Rare Diseases Whitepaper

Home , Sarepta Therapeutics, Vertex Pharmaceuticals

Future Treatment Approaches for Rare Congenital and Genetic Diseases

WHITEPAPER Author: Anna Osborne Principal Consultant, Informa Pharma Custom Intelligence

Introduction

Many biotech and pharmaceuticals companies more, regulatory and legislative initiatives such as have prioritized drug development for rare Breakthrough Therapy designation, which makes congenital and genetic diseases over the past it easier to work with the FDA on tailored trial few years given the high unmet need, rapidly designs, and the Orphan Drug Act, which provides advancing science, and favorable clinical seven years of regulatory exclusivity, have development paths. Rare congenital and encouraged development in this space. genetic diseases often have severe or even fatal manifestations, with few treatments available, In this whitepaper, we review the current market but emerging genetic data and new treatment landscape for rare congenital and genetic diseases modalities, such as gene therapy, are rendering and look forward to what treatment approaches monogenic diseases more tractable. What’s might be available soon.

2 / August 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) Approved therapies for rare congenital and genetic diseases

The focus of this analysis is limited to diseases by GARD, and emphasizes the huge unmet need that are classified as rare congenital and genetic that exists. Diseases with the largest number of diseases by the National Center for Advancing approved therapies include dwarfism, Lennox- Translational Sciences’ (part of the NIH) Genetic Gastaut syndrome, and cystic fibrosis (Figure 1). and Rare Diseases Information Center (GARD)1. However, even for these diseases the number According to Informa’s Pharmaprojects, only of approved therapies is very small compared 74 rare congenital or genetic diseases have an to more prevalent conditions, and the need for approved therapy. This accounts for less than 3% improved standards-of-care still remains. of all rare congenital and genetic diseases listed

Figure 1. Top 30 Rare Congenital and Genetic Diseases by Number of Approved Drugs

Dwarfism 10 Lennox-Gastaut syndrome 10 Cystic fibrosis 9 Antithrombin III deficiency 8 Gaucher's disease 8 Turner's syndrome 8 Blepharospasm 7 Wiskott-Aldrich syndrome 7 Alpha-1 antitrypsin deficiency emphysema 6 Homozygous familial hypercholesterolaemia 6 Sickle cell anaemia 5 Duchenne's muscular dystrophy 5 Fabry's disease 5 Wilson's disease 5 X-linked agammaglobulinaemia 5 Congenital fibrinogen deficiency 4 Infantile spasm 4 Prader-Willi Syndrome 4 Adenosine deaminase deficiency 3 Addison's disease 3 Primary congenital adrenal insufficiency 3 Transthyretin-related hereditary amyloidosis 3 Dravet syndrome 3 Familial cold autoinflammatory syndrome 3 Ichthyosis 3 Muckle-Wells syndrome 3 Neonatal onset multisystem inflammatory disease 3 Palmoplantar pustulosis 3 Paroxysmal nocturnal haemoglobinuria 3 Polycythaemia vera 3

0 2 4 6 8 10 12 Drug Count

Source: Pharmaprojects®, July 2020

1. NIH GARD (2020) Congenital and genetic diseases. Available from: https://rarediseases.info.nih.gov/diseases/diseases-by-category/5/ congenital-and-genetic-diseases [Accessed 10 July 2020].

Pipeline activity for rare congenital and genetic increasingly developers are also looking to diseases has increased considerably in the address unmet need in much rarer indications. past few years, and there are now many more For instance, the extremely rare indications products in development. Specifically, there are 27 primary hyperoxaluria type 1 and Hutchinson- rare congenital and genetic diseases with at least Gilford progeria syndrome both have products 10 products in active development, and a further in late-stage development. Small molecules 153 diseases have at least one product in active still dominate the pipeline, but more advanced development (Figure 2). Perhaps unsurprisingly, modalities such as gene therapies, cell therapies, the most prevalent conditions have the greatest and RNAi are increasingly being trialed. number of drugs in active development, but

Figure 2. Top 30 Rare Congenital and Genetic Diseases by Number of Drugs in Development

Cystic fibrosis 109 Duchenne's muscular dystrophy 79 Huntington's disease 73 Sickle cell anaemia 62 Retinitis pigmentosa 51 Haemophilia A 50 Haemophilia B 30 Paroxysmal nocturnal haemoglobinuria 24 Friedreich's Ataxia 20 Multiple system atrophy 20 Spinocerebellar ataxia 20 Dravet syndrome 18 Mucopolysaccharidosis I 17 Fragile X syndrome 16 Rett Syndrome 16 Charcot-Marie-Tooth disease 15 Hyperoxaluria 15 Spinal muscular atrophy 15 Prader-Willi syndrome 15 Usher syndrome 15 Gaucher's disease 14 Niemann-Pick disease 14 Angelman syndrome 13 Fabry's disease 13 Homozygous familial hypercholesterolaemia 13 Transthyretin-related hereditary amyloidosis 13 Lennox-Gastaut syndrome 12 Alpha-1 antitrypsin deficiency emphysema 11 Polycythaemia vera 11 Mucopolysaccharidosis IIIA 9 Mucopolysaccharidosis IIIB 9 Tuberous sclerosis 9 0 20 40 60 80 100 120 Drug Count Source: Pharmaprojects®, July 2020

4 / August 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) Key indications

Cystic fibrosis Currently, the company is riding high after the The treatment of cystic fibrosis (CF) lung disease launch of Trikafta, the first triple-combination is experiencing a period of rapid evolution, therapy, at the end of 2019. Trikafta dramatically supported by well-designed clinical trials and outperformed analyst expectations by generating improved understanding of the genetics and $895m in its first full quarter on the market3. The pathophysiology of the disease. Advances in CFTR modulator is intended to treat CF patients physical, antibiotic, and mucolytic therapies with at least one copy of the F508del mutation of have greatly improved the life expectancy of CF the CFTR gene, which accounts for about 90% of patients, while a large number of patients now all people with the disease. It has been estimated also have access to novel treatments targeting that 18,000 patients in the US are eligible for the underlying genetic cause of their disease. CF Trikafta, which has an annual list price of around transmembrane conductance regulator (CFTR) $311,000, and for 6,000 of these people, this is the modulators are a new class of drugs that act by first time they have had a potential medicine to improving production, intracellular processing, treat the underlying cause4. and/or function of the defective CFTR protein. With over 1,700 known CF-causing mutations While such pricing has inhibited market access in the CFTR gene2, there is a large degree of outside of the US, Vertex has finally secured a deal heterogeneity, and medications that have been with NHS England for its triple-combination drug developed so far are effective only in people – transforming a years-long bitter stand-off into with specific mutations. There are four approved an agreement that will see patients there receive CFTR modulators for people with certain CFTR the triple therapy faster than elsewhere in Europe. mutations: ivacaftor (Kalydeco), lumacaftor/ England is one of the most significant markets in ivacaftor (Orkambi), tezacaftor/ivacaftor the world for Vertex and its portfolio of CF drugs, (Symdeko), and elexacaftor/tezacaftor/ivacaftor as it has one of the biggest populations of patients (Trikafta). with the inherited condition5.

All four drugs are marketed by Vertex More potential CFTR modulators are in Pharmaceuticals, which holds a dominant development to address the underlying cause of position after steadily increasing the number of the disease in people with other CF mutations, genotypes and patients its portfolio can address. including AbbVie’s ABBV-2222 and ABBV-3067,

2. Cystic Fibrosis Foundation (2020) Types of CFTR Mutations. Available from: https://www.cff.org/What-is-CF/Genetics/Types-of-CFTR- Mutations/ [Accessed 20 July 2020]. 3. Cystic Fibrosis News Today (2020) PROMISE study examines Trikafta use among CF patients. Available from: https://cysticfibrosisnewstoday. com/2020/06/10/promise-study-trikafta-cystic-fibrosis-patients/ [Accessed 10 July 2020]. 4. Scrip (2019) Vertex Trikafta approved as first triple combo for cystic fibrosis with $311,503 price tag. Available from: https://scrip. pharmaintelligence.informa.com/SC126055/Vertex-Trikafta-Approved-As-First-Triple-Combo-For-Cystic-Fibrosis-With-311503-Price-Tag [Accessed 10 July 2020]. 5. Scrip (2020) Vertex secures rapid deal in England for CF triple therapy. Available from: https://scrip.pharmaintelligence.informa.com/ SC142513/Vertex-Secures-Rapid-Deal-In-England-For-CF-Triple-Therapy [Accessed 10 July 2020].

© Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) August 2020 / 5 while Vertex is continuing to advance new DMD is an X-linked recessive genetic disorder combinations and treatment modalities. caused by a lack of the protein dystrophin which leads to muscle weakness and early death. Exon The gene that causes CF was discovered in skipping works by allowing a smaller but still 1989; however, progress in the development functional dystrophin protein to be produced, of a gene therapy for the disease has been although the size of the dystrophin gene and much slower than originally anticipated. This range of potential mutations mean that this is is highlighted by the 26 gene therapies for CF not a “one size fits all” solution. That being said, listed in Informa’s Pharmaprojects that are no data suggest that over 80% of DMD patients longer in development. However, one mRNA have genotypes responsive to exon skipping, therapy, MRT5005, in development by Translate with potentially 14% responsive to exon 51 Bio, is currently in Phase II clinical development. skipping, 10% responsive to exon 53 skipping, Additionally, there is hope that the gene-editing and 9% responsive to skipping exon 457. Sarepta system CRISPR could be deployed successfully in also plans to expand its DMD portfolio with the treatment of CF, eventually bringing corrective casimersen, an exon 45 skipping therapeutic, therapies that could be deployed to every single which is currently in late-stage development. CF patient, regardless of genotype6. Although these therapies have seen considerable Duchenne’s muscular dystrophy (DMD) commercial success – albeit with contentious Treatment for DMD has advanced considerably clinical benefit – their sales could be usurped by in the last five years with the approvals of three a potentially curative DMD gene therapy. There new therapies. Deflazacort (Emflaza) was the first are several gene therapies in development for oral corticosteroid approved by the US Food and DMD which have the potential to revolutionize Drug Administration (FDA) to treat the condition in treatment, and Sarepta’s SRP-9001 is currently 2017. Deflazacort has been found to help patients leading the pack. The considerable potential of retain muscle strength as well as helping them this drug is illustrated by the sum Roche invested maintain their ability to walk, although as a steroid solely for ex-US rights; a considerable $750m the effect is non-specific. The other FDA-approved upfront fee was supported by Roche taking therapies are both exon-skipping antisense a $400m equity stake in Sarepta. In addition, oligonucleotides marketed by Sarepta – Exondys Roche will fund half of SRP-9001’s global clinical 51 (eteplirsen), approved in 2016, and Vyondys 53 development costs, invest up to $1.7bn in (golodirsen), approved in December 2019. regulatory and sales milestone fees, and pay

6. Cystic Fibrosis Foundation (2020) Gene editing for cystic fibrosis. Available from: https://www.cff.org/Research/Research-Into-the-Disease/ Restore-CFTR-Function/Gene-Editing-for-Cystic-Fibrosis/ [Accessed 10 July 2020]. 7. Action Duchenne (2020) Exon skipping. Available from: https://www.actionduchenne.org/what-is-duchenne/duchenne-explained/glossary- of-research-terms/exon-skipping/ [Accessed 10 July 2020].

6 / August 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) royalties estimated to be a mid-teens percentage therapy is not tailored to individual HTT of the product’s ex-US sales8. Sarepta’s gene mutations, and because of that it has the potential therapy is not the only one in development, and to treat all Huntington’s patients. Tominersen Pfizer is a competitor with its gene therapy, PF- drove a 40% reduction in the mutant protein in 06939926. However, this therapy continues to a Phase I/II trial, and a Phase III trial is ongoing fall behind SRP-9001, with disappointing Phase to evaluate its effect on Huntington’s disease Ib efficacy data and safety concerns prompting a progression. Tominersen has been awarded study halt. PRIME designation by the European Medicines Agency (EMA), a designation aimed to enhance Huntington’s disease support for the development of medicines that Unmet need in Huntington’s disease is huge, and target an unmet medical need. Meanwhile, the launch of a disease-modifying drug would another antisense oligonucleotide, WVE-120102, be a game changer. The only two FDA-approved is in development by WAVE Life Sciences. therapies, Lundbeck’s Xenazine and Teva’s However, WVE-120102 recently demonstrated Austedo, target vesicular monoamine transporters just a 12.4% placebo-adjusted reduction in and can help control the abnormal movements mutant HTT protein, which, while a statistically associated with Huntington’s, but can’t treat the significant result, was unfavorable in comparison underlying disease. Research strategies to develop to tominersen’s 30–52% effect on this surrogate efficacious therapeutics to treat Huntington’s efficacy marker. include gene silencing therapies to reduce or prevent the abnormal huntingtin (HTT) protein VX15/2503, another promising therapy being from being made, and therapies that aim to developed by Vaccinex, is an antibody against the prevent the damage to and death of nerve cells in protein SEMA4D. SEMA4D is involved in signaling the brain due to toxic HTT protein accumulation. processes leading to neuroinflammation and cell death, and VX15/2503 is designed to specifically A particularly promising therapy in development bind to and block the activity of SEMA4D. A is tominersen (previously known as IONIS-HTTRx Phase II clinical trial called SIGNAL is currently and RG6042), developed by Ionis Pharmaceuticals ongoing in the US, with initial results suggesting and later acquired by Roche. It is an antisense that the treatment is safe and may be effective oligonucleotide designed to target and destroy all in preserving brain structure in Huntington’s forms of mutated HTT protein. The investigational patients.

8. Scrip (2019) Sarepta secures $1.15bn from Roche in ex-U.S. DMD gene therapy deal. Available from: https://scrip.pharmaintelligence. informa.com/SC141393/Sarepta-Secures-115bn-From-Roche-In-ExUS-DMD-Gene-Therapy-Deal [Accessed 10 July 2020].

© Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) August 2020 / 7 Spinal muscular atrophy (SMA) However, Spinraza is now feeling the pressure There are currently two approved therapies from Novartis’s adeno-associated viral (AAV) for SMA, Biogen’s Spinraza (nusinersen) and vector-based gene therapy Zolgensma, which Novartis’s gene therapy Zolgensma, with was approved in May 2019 and comes with the Roche’s risdiplam waiting in the wings. The RNA promise of a potential cure with just one injection. interference drug Spinraza is priced at $750,000 In the US, the drug, through intravenous delivery, for the first year and $375,000 for each year is currently only approved in type 1 children afterwards, while Novartis’s Zolgensma, a one- younger than two years old, but Novartis is shot gene therapy, is priced at $2.1m, making aiming to reach older patients with an intrathecal it the industry’s most expensive one-time formulation. Zolgensma is expected to become treatment9. the standard of care for newborn-screened and young type 2 SMA patients, and the treatment has The FDA’s positive decision for Biogen and Ionis so far exceeded analyst expectations. Novartis Pharmaceuticals’ Spinraza in December 2016 noted that full-year sales for 2019 were $361m, came five months ahead of schedule, reflecting with $186m coming in the fourth quarter when the urgency at the agency to approve the first 100 new patients were treated11. treatment for SMA. The FDA was also very generous with Spinraza’s label, allowing the drug In May 2020, Japan’s regulatory authorities in all three subtypes of the disease – and in both decided to grant reimbursement to Zolgensma pediatric and adult patients – again emphasizing under the National Health Insurance scheme the lack of treatment for the rare genetic disorder. at the equivalent of around $1.56m per Spinraza, which corrects RNA splicing of the SMN2 administration, marking a watershed in drug gene and increases SMN protein levels, got off pricing in the country. Novartis has also secured to a strong start. Even though its $125,000-per- conditional approval in Europe for patients with a injection price tag initially drew some unwanted clinical diagnosis of SMA type 1, the most severe public attention, payers were on board, and as of form of the disease, or patients with up to three Q4 2019, Spinraza revenues had reached $243m copies of the SMN2 gene for babies and young in the US and $300m abroad10. children up to 21kg with SMA.

9. Reuters (2020) Roche aims to ‘underwhelm’ on SMA drug price to challenge rivals. Available from: https://uk.reuters.com/article/us-roche- sma/roche-aims-to-underwhelm-on-sma-drug-price-to-challenge-rivals-idUKKBN1ZD12F [Accessed 10 July 2020]. 10. Biogen (2019) Biogen reports full year 2019 revenues of $14.4 billion. Available from: https://investors.biogen.com/static-files/a2645e02- f862-4eac-9f69-511eeb95a704 [Accessed 10 July 2020]. 11. Scrip (2020) Zolgensma stands out in strong Q4 for Novartis. Available from: https://scrip.pharmaintelligence.informa.com/SC141557/ Zolgensma-Stands-Out-In-Strong-Q4-For-Novartis [Accessed 10 July 2020].

8 / August 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) Companies operating in the rare congenital and genetic diseases space

The largest pharma companies dominate Sarepta Therapeutics, Vertex Pharmaceuticals, the commercial landscape despite the lower and Ionis Pharmaceuticals that are developing development and marketing costs associated with the new products (Figure 4). Their prominence in targeting rare diseases. Takeda, Pfizer, Sanofi, the pipeline makes these companies perennial GlaxoSmithKline, and Novartis each have at least acquisition targets in a similar vein to Shire, whose eight approved therapies for rare congenital and $62bn takeout propelled Takeda to the top of genetic diseases (Figure 3). However, increasingly, Figure 3. it is the smaller, more specialist players such as

Figure 3: Top 30 Rare Congenital and Genetic Diseases Developers by Number of Approved Drugs

Takeda 12 Pfizer 10 Sanofi 10 GlaxoSmithKline 9 Novartis 8 Recordati 8 Roche 8 CSL Limited 6 Grifols 6 Leadiant Biosciences 6 Chiesi 5 Johnson & Johnson 5 Aspen Pharmacare Holdings 4 Bayer 4 Bristol-Myers Squibb 4 Generium Pharmaceutical 4 Ionis Pharmaceuticals 4 Merck KGaA 4 Sobi 4 Vertex Pharmaceuticals 4 Abiogen 3 Alexion Pharmaceuticals 3 Biogen 3 BioMarin 3 GENESIS Pharma 3 Horizon Therapeutics 3 Ipsen 3 Italfarmaco 3 Kyowa Kirin 3 0 2 4 6 8 10 12 14 Drug Count

Source: Pharmaprojects®, July 2020

Sarepta Therapeutics 22 Takeda 21 Novartis 19 Biogen 17 Vertex Pharmaceuticals 17 AbbVie 15 Pfizer 13 Regenxbio 13 Sanofi 13 Ionis Pharmaceuticals 12 Roche 12 Ultragenyx Pharmaceutical 10 Genethon 9 Astellas Pharma 8 BridgeBio 8 Sangamo Therapeutics 8 Taysha Gene Therapies 8 Alnylam 7 JCR Pharmaceuticals 7 ProQR Therapeutics 7 PTC Therapeutics 7 Sumitomo Dainippon Pharma 7 WAVE Life Sciences 7 Alexion Pharmaceuticals 6 Amicus Therapeutics 6 CRISPR Therapeutics 6 CSL Limited 6 Editas 6 Orchard Therapeutics 6 Regeneron 6 Rocket Pharmaceuticals 6 uniQure 6 0 5 10 15 20 25 Drug Count

Source: Pharmaprojects®, July 2020

10 / August 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) Key players

Sarepta Therapeutics neuromuscular-focused gene therapy startup Sarepta Therapeutics bills itself as “the leader Myonexus Therapeutics and its pipeline of in precision genetic medicine for rare diseases”, potential gene therapies for LGMDs. Myonexus’ and the company has built an impressive and approach uses the rh.74 AAV vector system competitive position in DMD, as well as more designed to systemically deliver a corrective copy recently expanding into limb-girdle muscular of the appropriate deficient gene to cardiac and dystrophy (LGMD), Charcot-Marie-Tooth disease, skeletal muscle, including the diaphragm, without and CNS-related disorders. In total, Sarepta has crossing the blood-brain barrier. Furthermore, 22 products in development for rare genetic most recently, in May 2020, Sarepta announced conditions. The company’s programs span across an agreement with Dyno Therapeutics, a biotech several therapeutic modalities, including RNA, applying artificial intelligence to gene therapy, to gene therapy, and gene editing. develop next-generation AAV vectors for muscle diseases using Dyno’s CapsidMap platform. Sarepta has achieved FDA approval for two DMD therapies: Exondys 51 (eteplirsen), and Sarepta is also putting its hope in LYS-SAF302 most recently for Vyondys 53 (golodirsen). The (SAF301), a gene therapy for the treatment of approval of Vyondys 53 marked a remarkable mucopolysaccharidosis type IIIA (Sanfilippo A four-month journey from FDA rejection to syndrome) under development by Lysogene. approval, a turnaround made possible by a formal Sarepta licensed exclusive worldwide dispute resolution which Sarepta filed with the commercialization (except in Europe) and agency. In addition, Sarepta has a further DMD manufacturing rights from Lysogene in 2018. therapy in late-stage development – a rolling NDA LYS-SAF302 uses the AAVrh10 virus to replace the submission for casimersen was announced in faulty SGSH gene with a healthy copy of the gene. January 2020 (see above analysis). A global Phase II/III clinical study is ongoing.

Sarepta originally made a name for itself in the Novartis field of RNA therapeutics, but is increasingly With the acquisition of The Medicines Company pivoting towards gene therapy and gene editing and the RNAi asset inclisiran in November in the longer term. In order to achieve this, 2019, Novartis becomes the only Big Pharma Sarepta has been busy in the deal-making space with presence across four advanced therapy in the last year and has focused on agreements platforms: cell, gene, radioligand, and RNA that center around AAV vectors. In 2019, therapies. The desire to diversify and minimize Sarepta and StrideBio agreed to collaborate on reliance on single products and technologies the development of AAV-based therapies for is undoubtedly a driver behind the acquisition, up to eight CNS and neuromuscular disease but it also allows Novartis to operate within targets, while Sarepta also acquired the private, cardiovascular population health. Novartis has

© Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) August 2020 / 11 submitted filings to the FDA and EMA for the use Vertex Pharmaceuticals of inclisiran in hyperlipidemia, but the drug is also As well as being a key player in the CF market in Phase III development for homozygous familial (see above analysis), like Sarepta and Novartis, hypercholesterolemia, an inherited condition Vertex is investing in AAV technology, and in which leads to very high cholesterol levels. April 2020 it entered into a strategic research collaboration with Affinia Therapeutics to As discussed in the above analysis, Novartis engineer novel AAV capsids to deliver genetic is responsible for marketing the world’s most therapies. The collaboration will leverage Affinia’s expensive one-shot treatment, as its SMA gene capsid engineering expertise and proprietary therapy Zolgensma is priced at $2.1m in the US. In AAVSmartLibrary alongside Vertex’s scientific, addition, Novartis received conditional approval clinical, and regulatory capabilities to accelerate for Zolgensma in Europe in May 2020, and has the development of genetic therapies. hit the ground running with access programs for the closely watched gene therapy. Novartis Vertex is also looking to expand beyond CF into is also interested in developing gene therapies severe neuromuscular disease, and in June 2019 for ocular diseases, led by its licensing of ex- the company announced that it plans to enhance US commercial rights to Luxturna (voretigene its gene editing capabilities and develop therapies neparvovec), approved for the curative treatment for DMD and myotonic dystrophy type 1 (DM1). To of certain inherited retinal diseases. Like Sarepta achieve this, Vertex bought privately held Exonics Therapeutics, Novartis has also formed a Therapeutics for $245m up front and extended collaboration with Dyno Therapeutics to develop and expanded a 2015 collaboration with CRISPR improved AAV vectors, but this collaboration will Therapeutics. focus on their use in gene therapies for ocular diseases.

12 / August 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) Key upcoming approvals

As part of this analysis we have picked out 10 of have focused on drugs that have the potential to the most anticipated new drug launches for rare treat patient populations not currently served by congenital and genetic diseases – in particular, we available therapies.

Table 1: Key upcoming approvals for rare congenital and genetic diseases

Estimated US Likelihood of Drug Company Indication Modality US approval status US approval date July to Duchenne’s muscular Antisense Viltolarsen Nippon Shinyaku NDA 90% September dystrophy oligonucleotide 2020

24 August Risdiplam Roche Spinal muscular atrophy NDA 99% Small molecule 2020

Eiger Hutchinson-Gilford 20 November Zokinvy NDA 89% Small molecule BioPharmaceutical s progeria syndrome 2020

3 December Lumasiran Alnylam Hyperoxaluria NDA 98% siRNA 2020

Sarepta Duchenne’s muscular Antisense Casimersen NDA 90% 25 June 2021 Therapeutics dystrophy oligonucleotide

Arimoclomol Orphazyme Niemann-Pick disease NDA 92% Small molecule N/A

Molybdenum cofactor Fosdenopterin BridgeBio Pharma NDA 89% Small molecule N/A deﬁ ciency

Castle Creek Cell-based gene FCX-007 Epidermolysis bullosa III 66% N/A Biosciences therapy Minoryx Leriglitazone Adrenomyeloneuropathy II/III 62% Small molecule N/A Therapeutics

Charcot-Marie-Tooth PXT3003 Pharnext III 60% Small molecule N/A disease

Source: Biomedtracker®, July 2020

© Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) August 2020 / 13 Viltolarsen two of the most expensive drugs in the world, Viltolarsen is an exon-skipping therapy in risdiplam is still expected to be very costly14. development for DMD by NS Pharma with its parent company Nippon Shinyaku. Viltolarsen is Zokinvy intended to treat the 10% of DMD patients with Zokinvy (lonafarnib) is an orally active inhibitor of mutations amenable to exon 53 skipping. While farnesyltransferase in late-stage development for exon skipping is not a cure for DMD, it has the Hutchinson-Gilford progeria syndrome, an ultra- potential to lessen the severe muscle weakness rare condition in which children age too quickly and atrophy that is the hallmark of the disease, and for which there are no approved therapies. and as such exon skipping therapies have been Current treatments focus on managing symptoms, able to command high price points. Sarepta’s but Zokinvy is hypothesized to address the course Vyondys 53, which works in the same way as of the genetic disease. Eiger BioPharmaceuticals’ viltolarsen, is already on the US market, priced at unconventional NDA includes data from two an annual cost of $300,00012,13. single-arm, open-label studies with a combined 63 patients that received Zokinvy and a historical Risdiplam control group of 103 untreated patients. After Risdiplam, an SMN2 splicing modifier in two years, mortality among Zokinvy patients was development by Roche, is likely to be the first oral 3.7% compared to 33.3% for the untreated group, treatment for people with SMA as both Spinraza equivalent to a risk reduction of 88%15. Zokinvy and Zolgensma are injectables. Applications to has been granted Orphan Drug designation market Roche’s SMA drug have already been for progeria by the FDA and EMA, as well as submitted in eight countries including the US, Breakthrough Therapy and Rare Pediatric Disease where a decision is expected on 24 August 2020. designations by the FDA. Its initial target population is expected to include both newborns with type 1 SMA and type 2–3 Lumasiran patients up to the age of 25 years, providing a Lumasiran, an RNAi in development by Alnylam, broad commercial and competitive opportunity. is slated to be the first drug approved specifically Furthermore, Roche has suggested that it plans for the ultra-rare kidney disorder primary to undercut both Biogen and Novartis on price hyperoxaluria type 1. Lumasiran has been shown in order to make up for being third-to-market. to help patients clear a toxic substance called However, given that Zolgensma and Spinraza are oxalate from their kidneys and other vital organs.

12. Scrip (2019) Sarepta secures $1.15bn from Roche in ex-U.S. DMD gene therapy deal. Available from: https://scrip.pharmaintelligence. informa.com/SC141393/Sarepta-Secures-115bn-From-Roche-In-ExUS-DMD-Gene-Therapy-Deal [Accessed 10 July 2020]. 13. Muscular Dystrophy News Today (2019) Vyondys 53 available to Duchenne patients in the U.S. Available from: https:// musculardystrophynews.com/2019/12/20/vyondys-53-available-duchenne-patients-in-the-us/ [Accessed 10 July 2020]. 14. Reuters (2020) Roche aims to ‘underwhelm’ on SMA drug price to challenge rivals. Available from: https://uk.reuters.com/article/us-roche- sma/roche-aims-to-underwhelm-on-sma-drug-price-to-challenge-rivals-idUKKBN1ZD12F [Accessed 10 July 2020]. 15. Gordon LB, et al. (2018) Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. Available from: https://pubmed.ncbi.nlm.nih.gov/29710166/ [Accessed 20 July 2020].

14 / August 2020 © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) In the Phase III ILLUMINATE-A trial, Alnylam’s thought that increased HSP70 expression assists drug met the primary objective of a significant in the correct folding of mutant NPC1 and NPC2 reduction compared to placebo in urinary oxalate proteins, thus allowing them to process the excretion over 24 hours, averaged across months accumulation of lipids. It is this abnormal build- three to six. If approved, lumasiran would become up of cholesterol and other fats within various Alnylam’s third approved RNAi product, further tissues in the body, including the brain, that drives validating the clinical success of its drug discovery the pathophysiology of the disease. Orphazyme platform. announced in May 2020 that it has initiated the submission of its NDA for a rolling review by the Casimersen FDA. Casimersen is another exon skipping therapy which is being developed by Sarepta Therapeutics Fosdenopterin to treat DMD patients with mutations amenable to Fosdenopterin is a cyclic pyranopterin exon 45 skipping. Casimersen would be the first monophosphate replacement therapy in available therapy to treat the 9% of DMD patients development to treat patients with molybdenum amenable to exon 45 skipping, and similarly to cofactor deficiency (MoCD) type A. Currently, Vyondys 53 and Exondys 51 it is expected to be there are no approved therapies that alter the very expensive16. With the potential approval of course of the disease, which results in severe and casimersen in June 2021, Sarepta would be able to irreversible neurological injury. Fosdenopterin target its portfolio to approximately one third of aims to reduce the build-up of toxic sulfites DMD patients. Similarly to its predecessor brands, and alleviate CNS symptoms in infants and Sarepta will face competition in the form of exon children with MoCD type A. BridgeBio Pharma 45 skipping pipeline drugs, as Daiichi Sankyo has subsidiary Origin Biosciences has initiated a rolling progressed its candidate (DS-5141b) into Phase II submission of an NDA with the FDA while two development. global clinical trials are ongoing, although until these produce data little is known publicly about Arimoclomol the drug’s clinical profile. Arimoclomol has the potential to be the first ever drug approved for the treatment of Niemann- FCX-007 Pick disease type C in the US. Arimoclomol acts FCX-007 is a genetically modified autologous by targeting heat-shock protein 70 (HSP70). It is fibroblast cell therapy that encodes the COL7

16. Action Duchenne (2020) Exon skipping. Available from: https://www.actionduchenne.org/what-is-duchenne/duchenne-explained/glossary- of-research-terms/exon-skipping/ [Accessed 10 July 2020].

© Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) August 2020 / 15 gene, which is defective in patients with recessive the efficacy and safety of leriglitazone is being dystrophic epidermolysis bullosa. Fibroblasts evaluated in a Phase II/III clinical trial, with top-line are harvested from the affected patient and results expected to be announced in Q4 2020. transfected to encode functioning COL7 before Additional evaluation within Friedreich’s ataxia is being cultured and injected back into wound sites also ongoing, owing to the drug’s potential broad to aid in the healing process. FCX-007 has received neuroprotective effect. several FDA designations including Orphan Drug, Fast Track, RMAT, and Rare Pediatric PXT3003 Disease. Fibrocell, now part of Castle Creek PXT3003 is an investigational combination therapy Pharmaceuticals, projects enrollment and dosing of baclofen, naltrexone, and sorbitol – three of patients will be completed in the Phase III trial approved treatments that act on the nervous of FCX-007 in Q3 2020, and that data collection system – and is formulated as an oral solution that for the primary endpoint will be completed in the is given twice a day. PXT3003 is in development fourth quarter of 2020. for the treatment of Charcot-Marie-Tooth disease type 1A (CMT1A), an inherited genetic disease in Leriglitazone which the motor and/or sensory peripheral nerves Leriglitazone, developed by Minoryx Therapeutics, are affected, resulting in muscle weakness and is an experimental oral medication for the wasting, as well as sensory loss. There is currently treatment of adrenoleukodystrophy (ALD). no cure for CMT1A, and treatments include While PPAR gamma agonists are best known for physiotherapy, splints, occupational therapy, and promoting peripheral insulin sensitivity in type sometimes surgery. While its developers Pharnext 2 diabetes, leriglitazone has the ability to cross have already established treatment efficacy in a the protective blood-brain barrier and enter the Phase III trial, PLEO-CMT, a second confirmatory CNS. Once there, it aims to prevent processes trial was requested by the FDA to address the associated with ALD, including inflammation formation of crystals in its high-dose formulation. and oxidative stress, protecting nerve cells from Provided this additional clinical expense can be damage. The EMA granted leriglitazone Orphan funded, PXT3003 is likely to become the first Drug designation in 2016, and the FDA followed treatment specifically approved for patients with suit in 2017. The FDA also granted leriglitazone CMT1A. Fast Track designation in January 2020. Currently,

The industry is increasingly focused on narrowly considerable proportion of the population, and defined diseases and scientific advancements, health systems are not equipped to keep paying and incentives for focusing on rare congenital and the high prices associated with many recently genetic diseases have led to the development of approved therapies. If payers increasingly many new therapies that have the potential to restrict treatment to certain subgroups, such transform patient outcomes. Yet as more high- as those who benefit most in trials, this may priced therapies are approved, they continue to have a detrimental impact on innovation and challenge affordability and access. Collectively, development in the rare congenital and genetic rare congenital and genetic diseases affect a diseases space.

About The Author

Anna Osborne Prior to joining the Custom Intelligence team, Principal Consultant, Informa Pharma Custom Anna was an analyst at Informa Pharmaprojects. Intelligence Here, she expertly curated the drug development database, provided research support to clients Anna forms part of the leadership team at and produced custom analytics projects, Informa Pharma Custom Intelligence, a team transforming clinical study data and drug data which specializes in pharmaceutical and into actionable insights. Anna’s strong scientific healthcare consultancy. Anna’s team informs background enables her to fully understand the investment, clinical development, and commercial therapeutic potential of developmental therapies. planning decisions across the product lifecycle for Before joining Informa, Anna completed the top-tier and mid-cap pharmaceutical companies, Wellcome Trust PhD training program in Infection as well as biotech and medtech companies. and Immunology at Imperial College London, and she holds a first-class degree in Molecular Biology Anna has a keen interest in rare diseases and from the University of York. has led multiple projects in this area including opportunity assessments, market landscapes, If you have any questions, please call patient-based forecasts, and indication and Anna on +44 7733 225 410 or email her at product prioritization exercises. [email protected].

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