or environmental, social & Development governance (ESG) reporting follows. Our People
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95 More authentic – Culture of transparency
Idorsia aims to be open and transparent on the impact we have as a company on the environment, economy and society in general. We take our responsibility very seriously and seek dialogue with all our stakeholders to find out what really matters to them.
Increasingly, stakeholders are looking representatives from seven groups indicated beyond the financial performance of in bold below – chosen because of the high a company to its overall impact on the impact they have on our immediate business economy, environment and society in needs – to validate and prioritize the topics general. Idorsia takes a proactive approach that had been identified. in responding to these expectations. In 2020, we set out to develop a tailored sustainability reporting strategy and framework for Idorsia. Governments & Suppliers health authorities To lay the foundations for our sustainability Patients & Contents reporting – also known as non-financial Local communities navigation patient associations or environmental, social & governance Partners Contents (ESG) reporting – we conducted a so- Healthcare called materiality analysis and associated Employees Idorsia – stakeholder engagement activities. Investors professionals Reaching out (including management) & medical community for more & analysts To begin with, we prepared a comprehensive Our Research & list of both internal and external stakeholder Payors Media Development Industry associations groups that have an interest in Idorsia Our becoming a sustainable company, based Scientific & academic People Board of on our contribution to value creation. We community > Our also identified the “material” topics that will directors Responsibilities be key to our success. We then engaged
96 Risk management & business continuity Diversity & inclusion Compliance & business ethics Supply chain
Employee welfare & Environmental engagement impact
Partnerships Material Highest & scientific topics priority collaborations
Product Transparent Investment in innovation communications communities
Product safety & quality The materiality analysis, based on the We are working towards reporting in quantitative and qualitative assessment accordance with the Global Reporting of the stakeholder engagement process, Initiative (GRI) standards, beginning with the Access to revealed the priorities depicted above. Core option and becoming more robust, by medicines providing additional performance indicators Contents Idorsia takes a pragmatic approach to and setting ourselves targets as we grow. navigation sustainability reporting. We will report on all We may use additional standards – such Contents 12 topics that were identified as being key as those of the Sustainability Accounting to our sustainable future and of greatest Standards Board (SASB) – to support the Idorsia – Reaching out interest to our stakeholders. We want to reporting of sector-specific topics. for more meet the expectations of our stakeholders, providing the desired information in an For more information on Idorsia’s Our Research & engaging format. We will ensure that our commitment to stakeholders, our approach Development efforts and progress with the high-priority to corporate responsibility, and quantitative Our topics are described in greater detail, and data on Idorsia’s carbon emissions, water People the present report already provides greater usage and waste management, please visit > Our transparency on these topics. our website: Responsibilities www.idorsia.com/our-responsibilities
97 Our brand strategy
More ideas – Changing the world
Joyful colors, science-driven icons and Contents bold messages: this is the brand world of navigation Idorsia. Contents The core idea of the Idorsia brand is Idorsia – Reaching out “Reaching out for more”. It is perfectly for more expressed in the energetic, intelligent and creative corporate design, and in the unified Our Research & key messages. Development
Our The unique brand identity helped Idorsia People from day one to create impact in the market, Our attract gifted talents, and save costs in Responsibilities brand management.
98 “When Idorsia was founded in 2017, we wanted to create a pharma brand that the world had not yet seen.” Intelligent principle: all visuals are Jean-Paul Clozel derived from one Co-founder and CEO of Idorsia super-visual.
Joyful and scientific at once.
Drug Discovery & Clinical Development
Idorsia’s drug discovery focuses on novel molecular target families, implementing appropriate state-of-the-art technologies. In particular, the target families include G-protein coupled receptors (“GPCRs”), ion channels and certain enzymes. The drug discovery team facilitate the combination of drug discovery technology with human expertise and teamwork, in a single Reaching out research center based in Allschwil, Switzerland.
Drug Discovery Idorsia’s clinical development comprises steer the compounds from entry-into- and Clinical Development a broad spectrum of expertise clustered human studies through to submission of for more within multiple departments: therapy the dossier to health authorities, approval Development area units, strategic development, clinical and maintenance of the licence during Pipeline pharmacology, biostatistics and data the commercialization phase until loss of This is Idorsia Lucerastat management, drug safety, drug regulatory exclusivity of the medicine in the major affairs, clinical operations and life cycle markets and beyond. Idorsia’s clinical Aprocitentan management. Life cycle cross-functional development manages clinical programs ACT-541468 teams – under the leadership of a life cycle to the appropriate scientific, medical and (DORA) leader – bring expertise from preclinical operational standards to generate the development, clinical development and information required by health authorities Clazosentan technical operations to the efficient worldwide. Cenerimod development of new medicines. They
Other Compounds
1 Enabling both Robust design, endless variations and born digital. high recognition.
99 Be prepared for more
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