Takeda Pinpoints Four Infectious Diseases Under Vaccines Strategy

1 September 2017 No. 3869

Scripscrip.pharmamedtechbi.com Pharma intelligence | informa agile,” Dubin said. “There are now diseases that develop rapidly and being able to re- spond quickly to these threats is one of the challenges we developers currently face,” he said. Dubin is also the global program team lead for Takeda’s Zika vaccine program – which is yet to enter the clinic. He believes progress for this candidate will be rapid. “Even though we are still in preclinical development with our Zika vaccine, because of the program that we’ve designed, we ex- pect this vaccine to move very quickly once we initiate clinical development,” he said. Clinical studies for Takeda’s Zika vaccine will start before the end of 2017, Dubin noted. Meanwhile, Takeda is also exploring a vaccine program for norovirus, the most com- Shutterstock: Azad Pirayandeh Shutterstock: mon cause of acute gastroenteritis across all ages. “It’s actually a very interesting virus in that it is one of the few bugs that essentially Takeda Pinpoints Four Infectious affects every individual on earth,” Dubin said. Takeda has a vaccine candidate in Phase IIb development for norovirus. It was the Diseases Under Vaccines Strategy first company to launch a human trial for a LUCIE ELLIS [email protected] norovirus preventive treatment and it is currently running the first field efficacy trial for akeda Pharmaceutical Co. Ltd. has the Zika virus. “We’re not trying to tackle a norovirus product with an FDA investiga- been developing and producing every disease or a very broad range of dis- tional new drug designation. T vaccines for over 70 years but more eases,” he told Scrip, adding that the R&D Dubin highlighted the biggest challenge recently the company has formed a special- unit is currently focused on four key vac- of designing a clinical study for such an un- ized, global vaccine business unit with the cine programs. predictable virus: “There are frequent out- mission of developing novel vaccines to ad- Takeda’s vaccine unit is targeting Zika, breaks of norovirus that occur all over the dress global infectious disease threats. norovirus, dengue fever and polio. There are world. There is a bit of seasonality to it but A growing entity, Takeda’s vaccine busi- currently no approved vaccines for Zika or it’s difficult to predict where norovirus will ness is keen to use its “agility” and “flexibility” norovirus and Dubin hopes to see Takeda strike next.” to discovery new vaccines fast, according to lead the charge in these research areas. To address this issue, Takeda is running its senior vice president of the group’s global Based in Zurich, Dubin already has experi- Phase IIb proof-of-concept efficacy study medical office, Gary Dubin. ence of bringing a first-of-its-kind vaccine in a naval base in the US. Dubin added that Dubin, who spent 20 years at Glaxo- to market, having led development of GSK’s the military has a long-standing interest in SmithKline PLC before making a move globally used human papilloma virus inocu- norovirus because it is something that can sweep through military bases, disabling to Takeda in 2015, is preparing Takeda’s lation, Cervarix. large proportions of its troops. vaccine business to be able to react rap- “Takeda’s focus, coupled with the small idly to emerging global health threats like size of the vaccines unit, makes us pretty CONTINUED ON PAGE 9

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AZ Makes Fresh mRNA Move Market Intelligence Titans Of Pharma A €25m respiratory collab with German Lupus pipeline showing signs of A snapshot of the industry’s top biotech Ethris (p4) renewal following disappointments (p6) leaders and their businesses (p12) IN THIS ISSUE

from the editor [email protected]

Scrip took a look at the leadership of the industry’s big- maceuticals’ Leonard Schleifer received ($28.3m, down gest companies, and found out that the CEOs of the top from $47.5bn in 2015 reflecting a dip in the number of 15 firms received more than a quarter of a billion dol- options awarded as well as a larger decline in their value lars’ worth of overall compensation in 2016. It sounds as the company’s share price sagged). a lot, but a fair bit is in stock options, and it should be It is refreshing to see a woman join the ranks of the noted that those same firms reported nearly $100bn in titans for the first time, although it is too soon to know net income and had a combined market capitalization if Emma Walmsley’s compensation for leading GlaxoS- of around $2.2 trillion. mithKline will measure up to that of her male counter- In the broader context, no pharma executive came parts. Her predecessor, Sir Andrew Witty, was actually close to US cable company Charter Communications’ quite modest in his takings with just £6.8m last year. CEO Thomas Rutledge, who got $98.5m (although this To see more details on 10 of the leading companies’ was boosted by a five-year stock option award that won’t leaders, along with information on R&D heads, turn to be repeated before 2020). Nor did any of the top 15 p12-13, or visit our website to view the full 15 “Titans firms award their leaders as much as Regeneron Phar- of Pharma”.

LEADERSHIP ADVERTISING DESIGN Phil Jarvis, Mike Ward Christopher Keeling Paul Wilkinson SUBSCRIPTIONS DESIGN SUPERVISOR Scrip Daniel Frere Gayle Rembold Furbert

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2 | Scrip | 1 September 2017 © Informa UK Ltd 2017 AC Immune’s Novartis Making Pipeline Boost Optimistic Noises

UK Charity Studies 20 11 Lilly’s Inhibitor 16 21

exclusive online content inside: ALCYONE Paves Way For J&J/Genmab’s Darzalex COVER / Takeda Pinpoints Four Infectious Diseases Under In Frontline Myeloma Vaccines Strategy http://bit.ly/2vomjrJ 4 AZ Makes Fresh mRNA Move With Ethris Respiratory Pact Data supporting a role for J&J/Genmab’s anti-CD38 monoclonal antibody in newly diagnosed multiple myeloma are “as good 6 Inside The Lupus Pipeline: Reasons For Optimism as could be expected,” but the backbone regimen in the trial is rarely used in the US. 8 Lupus Nephritis May Be As Straightforward As Lupus R&D Gets Trial And Trial: Bracing For Commercialization Of Cell & Gene Therapies 9 Akari To Reboot Tick-Based Group’s Prospects http://bit.ly/2xGnPCd As novel cell and gene therapies edge closer to the US 10 Sanofi-Backed Voyager Therapeutics Hails Gene market, reimbursement for expensive, long-lasting treatments Therapy’s Arrival remains uncertain. AmerisourceBergen Senior VP-Strategy & Commercialization Amy Grogg predicts the first launches will 11 AC Immune Beefs Up Neurodegenerative Pipeline involve many different reimbursement models. 12 Infographic: Titans Of Pharma

Eisai Fortifies Play With India-Specific Priced Fycompa 14 The Price Is Right: Amgen Defends Repatha At $9,669 http://bit.ly/2vAMbg0 Against More Critics Eisai expects products like Fycompa and Lenvima, backed by innovative price planks pivoted around improving patient 16 UK Charity Starts Early-Stage Clinical Studies Of Lilly’s access, to intensify growth in India. Fycompa now debuts at a Cdc7 Inhibitor sub-$1 per day pricing in India. 17 Topas Bags Big Pharma Partner With Lilly Pact China Investment Roundup: A Summer Of Cross-Border Transactions 17 Apellis Eyes Progress For Lead AMD Product http://bit.ly/2xJh0zQ 18 Quite A Range: Adamas Ponders $10,000-$30,000 It was a busy summer for Chinese pharmaceutical companies Price Tag For Gocovri and investors who went global shopping, eying mega acquisition deals since China announced plans to accept 19 Merck KGaA’s MS Drug Mavenclad May Defy Doubters overseas clinical trial data and global multicenter studies as part of its policies. 20 Samsung Looks Beyond Biosimilars Via Takeda Tie-Up

Pharma Calls On UK Govt To Fund Centers of Excellence 20 Destiny Advances First-In-Class Antibiotics http://bit.ly/2vo82eJ The Medicines Manufacturing Industry Partnership says £140m 21 Novartis Plays Access Card As Kisqali Gets EU Approval invested in four centers would provide high-skilled jobs and make the UK the first place in the world where drugs can be 22 Pipeline Watch discovered, made and packaged. 23 Novartis Starts ‘Complex’ Trial of Novel Malaria Therapy

Duzallo Approval Opens Gout Opportunity 23 Appointments For Ironwood http://bit.ly/2vA78rt Pricing for Duzallo, a fixed-dose combination ofZurampic (lesinurad) with generic allopurinol, will likely be on par with Zurampic’s solo price tag of $371 per month to smooth the way @PharmaScrip /scripintelligence with payers. /scripintelligence /scripintelligence

scrip.pharmamedtechbi.com 1 September 2017 | Scrip | 3 DEALS

CKD BiO - SERVICE AREA AZ Makes Fresh mRNA Move With Ethris Respiratory Pact CRO/CMO Specialist • Strain development from wild KEVIN GROGAN [email protected] type screening with broad spectrum of microorganisms straZeneca PLC is expanding its presence in the messenger due to chemical modifications in their building blocks”. Ethris Delivering the life-saving fermentation (Streptomyces, Fungi, RNA space through a collaboration with German biotech also notes that its SNIM RNAs can be administered repeatedly, technology into the world Bacteria, Yeast) AEthris GMBH that will focus on its core respiratory area. leading to sustained production of therapeutically active pro- The five-year deal will see the companies develop new stabi- teins within the body. • Novel process development & lized non-immunogenic modified (SNIM) RNA therapies for respi- Optimization to industrial scale ratory diseases using Ethris’ proprietary technology. The plan is RESPIRATORY KEY PLATFORM to find multiple new targets for investigation in asthma, chronic Given AstraZeneca’s travails in oncology, highlighted by the failure • Cost savings via most optimal obstructive pulmonary disease and idiopathic pulmonary fibrosis. of its PD-L1 inhibitor Imfinzi (durvalumab) in the high-profile Phase scaled operation Cashwise, Munich-based Ethris will receive €25m upfront plus III MYSTIC trial to hit the PFS endpoint in non-small cell lung cancer, research funding and is eligible for R&D milestones and royalties. the Ethris deal is a timely reminder that respiratory is a key platform • Analytical method AstraZeneca, through its R&D biologics unit MedImmune, will have in AstraZeneca’s long-term growth plans. Its blockbusters Symbicort development & Process the option to take exclusive worldwide licenses for each target cov- (budesonide/formoterol) and Pulmicort (budesonide) are still sell- validation ered within the collaboration. ing well despite being battered by generic competition but there is AstraZeneca is no stranger to mRNA, which involves deliver- pressure on the targeted late-stage asthma products benralizumab • Impurity characterization & ing genetic instructions to cells which drive the target cells to and tralokinumab to offset the patent losses. Stability studies produce selected proteins to help prevent or fight diseases, hav- The pressure increased in May when tralokinumab failed the Phase • Full support of RA documents ing been in partnership with Moderna Therapeutics LLC since III STRATOS 1 study in severe asthma patients inadequately controlled March 2013. Its original deal with the privately held US biotech, despite receiving inhaled corticosteroids plus a long-acting beta2- • Other customized services which focused on cardiovascular, metabolic and renal diseases agonist. However, AstraZeneca still has high hopes for the drug in as well as cancer and involved an upfront payment of $240m, a sub-population of patients with an elevated biomarker associated plus a potential extra $180m for the achievement of three tech- with increased IL-13 activity. CORE TECHNOLOGY nical milestones. Analysts believe benralizumab has a better chance of success. AND RESEARCH That pact was expanded in January 2016 to include two specific Datamonitor Healthcare’s PharmaVitae team forecasts that the in- immuno-oncology programmes and in August last year, AstraZen- terleukin-5 inhibitor will see greater uptake than other late-phase Fermentation & Synthesis Fermentation biologics for the treatment of asthma and it will generate revenues eca increased its stake in Moderna with a $140m investment. That • Classical mutation brought its holding in the latter to around 9%. (Also see “Biopharma of $2.4bn by 2025. They think benralizumab has a faster onset of for Intermediates/APIs/NCEs Unicorn Moderna Highlights Secretive Pipeline As Investors Await IPO” action compared to GlaxoSmithKline PLC’s Nucala (mepolizumab) • Genome shuffling Scrip, 16 Jan, 2017.) and Teva Pharmaceutical Industries Ltd.’s Cinqair (reslizumab), • Gene manipulation However, it seems that AstraZeneca believes that Ethris is the the two IL-5 biologics that reached the asthma market in late 2015 CAPABILITY best mRNA partner when it comes to respiratory. The latter’s and early 2016. • Omics technology • Fermentation: 1,500 m3 Fermentors (12 m3 to 100 m3) technology can be targeted to the lungs where it helps to re- Further down the respiratory pipeline, AstraZeneca recently • Filtration place, inhibit or augment proteins that are involved in causing entered into a deal with Pieris Pharmaceuticals Inc. to develop 3 or exacerbating respiratory disease, and it is hoped that mRNA- inhaled products based on the latter’s Anticalin technology. (Also • Synthesis: 26 m Reactors • Condensation 3 based therapeutics may also modify the course of the disease see “AstraZeneca Taps Pieris For Inhaled Asthma Anticalins” Scrip, 3 (plus 1 m Reactors for high potency APIs) • Chromatographic column or its symptoms. May, 2017.) 3 Bahija Jallal, executive vice president at MedImmune, noted in Published online 21 August 2017 • Probiotics: 6 m Fermentors a statement that “rapid advances over the last decade have made Probiotics mRNA a very promising tool for clinical application, and we are ex- • Development of health ADDITIONALLY cited to collaborate with Ethris, whose advanced platform is lead- functional microorganism ing in RNA delivery to the lung”. She added that the pact “comple- • Beyond international GMP standards ments our respiratory science focused on early intervention and • Culture optimization (Approvals of USFDA, AIFA, TGA, WHO, PMDA, etc) disease modification by adding novel ways to target disease mech- LET’S GET • Coating technique for anisms that cannot be addressed by other approaches currently in our pipeline.” • Commercial activity over 60 countries stabilization Most mRNA research has focused on vaccines and Ethris claims SOCIAL • Microbiome study that historically it has not been usable as a therapeutic agent be- • Strong collaboration with Multinational Companies cause when delivered into the body it activates the immune system We are tweeting, liking and sharing the latest Synthesis and is highly unstable. In addition, in order to be functional, mRNA industry news and insights from our global • High potency products must enter the target cells of interest by crossing the cell mem- team of editors and analysts, join us! Best qualified CRO & CMO Partner, CKD BiO Corporation brane, which requires a carrier system to transport it into them. with unique customized service 8, Chungjeong-ro, • Hydrogenation The German group, founded in 2009, says its technology can @PharmaScrip over 40 years Seodaemun-gu, Seoul, Korea deliver candidates which “overcome the innate instability and Tel: +82-2-2194-0515 • Catalytic reaction immunity of mRNA [as] they evade the innate immune system Fax: +82-2-2194-0585 • Crystallization Homepage: www.ckdbio.com E-mail: [email protected] • Chromatographic column 4 | Scrip | 1 September 2017 © Informa UK Ltd 2017 HEADLINE NEWS

CKD BiO - SERVICE AREA • Strain development from wild CRO/CMO Specialist type screening with broad spectrum of microorganisms Delivering the life-saving fermentation (Streptomyces, Fungi, technology into the world Bacteria, Yeast) • Novel process development & Optimization to industrial scale • Cost savings via most optimal scaled operation • Analytical method development & Process validation • Impurity characterization & Stability studies • Full support of RA documents • Other customized services

CORE TECHNOLOGY AND RESEARCH Fermentation & Synthesis Fermentation for Intermediates/APIs/NCEs • Classical mutation • Genome shuffling • Gene manipulation CAPABILITY • Omics technology • Fermentation: 1,500 m3 Fermentors (12 m3 to 100 m3) • Filtration 3 • Synthesis: 26 m Reactors • Condensation 3 (plus 1 m Reactors for high potency APIs) • Chromatographic column • Probiotics: 6 m3 Fermentors Probiotics • Development of health ADDITIONALLY functional microorganism • Beyond international GMP standards • Culture optimization (Approvals of USFDA, AIFA, TGA, WHO, PMDA, etc) • Coating technique for • Commercial activity over 60 countries stabilization • Strong collaboration with Multinational Companies • Microbiome study

Synthesis Best qualified CRO & CMO Partner, CKD BiO Corporation • High potency products with unique customized service 8, Chungjeong-ro, • Hydrogenation over 40 years Seodaemun-gu, Seoul, Korea Tel: +82-2-2194-0515 • Catalytic reaction Fax: +82-2-2194-0585 • Crystallization Homepage: www.ckdbio.com E-mail: [email protected] • Chromatographic column scrip.pharmamedtechbi.com 1 September 2017 | Scrip | 5 MARKET INTELLIGENCE

Inside The Lupus Pipeline: Reasons For Optimism JESSICA MERRILL [email protected]

he lupus drug development land- of patients with SLE and moderate efficacy hibits the survival of B cells including auto- scape is showing signs of renewal af- in clinical trials didn’t result in the blockbust- reactive B cells. Some drug makers are also T ter a string of disappointments, with er GSK had been hoping for. evaluating B-cell depleting strategies. several new drugs for systemic lupus ery- Benlysta even today remains a niche “For many years, these insights have been thematosus (SLE) and lupus nephritis (LN) product, though growing double digits building,” said GSK clinical development moving through mid-to-late stage develop- and GSK continues to invest behind it, in- leader Raj Punwaney. “It’s understanding all ment. Big pharmas like AstraZeneca PLC, cluding new trials in lupus nephritis, in pe- these areas, B-cells, T-cells, innate immunity Johnson & Johnson and Roche’s Genen- diatric patients and in combinations, as well that has started to come to fruition over the tech Inc., as well as smaller companies like as a recently launched new subcutaneous last decade or so, and I think that is certainly Aurinia Pharmaceuticals Inc. and Corbus formula. But given the prevalence of the why we have seen many different assets Pharmaceuticals Holdings Inc. are push- disease and the substantial unmet need in coming forward and being tested in the ing ahead in lupus, despite considerable lupus, many drug makers are enthusiastic clinic now.” challenges. about the opportunity. Experts insist it is a “From my perspective, this is the best blockbuster market opportunity. DEPLETING B-CELLS time ever for development of new thera- There are many subsets of lupus, but at Genentech is studying Gazyva (obinutu- pies for lupus,” Lupus Foundation of America the core of the disease is a hyperactive im- zumab), approved for chronic lymphocytic CEO Sandra Raymond said in an interview. “I mune system that attacks the body’s healthy leukemia and follicular lymphoma, for the would say that right now there is probably cells. SLE is a chronic disease that waxes and treatment of lupus nephritis in the Phase II over $1bn and closer to $2bn being spent wanes and can result in chronic fatigue, NOBILITY trial. Gazyva is a monoclonal an- in this field. My glass is half-full. I feel really joint pain, skin flushes or organ damage. LN tibody that targets the CD20 antigen ex- optimistic about the landscape for lupus is a more acute subset of lupus, when the pressed on the surface of B-lymphocytes. development.” disease targets the kidneys and can lead to Genentech already tested its first-genera- Other experts working in the field of kidney failure. There is also cutaneous lupus tion CD20 B-cell depleting therapy Rituxan lupus agree. “I’m amazed by how much in- erythematosus, a form of lupus that impacts (rituximab) in lupus, but announced disap- terest there is. There’s got to be probably 20 the skin. Many researchers working in the pointing results in 2009. to 30 drugs in development for lupus,” said field suspect lupus might be sub-segment- “We didn’t get the results we were hop- lupus specialist Richard Furie, chief of the di- ed even further as drug makers learn more ing for, but we did get a lot of learnings from vision of rheumatology at Northwell Health about the disease. that, and we’ve used that in developing our and an investigator in several lupus trials. new program with lupus nephritis and NO- Biomedtracker lists more than two dozen LEARNING FROM EXPERIENCE BILITY,” Siegel said. drugs in Phase II or Phase III development The heterogeneity of lupus has been one Obinutuzumab depletes B-cells in a dif- for systemic lupus erythematosus (SLE) and of the biggest challenges to drug develop- ferent way that could be more effective lupus nephritis (LN). ment. As Genentech’s Siegel explained it, at addressing the driver of disease activity, “I’m quite encouraged about the state of “We know in lupus there are a number of he said. “Obinutuzumab has been shown the field,” added Jeffrey Siegel, who as an different processes that drive disease activ- to deplete B-cells in tissues and not just FDAer helped develop the agency’s lupus ity. We know that B cells are important. We in peripheral blood. We understand from guidance document and now works at know that different cytokines are important experimental models that obinutuzumab Genentech as global head of rheumatol- and we know that certain cells are impor- depletes B-cells in lymph nodes, which is ogy and rare diseases and immunology tant, antibodies and cytokines. We don’t important in an immune response in lupus product development. know for sure which ones are on a critical and is one of the reasons we think obinu- Lupus has been almost an anomaly in path to driving disease activity.” tuzumab is particularly promising for lupus autoimmune disease, where the drug in- The challenge is figuring out the critical nephritis.” dustry has invested heavily over the last two processes that are driving disease activ- decades and where diseases like rheuma- ity and developing therapeutics to target ANIFROLUMAB IMPRESSES toid arthritis, psoriasis and ulcerative colitis them. Other drug companies are exploring differ- have seen dramatic improvements. Lupus, Some learnings from the development ent mechanisms of action. AstraZeneca is however, has seen little in the way of new and experience with Benlysta have helped one of the current leaders in the field, with therapeutics in the last 50 years. Glaxo- advance the field, and the same is true for a drug called anifrolumab currently in Phase SmithKline PLC’s Benlysta (belimumab) is some drugs that failed in clinical develop- III testing. Anifrolumab is a monoclonal an- the one exception. It was approved by the ment. Benlysta is a first-in-class BLyS-specific tibody against the type I interferon (IFN) FDA in 2011 with a lot of fanfare, given the inhibitor that blocks the binding of soluble receptor that inhibits the activity of all type high unmet medical need, but the FDA ap- BLyS, a B-cell survival factor, to its receptors I IFNs, which play a role in lupus. The posi- proval in a narrow indication in just a subset on B-cells. By binding to BLyS, Benlysta in- tive results of a Phase II trial testing anifro-

6 | Scrip | 1 September 2017 © Informa UK Ltd 2017 MARKET INTELLIGENCE

lumab in SLE were published in Arthritis and Phase I trial in lupus, and gained a poten- scale like the Safety of Estrogens in Lupus Rheumatology in November 2016, showing tial new lupus drug with the acquisition of Erythematosus National Assessment Sys- the study met its primary and secondary Actelion Pharmaceuticals Ltd. earlier this temic Lupus Erythematosus Disease Activ- endpoints with treatment with anifrolumab year, cenerimod, an S1P1 modulator. ity Index (SELENA-SLEDAI). The approval of resulting in significantly greater rates of im- “We have a number of early/mid/late Benlysta was based on two Phase III stud- provement across a broad range of com- compounds in development in immunol- ies that relied on a novel composite end- posite and organ-specific disease activity ogy that may have relevance to the lupus point that was not validated at the time, measures (SLE Responder Index 4), as well population,” J&J’s global therapeutic head- known as the SLE Responder Index-4 (SRI- as reduction in oral corticosteroid use, com- immunology Susan Dillon said. 4), which GSK and partner Human Ge- pared with placebo. Celgene Corp. believes SLE is an excel- nome Sciences Inc. developed with the “I’m truly very excited about their Phase II lent targeted market for its immunology support of the FDA, as a three-component results. I think the entire lupus key opinion and inflammation unit to invest in. The com- endpoint to capture clinically meaningful leader community was very excited,” Lupus pany is testing two different approaches changes in disease activity through assess- Foundation of America’s Raymond said. early in the clinic. ment of clinical manifestations, laboratory Furie, who was the principal investigator “In our case, we believe that we have now values, organ system effects and general in the Phase II trial, noted that “the Phase II identified a mechanism that may address health status. data were the best clinical trial data we’ve multiple disease pathways,” I&I president “There are limited regulatory precedents, ever seen in lupus, especially for patients Terrie Curran said. Celgene is testing CC-220 and the published guidance are very broad,” with rash.” in a Phase II dose-ranging study. It’s a novel J&J’s Dillon said. “Furthermore, the lupus Datamonitor Healthcare forecasts that oral immunomodulatory drug that binds to community only recently began to embrace anifrolumab will see the highest uptake of cereblon, which reduces levels of ikaros and some endpoints, like the SRI, that appear to new targeted therapies in the US and EU aiolos, two proteins implicated in the devel- perform reasonably in trials.” by 2022. opment and survival of the immune cells Plus, many patients who participate in AstraZeneca has initiated two Phase III that help cause inflammation in lupus. clinical trials are on strong background ther- trials, with enrollment already completed in Lupus patients have higher than normal apy, including antimalarial drugs, cortico- the first trial and the second one expected levels of ikaros and aiolos and Curran be- steroids and immunosupressants, including to be fully enrolled later this year. AstraZen- lieves that targeting the proteins associated Roche’s CellCept (mycophenolate), which eca is targeting a regulatory filing for anifro- with lupus, instead of the varying physical can influence clinical data. lumab in 2019. symptoms, offers the potential to transform As the clinical trial failures in lupus have “We modeled our Phase III trial very simi- the treatment paradigm. mounted, some in the community have larly to the Phase II trial,” Raj Tummala, the In January, Celgene announced the ac- begun to believe that the trend is the re- global clinical lead for anifrolumab told quisition of a company called Delinia, sult of flawed clinical trial design rather Scrip. “One of the key learnings that we Inc. for $300m upfront; the company spe- than efficacy. learned in Phase II was that site selection cialized in the development of targeted Some drug makers are now focusing on was really critical. You have to include sites regulatory T-cell (Treg) therapies to treat lupus nephritis rather than SLE, partly be- that really understand lupus, so we built that immune disorders without suppressing the cause of the critical unmet need, but also because the clinical trial design and end- into our Phase III program.” One of the big- immune system – and Celgene believes the points in the targeted, organ-specific subset gest differences in the Phase III trials is that lead drug candidate, DEL106, could work seems more clear cut. the primary endpoint is at one year, versus in lupus and other autoimmune diseases. six months with the Phase II study. DEL106 is a novel interleukin-2 (IL-2) mutein COMBINATIONS A POSSIBILITY In Phase II, AstraZeneca also narrowed Fc fusion protein designed to preferentially Some experts in the field are starting to down a subgroup of patients who were upregulate Tregs. think about combining novel targeted more likely to benefit from treatment, those agents to deliver a bigger efficacy punch to patients with an elevated IFN gene signa- CHALLENGING ENDPOINTS patients. GSK is already studying Benlysta in ture at baseline. The company incorporated Another issue for drug developers working combination with Rituxan in Phase III. the same subgroup into the Phase III trials in lupus is determining the best clinical trial “We are very motivated at GSK to try to and anifrolumab is being developed with an endpoints to study to show efficacy. advance the field of therapy for lupus and IFN gene signature test. “If you look at several different patients that’s really the motivation behind the com- “From what we understand, 75% to 80% with lupus, they present in completely dif- bination therapies,” Punwaney said. “We of lupus patients have type 1 IFN gene sig- ferent ways,” Genentech’s Siegel said. “One don’t want to just make patients feel im- nature that is high,” Tummala said. patient may present with skin problems and proved, but help them feel well again.” Johnson & Johnson is taking yet another joint problems, another with kidney prob- Published online 18 August 2017 approach, studying its currently marketed lems and joint abnormalities.” Stelara (ustekinumab), approved for plaque “Figuring out ways to study drugs to see View Select Drugs In Mid-Stage Clinical psoriasis, psoriatic arthritis and Crohn’s dis- if they have benefits for all manifestations Development For SLE And LN here: ease, in a Phase II trial for SLE. The company of lupus has been quite complicated,” he http://bit.ly/2wZVY2O is also exploring an interferon in an early said. Trials typically rely on a composite scrip.pharmamedtechbi.com 1 September 2017 | Scrip | 7 MARKET INTELLIGENCE

Lupus Nephritis May Be As Straightforward As Lupus R&D Gets JESSICA MERRILL [email protected]

argeting lupus nephritis could be a more straightforward IIb study, showing the drug improved complete renal response rate for path to market for new lupus drugs – or at least that is what patients with lupus nephritis relative to the comparator at 48 weeks. T some drug makers are hoping. Lupus nephritis affects a In May, Aurinia initiated a confirmatory Phase III trial, AURORA, that smaller subset of patients than the more common systemic lupus will similarly compare voclosporin to placebo when added to current erythematosus (SLE) and it could have some advantages when it standard of care with CellCept and corticosteroids, at 52 weeks. The comes to drug development: diagnosis is done by a test, the clini- company expects results sometime in 2019. cal endpoints are well defined, the condition can be life-threatening, Gazyva, meanwhile, is a monoclonal antibody that targets the and there are no approved treatments. CD20 antigen expressed on the surface of B-lymphocytes. Genen- Given the high hurdle to developing new drugs for lupus and the tech already tested its first-generation CD20 B-cell depleting therapy high rate of clinical trial failures in the field, some drug makers like Rituxan (rituximab) in lupus, but announced disappointing results in Aurinia Pharmaceuticals Inc. and Roche’s Genentech Inc. are hop- 2009. Obinutuzumab depletes B-cells in tissue as well as in peripheral ing that by targeting lupus nephritis, they will have better success. blood, which could make it more effective at addressing the driver of The drug industry is investing substantially in drug development disease activity, he said. across the lupus spectrum, with several drugs now moving through “For lupus nephritis, there are not that many variations on a trial mid- to late-stage development. Advancements in the understand- design,” Northwell’s Furie said. “We have metrics for measuring out- ing of the autoimmune disease, the unmet need and the multi-bil- comes in lupus nephritis.” Furie is leading Genentech’s Phase II trial of lion commercial opportunity are all driving investment. obinutuzumab, called NOBILITY. “I list lupus nephritis as the number one unmet need,” said lupus “It’s basically lab tests, proteinuria, blood creatinine, which is a specialist Richard Furie, chief of the division of rheumatology at measure of kidney function,” he added. But that doesn’t mean the Northwell Health and an investigator in several lupus trials. SLE is an area isn’t without its challenges. “In a way, it’s straightforward. The autoimmune condition in which a hyperactive immune system at- problem is there are confounding background medicines.” tacks the body’s healthy tissues. It manifests in many ways, targeting Genentech hopes to ease the issue of concomitant medicines in the skin, joints and organs. Lupus nephritis happens when the im- NOBILITY by permitting lower concomitant doses of corticosteroids mune system targets the kidneys, which can lead to kidney failure, and mycophenolate mofetil, though levels that are still consistent dialysis or transplantation. with current treatment guidelines, Siegel added. There is some discrepancy over the prevalence of lupus in the US, Lupus Foundation of America CEO Sandra Raymond agreed the which some experts say is hundreds of thousands of patients while background medications can confound trial results. “We’ve got peo- the Lupus Foundation of America puts much higher at 1.5m. Aurinia ple on strong background medications in trials where it is very dif- believes about 500,000 people in the US have SLE, and as many as ficult to see the difference between the investigational medication 60% of them have clinical lupus nephritis requiring treatment. and the background medication they are on,” she said. In the Aurinia Phase IIb clinical trial, the primary endpoint was A SERIOUS CONDITION WITH TANGIBLE EFFECTS complete response based on a composite endpoint including: con- Aurinia chief medical officer Neil Solomons said the serious nature of firmed urine protein/creatinine ratio (UPCR) of less than or equal to lupus nephritis is important because it is so tangible. 0.5 mg/mg; normal, stable renal function, presence of sustained, low “Patients understand it. It’s also considered a very severe manifes- dose steroids; and no administration of rescue medications. tation of lupus,” he said. “Often the very thing they are worried about Healthy individuals usually excrete very small amounts of protein is lupus nephritis. They can tolerate the fatigue, but the kidney in- in the urine, while increased protein excretion is usually a sign of kid- flammation is going to send them to the hospital.” ney damage. Genentech’s global head of rheumatology, rare diseases and im- Confirming the right patients are enrolled in clinical trials for lupus munology product development Jeffrey Siegel said, “We think lupus nephritis is also more straightforward than trials for SLE because di- nephritis is an area of particular unmet medical need. With current agnosis is confirmed with a biopsy. treatment, there is a lot of toxicity.” “From our perspective as drug developers, lupus nephritis is easy There are no approved treatments for lupus nephritis, but standard to diagnose,” said Auinia’s Solomon. “That doesn’t mean it is common of care is typically intense immuno-suppressants, namely Roche’s or really obvious. It means the diagnoses of lupus nephritis has been CellCept (mycophenolate mofetil) and corticosteroids. well described. You have to have lupus, but you also have to have a Aurinia’s voclosporin in Phase III and Genentech’s Gazyva (obinutu- kidney biopsy. There’s no similar diagnostic test for lupus of the joints.” zumab) in Phase II are two of the most advanced drugs in develop- All of this is not to say there aren’t significant challenges to devel- ment for lupus nephritis. Voclosporin is a novel calcineurin inhibitor that oping new drugs for lupus nephritis, but the focus could pay off and blocks interleukin-2 and T-cell mediated immune responses. Voclospo- enhance the understanding of lupus more broadly. rin is getting some attention after the drug performed well in a Phase Published online 22 August 2017

8 | Scrip | 1 September 2017 © Informa UK Ltd 2017 HEADLINE NEWS/CEO APPOINTMENT

CONTINUED FROM COVER the goal of producing at least 50 million “It is difficult to design these studies, to doses a year for a period of five years. “We Akari To Reboot some extent you’re at the mercy of the fickle think this will make major inroads into ad- Tick-Based epidemiology,” he said. Takeda will await the dressing the shortage of inactivated polio results of its Phase IIb field efficacy trial be- vaccine and really help the polio eradica- Group’s Prospects fore determining the next steps for its noro- tion endgame,” he said. virus vaccine. In dengue fever, Takeda is developing a Akari Therapeutics PLC has hired David Horn Solomon, the former Takeda’s vaccines unit is focused on CEO of Denmark-based Zealand protective agents against zika, dengue fever, Pharma AS, and given him the chal- polio and norovirus lenge of restoring investor trust in the NASDAQ-listed biotech while also designing how to best progress its drug pipeline of tick-derived molecules. Solomon – who as CEO of Zealand oversaw the development of lixisena- tide which is now commercialized by Sanofi as Lyxumia/Adlyxin – will take on his new role based in New York City from Aug. 28. Solomon had also been the CEO of Bionor Pharma ASA and until his appointment at Akari was the managing partner of Sund Capital, a Nordic healthcare Shutterstock: CNK02 Shutterstock: investment fund. Akari’s lead molecule is Coversin, a ‘One of the critical steps in the eradication of polio recombinant small protein (16,740 Da) derived from a native protein discov- is going to involve the transition from live oral polio ered in the saliva of the Ornithodoros moubata tick. The protein modulates vaccine to inactivated polio vaccine’ the host immune system to allow the parasite to feed without alerting the host to its presence or triggering an UNMET NEEDS IN POLIO vaccine it hopes can be used in younger immune response. Coversin is current- & DENGUE patients than the current option on the ly in ongoing Phase II trialing in the Takeda’s other two disease targets – dengue market. Sanofi’s world-first dengue vac- rare blood disease paroxysmal noctur- fever and polio – do have available vaccine cine, Dengvaxia, is currently approved for nal hemoglobinuria (PNH). treatments, but the company believes it can use in people aged nine and over. Takeda In an interview with Scrip in fill gaps in these markets with its candidates. hopes its vaccine candidate will be indi- February, Akari’s former CEO Gur In polio, the vaccine unit is developing an cated for use in those as young as four. Roshwalb explained the science inactivated inoculation – a program that is The company recently completed enroll- behind Coversin and its use of the being funded via a grant from the Bill and ment for a Phase III pivotal trial that in- human immune system’s comple- Melinda Gates Foundation. “Efforts to eradi- cludes children between the ages of four ment system, and why, if successful, cate polio have evolved over many, many and sixteen. Dubin also noted that in ear- the second-generation complement years and to-date we still have not eradi- lier-stage trials, Takeda’s dengue vaccine inhibitor would compete with Alex- cated the disease, although we are getting has shown a balanced response across ion Pharmaceuticals Inc.’s very ex- closer and closer to this goal,” Dubin noted. the four dengue serotypes. pensive Soliris (eculizumab), current- “One of the critical steps in the eradication He believes dengue will be Takeda’s ly the only approved complement C5 of polio is going to involve the transition most important vaccine in the com- inhibitor. But Roshwalb was forced from live oral polio vaccine to inactivated ing months, as the company progresses to resign three months later after polio vaccine.” through late-stage development. “There is an internal review was conducted Dubin highlighted that there was a a large burden of dengue disease in chil- amid controversy and litigation global shortage of inactivated polio vac- dren below the age of nine, so we think launched by Akari shareholders, a cines. Takeda is working with the Gates population is going to be a very important storm that also pulled down the target for our program.” Foundation and other public health agen- biotech’s share price. Published online 23 August 2017 cies to develop this vaccine quickly, with [email protected] 22 Aug 2017 scrip.pharmamedtechbi.com 1 September 2017 | Scrip | 9 EMERGING COMPANY PROFILE

Sanofi-Backed Voyager Therapeutics Hails Gene Therapy’s Arrival LUBNA AHMED [email protected]

fter many starts and stops, US-based neurotransmitter drop, motor symptoms, the FDA,” Paul said. “In the event we should Voyager Therapeutics Inc.’s CEO such as tremors, slow movement or loss of learn something in the Phase II study, that will ASteven Paul believes gene therapy movement and rigidity, increase. Parkinson’s readout before the Phase III is locked meaning is finally here. patients have reduced levels of the en- we can change the endpoint based on what With a focus on neurological diseases zyme, aromatic L-amino acid decarboxylase we learn, avoiding the risk of starting over.” and an ongoing collaboration with Sanofi’s (AADC), that converts precursor levodopa Voyager is not the only gene therapy Genzyme Corp., Voyager is a gene therapy into dopamine. company hoping to get a ‘one-shot’ gene company developing therapies for Parkin- Voyager’s lead product VY-AADCO1, cur- therapy approved, Oxford BioMedica son’s disease, a monogenic form of amyo- rently in Phase Ib and one of the programs PLC is using its LentiVector delivery system trophic lateral sclerosis (ALS), Huntington’s Sanofi has opt-in rights to and is heavily in- to produce not one, but three enzymes, disease, Friedreich’s ataxia, frontotemporal volved with, uses the AAV-2 capsid delivery including AADC and another that makes dementia, Alzheimer’s disease and severe, system and a cytomegalovirus promoter to levodopa, to increase dopamine levels and chronic pain. Its furthest-developed pro- encourage the expression of AADC. Paul reverse symptoms. gram is VY-AADC01 for Parkinson’s in Phase emphasized that this is set to be a ‘one-time’ Paul described this system as a “more Ib, for which data are expected shortly. treatment, will be surgically administered challenging strategy” and one that could be Voyager was founded in 2014 and over and has the potential of enhancing the con- difficult to regulate. “You’d want to reduce the years stacked up $285m, with cash from version of levodopa to dopamine, thereby the possibility of overreaction and overstim- Series A and Series B private-round invest- improving symptoms. ulation of the dopamine receptors,” he said, ments (totaling $105m) in 2014 and 2015, In Dec. 2016, Voyager announced positive and Voyager’s technology is built in a way the collaboration with Genzyme ($100m up interim results from the Phase Ib trial. Paul that the level of levodopa, the substrate for front in cash and equity) and the completion explained that the study has three cohorts AADC, can be regulated just by controlling of an $80m IPO in 2015. The company hopes in this trial, with the dosage increasing in the oral dose of levodopa. to advance not only the Parkinson’s program each and so far, they have observed im- into Phase II early next year, but another of its provement in motor symptoms in the first OTHER PROGRAMS programs into the clinic by 2018/2019. two cohorts. He added that it is their aim to In addition to its Parkinson’s program, Voy- Like many gene therapy companies, Voy- reduce the patients’ need to take high doses ager also has various other products in pre- ager is using adeno-associated virus (AAV) of levodopa, something that was also ob- clinical development, including VY-S0D101 as a delivery vehicle. Late last year, Voyager served in the study so far. for monogenic ALS, VY-HTT01 for Hunting- obtained a co-exclusive license to California “By giving this gene that allows the brain ton’s disease, VY-FXN01 for Friedreich’s ataxia, Institute of Technology (Caltech)’s AAV cap- region to start producing dopamine again, VY-TAU01 for frontotemporal dementia/Al- sids technology, which has demonstrated one of the goals is to get the dose of the zheimer’s disease and VY-NAV01 for pain. Al- enhanced crossing of the blood brain bar- levadopa down and in cohort two, it went though Voyager is handling the main aspects rier, a feature that can improve central ner- down by 35%.” of these programs, Sanofi may opt-in to the vous system diseases drug delivery. With cohort three a higher dose of gene Huntington’s and Friedreich’s programs. Paul says problems with the safety and ef- therapy, the company is hoping for even These diseases are caused by muta- ficacy of vectors have been why the gene better results to announce by the end of tions that enhance the activity of a protein therapy field has taken so long to bear fruit. September. (known as gain of function) that can be Advances here, and in the understanding of Voyager plans to start a pivotal registra- toxic and Voyager aims to use its one-time the genetic underpinnings of certain diseases, tion trial at the end of this year and Paul ex- therapy to silence them. Treatments for mean that the field is now making headway. plained that they will be structuring the trial these diseases differ from the Parkinson’s “It looks like gene therapy is finally here in an “interesting way”. The company expects therapy in that they are made up of the AAV and we want to be a big part of that,” Paul to start dosing patients for a ‘small’ Phase II and a transgene with a micro-RNA (miRNA) said. “It is a whole new genre of medicine.” study early next year and will measure the that selectively silences or knocks down the relevant biomarkers before and after admin- offending gene. PARKINSON’S PROGRESS istration of the gene therapy. If this brings Voyager is open to partnerships, particu- Currently there are no approved therapies positive results, Voyager will file a BLA sub- larly with those companies that have the that can reverse the progression of Parkin- mission for approval, based on that trial, with right scientific capabilities and an interest son’s disease, which is characterized by a the following Phase III a confirmatory study. in CNS drug development, especially in Al- loss of neurons in the brain that produce the “We believe we only need one good trial to zheimer’s disease, Paul said. neurotransmitter dopamine. As levels of this get this therapy approved by the regulators, Published online 22 August 2017

10 | Scrip | 1 September 2017 © Informa UK Ltd 2017 NEUROLOGY

AC Immune Beefs Up Neurodegenerative Pipeline JOHN DAVIS [email protected]

Even Eli Lilly & Co., which was dismayed by the failure of solan- ezumab in Phase III studies, has more recently reported the start of Phase I studies with a new antibody selective for amyloid beta-42, MEDI1814, in collaboration with its partner AstraZeneca PLC. The new antibodies made by AC Immune are targeted against alpha-synuclein, a well-established target in Parkinson’s disease and other Lewy body diseases, and against TDP-43 (TAR DNA binding protein 43), a recently identified target of interest in neuro-orphan indications such as frontotemporal lobar degeneration. The antibodies bind to the pathological forms of alpha-synuclein and TDP-43, and as these targets may also play a role in other neurodegenerative diseases like Alzheimer’s disease, the antibodies may be useful in those diseases too.

A THREE-PILLAR STRATEGY AC Immune is pursuing what it is calling a three-pillar strategy. “We have Alzheimer’s disease as one major pillar, the next is neurodegen- Shutterstock: vectorfusionart Shutterstock: eration and neuro-orphan indications, and the third is diagnostics,” Pfeifer noted. Diagnostic products in particular are considered key for ntibodies targeted against pathological processes in one future growth of the company: “they enable clinical trials in the other neurodegenerative disease might be effective in other dis- two pillars, and are a means of creating revenues in partnerships Aeases, including Alzheimer’s, according to the Swiss biotech with other companies.” AC Immune is collaborating with Genentech AC Immune SA which is beefing up its early discovery pipeline with Inc. (Roche) which is conducting two Phase III studies (CREAD1 and such “next-generation” antibodies. CREAD2) with the Swiss company’s Abeta antibody, crenezumab, in AC Immune uses a proprietary technology, SupraAntigen, that dis- patients with prodromal or mild Alzheimer’s disease, with CREAD1 plays antigens on the surface of liposomes and is thought to be ideal expected to read out in 2020. for producing antibodies for the treatment of diseases like those of the CNS caused by pathological proteins that differ only slightly from The antibodies bind to the healthy proteins, i.e., they have different shapes or are not folded in the correct manner. pathological forms of alpha- “We can quickly identify molecules that are directing the disease state. I am hoping the molecules will have the disease-modifying synuclein and TDP-43 properties we are looking for,” said Andrea Pfeifer, CEO of the Laus- anne, Switzerland-based company, which completed an IPO on US Since the IPO, AC Immune has reported encouraging data on a po- NASDAQ just over a year ago. (Also see “IPO Update: Novan, AC Im- tential anti-Abeta therapeutic vaccine, ACI-24, that is in early clinical mune End Summer Slowdown As Market Improves” Scrip, 29 Sep, 2016.) studies. And next year AC Immune expects to have interim Phase Ib Pfeifer is not downhearted by other companies’ failed investi- data on the use of ACI-24 for addressing Alzheimer’s in people with gational products in neurodegeneration, saying she is “absolutely Down’s syndrome who have a higher risk of developing the disease. convinced we will be seeing some positive data coming out of this Also in early clinical studies is ACI-35, an anti-pTau therapeutic vac- research.” The European company executive is not alone in having cine for Alzheimer’s disease being developed in collaboration with that conviction: pharma companies like Biogen and Roche are also Janssen Biotech NV, and an anti-Tau antibody, R07107505, for Al- continuing to pursue research into antibodies and other molecules zheimer’s disease in development with Genentech, with the later in Alzheimer’s disease (Also see “Alzheimer’s Update: Amyloid Hypoth- expected to enter Phase II studies in the coming months. esis Lives On At Biogen, Lilly, Merck, Pfizer, Roche” Scrip, 11 Dec, 2016.). Published online 25 August 2017

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scrip.pharmamedtechbi.com 1 September 2017 | Scrip | 11 INFOGRAPHIC

TITANS OF PHARMA A snapshot of the industry’s top leaders and the businesses they oversee

Johnson Gilead & Johnson Pfizer Merck & Co Sciences AbbVie Roche Novartis Sanofi GlaxoSmithKline AstraZeneca US US US US US Switzerland Switzerland France UK UK

Alex Ian Kenneth John Richard Severin Joseph Olivier Emma Pascal CEO Gorsky Read Frazier Milligan Gonzalez Schwan Jimenez Brandicourt Walmsley Soriot

Appointed To Role In 2012 2010 2011 2016 2013 2008 2010 2015 2017 2012 (at company inception) Previous Position Chair, Pfizer SVP, Group President, President and COO, Head of CEO, Division Head, CEO, CEO, COO, Roche J&J Medical Devices President, Worldwide Merck & Co, Inc Gilead Sciences Pharmaceutical Roche Diagnostics Novartis Bayer Healthcare GSK Consumer Pharmaceuticals Biopharmaceuticals Products Pharmaceuticals Healthcare Group at Abbott Laboratories Background Began career as sales Career spent at Legal: joined Merck Joined Gilead in Spent 30 years Economics, Law Bachelor’s degree Physician by Before joining Formerly CEO rep at Janssen Pfizer, joined as in 1992 as general 1990 as research at Abbott. degrees, joined in economics training, had GSK in 2010 was of Genentech, Pharmaceutical, J&J. an auditor. Has counsel. scientist. Studied Roche as trainee then MBA; prior to leadership roles with L’Oréal for 17 doctor of veterinary Defected to Novartis chemical engineering biochemistry. in corporate Novartis had senior at Pfizer before years in marketing medicine and as head of pharma for and accounting finance in 1993. leadership roles at Bayer. and general MBA holder. North America 2004- qualifications. HJ Heinz Co. management. 2008 before returning.

2016 Compensation1 $26.9m $17.3m $21.8m $13.9m $21.0m CHF11.6m CHF12.0m EUR9.7m n/a3 £9.8m (+12.9%) (-3.7%) (-10.0%) (+68.4%)2 (+0.8%) (-2.6%) (+3.4%) (-42.3%) (+22.6%)

2016 Company Sales $71.9bn $52.8bn $39.8bn $30.4bn $25.6bn CHF52.6bn $48.5bn EUR33.8bn £27.9bn $23.0bn

2016 Company Net Profit $16.5bn $7.2bn $5.7bn $13.5bn $6.0bn CHF9.7bn $6.7bn EUR4.5bn £1.1bn $3.5bn

Market Cap (June 30, 2017) $355.9bn $200.5bn $175.6bn $92.5bn $115.4bn CHF206.7bn CHF207.3bn EUR105.6bn £80.4bn £65.0bn

Paul Mikael Roger Norbert Michael n/a Vasant Elias Patrick n/a R&D Head Stoffels Dolsten Perlmutter Bischofberger Severino no single R&D chief Narasimhan Zerhouni Vallance no single R&D chief Appointed To Role In 2009 2010 2013 2007 2014 n/a 2016 2011 2012 n/a Previous Position Worldwide Chairman, Head of Wyeth Head of R&D, Amgen EVP, R&D, Gilead SVP, Global n/a Global Head of Scientific Advisor SVP, Medicines n/a Pharmaceuticals R&D, previously at Development and Development, to CEO Christopher Discovery and (J&J) Boehringer Ingelheim Corporate Chief Novartis Viehbacher Development, GSK and AstraZeneca Medical Officer, Pharmaceuticals Amgen

$12.7m $8.2m $7.1m $6.2m $7.2m CHF3.6m £0.78m 1 n/a n/a n/a 2016 Compensation (+18.0%) (+35.8%) (-14.5%) (-11.3%) (+9.7%) (from Feb 2016) base salary

1 base salary, bonus & long-term incentives (including equity awards), 2 assumed CEO position Mar. 10, 2016 3 Overall 2017 package will be c.25% less than the £6.8m received by Sir Andrew Witty in 2016

12 | Scrip | 1 September 2017 © Informa UK Ltd 2017 INFOGRAPHIC