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]. © Informa UK Ltd 2020 (Unauthorized photocopying prohibited.) August 2020 / 3 Therapies in development for rare congenital and genetic diseases 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