Medicines that treat high prevalence conditions affecting many millions of patients around the globe will offer hope to many as 11 new potential blockbuster drugs are named on this year’s list. The list focuses on the treatment and possible cure for chronic, progressive and often debilitating diseases and conditions, including breast cancer, multiple sclerosis (MS), type 2 diabetes, haemophilia and migraine.
Since 2013, the Cortellis Forecast team at Clarivate has applied its proprietary technologies, tools and techniques trusted by its global life sciences customers to produce the Drugs to Watch list, which this year features 11 products. Each edition of the report showcases drugs entering the market that year with the potential to become blockbusters within five years. A blockbuster drug is defined as one that reaches the milestone of $1bn USD in annual sales.
Drugs in phase 2 or phase 3 trials, at preregistration or registration stage, or already launched early in 2020 were selected for analysis, and filtered for drugs that had total forecast sales of $1bn or more in 2024. This filtering process produced a list of drugs which was then manually reviewed to determine whether these products were likely to go to market in 2020, based on factors such as the company’s expected approval or launch dates. Each of the 11 drugs was subsequently researched and evaluated in its individual context, including clinical trial results, regulatory status, the market for each drug (including analysis of competitor drugs) and regulatory designations (eg, Orphan Drug, Priority Review).
Drugs for central nervous system indications and cancer dominate much of the list, in sharp contrast to the 2019 list which contained no cancer drugs. The 11 drugs are almost universally accelerated in their development by orphan drug status or other designations intended to spur closer cooperation between regulators and drug developers with the intention of accelerating their availability to patients. The 11 drugs identified collectively hold 18 orphan drug designations, four FDA breakthrough therapy designations, two EU PRIME designations and one Japanese SAKIGAKE designation.
This year’s list also highlights three first-in class medicines compared with last year’s list, which contained only one first-in-class medicine, peanut allergy vaccine Palforzia. The three from this year’s list are: Valrox, which if approved, would become the first gene therapy for any form of haemophilia; Inclisiran, from The Medicines Company, which could become the first siRNA-based inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) to win approval; and Immunomedics’s sacituzumab govitecan, which is poised become the first antibody-drug conjugate to target TROP-2, a pan-epithelial cancer antigen.
The medicines on the list will face substantial pressures to differentiate themselves, as they are poised to enter indications already crowded with competitors. Some are expected to offer improved safety vs. alternative therapies, especially around cardiovascular risk, while others will seek to highlight novel mechanisms of action or even curative potential. The list and analyses examine the 11 treatments identified, along with an analysis of the competitive market dynamics each is expected to face. Here is a quick profile of each drug featured in 2020:
1. Rimegepant from BioHaven Pharmaceuticals is an antagonist of calcitonin gene-related peptide (CGRP), recently approved in the US for the acute treatment of migraine, with prevention trials also ongoing. The drug entered into a market largely dominated by OTC products and triptans. Triptans are considered first-line therapy for the acute treatment of migraine and are widely available generically, although the market is undergoing transformation by prophylactic options such as CGRP monoclonal antibodies. To succeed in the acute treatment setting, rimegepant will also have to beat competitors like Reyvow and Ubrelvy, both of which are also oral drugs with very attractive profiles. Eli Lilly/Dong Pharmaceuticals’ 5-HT1f agonist Reyvow was approved in the US in October 2019 as the first acute treatment for migraine in 20 years. Allergan’s Ubrelvy is the only other oral CGRP antagonist approved for acute migraine, which entered the market ahead of rimegepant. Despite the fierce competition, sales of $49m are still forecast for this year, rising to $1.03bn in 2024.
2. Ozanimod, developed by Bristol-Myers Squibb, is an orally delivered agonist of sphingosine-1- phosphate type 1 (S1P1) and S1P5 receptors, two proteins with a pivotal role in the trafficking of B and T cells outside the lymph nodes, to treat relapsing forms of multiple sclerosis. The FDA accepted the filing for Ozanimod in June 2019 with a target PDUFA date of 25 March 2020. A filing was also submitted to the EMA in March 2019, with approval expected in 1H20. It faces multiple competitors across both oral and injectable therapies, as well as a stiff pricing environment due to the presence of generics and biosimilars. To succeed, it will have to differentiate from its direct competitors, particularly the first-in-class S1P1 agonist Gilenya, by leveraging potential cardiovascular safety advantages. Despite the expectation that it will face intense competition in the crowded multiple sclerosis market, sales of $80m are forecast for this year, rising to $1.621bn in 2024.
3. Novartis’ OMB-157 is a monthly or 12-weekly subcutaneous formulation of the anti-CD20 monoclonal antibody Arzerra (which is indicated as an intravenous infusion for chronic lymphocytic leukaemia) in phase 3 development to treat relapsing forms of multiple sclerosis. As with ozanimod, if OMB-157 is approved it will find a very crowded multiple sclerosis market with some very notable competitors, particularly in the anti-CD20 monoclonal antibody class. To succeed, it will have to differentiate from its main direct competitor, the anti-CD20 monoclonal antibody Ocrevus, which has the first-to-market advantage, has labelled indications covering 95% of all multiple sclerosis sufferers and a highly competitive six-month dosing schedule. Even if bettering Ocrevus appears unlikely, the drug will provide another option to contribute to Novartis’ growing multiple sclerosis armamentarium, with sales of $140m still forecast for this year, rising to $1.261bn in 2024.
4. Vadadustat is an inhibitor of hypoxiainducible factor (HIF)-prolyl hydroxylase (HIF-PH) from Akebia Therapeutics/ Mitsubishi Tanabe Pharma/Otsuka that targets anaemia in chronic kidney disease (CKD). By inhibiting HIF-PH, vadadustat preserves HIF, which is then able to stimulate the production of erythropoietin and improve iron regulation, thus restoring red blood cell production and function in CKD patients. The drug is under regulatory review in Japan, where a filing was submitted in July 2019. Launch is expected in FY 2020 and filings in the US and EU are planned. With longstanding competitors experiencing setbacks due to links with cardiovascular events and tumours, vadadustat’s success will be determined by its capacity to differentiate from other prolyl hydroxylase products, particularly from first-to-market Evrenzo (which was featured in the 2019 Drugs to Watch report). Sales are projected at $1.589bn in 2024.
5. Filgotinib from Gilead/Galapagos is an oral JAK1 inhibitor in regulatory review in the US, EU and Japan for rheumatoid arthritis Overactivation of the JAK family of kinases leads to an aberrant production of pro-inflammatory mediators, which are involved in the pathogenesis of rheumatoid arthritis, and inhibition of JAK proteins is an established method of controlling the symptoms of this disease. If approved, filgotinib will be a late entrant into a very crowded market, which is currently dominated by small molecules and biologicals, many of which are recommended for first-line use. The drug must leverage its competitive profile as it will face significant competition from entrenched biological agents (and biosimilar versions), including Humira and Enbrel, as well as direct competition from other JAK inhibitors such as Xeljanz and Rinvoq. Sales of $21 million are forecast for this year, rising to $1.433bn in 2024.
6. BioMarin Pharmaceutical’s Valrox is an injectable gene therapy that corrects the genetic defect underlying haemophilia A – a genetic disorder caused by a missing or defective clotting protein called factor VIII (FVIII). Valrox is in regulatory review in the US, with a PDUFA date of 21 August 2020, with an MAA also being reviewed in the EU. If approved, Valrox would be the first potentially curative approach to haemophilia A, eliminating the need for blood transfusions and FVIII replacement therapy after a single infusion. The haemophilia market is conservative in adopting new therapies, and patients may be reluctant to switch to new products if their current replacement therapy works well. However, an unmet need remains, as approximately 75% of haemophilia A patients do not respond adequately to their treatment or even do not receive treatment at all. As potentially the first curative approach to haemophilia A, the drug is expected to take a leadership position in the market, despite competition from current standard of care FVIII replacement therapies. Even with a relatively low worldwide prevalence of about 400,000 patients, haemophilia A still represents a large market, particularly considering that BioMarin is looking at pricing of between $2m and $3m, which would make Valrox the most expensive one-time therapy, topping Novartis’ Zolgensma at $2.1m (which featured in the 2019 Drugs to Watch report). For this reason, even if the penetration is modest, Valrox could post significant revenue. Sales of $17.45m are forecast for this year, rising to $1.297bn in 2024.
7. NovoNordisk’s Rybelsus is an oral once-daily formulation of semaglutide, a long-acting glucagon-like peptide (GLP)-1 analog. Upon interaction with the GLP-1 receptor, it stimulates the secretion of insulin in a glucose-dependent manner. Rybelsus is available in the US to improve glycaemic control in adults with type 2 diabetes. It faces competition from entrenched generic metformin and sulphonylureas, as well as from more novel drug classes, particularly SGLT-2, inhibitors, DDP4 inhibitors and injectable GLP-1 agonists. As the first oral GLP-1 agonist, Rybelsus could be a game changer by combining the convenience of a once-daily pill with the significant glucose-lowering activity and cardiovascular benefits of the GLP-1 receptor agonist class. Sales of $379m are forecast for this year, rising to $3.214bn by 2024.
8. Inclisiran from The Medicines Company (now a Novartis wholly owned subsidiary) is being reviewed for approval in hypercholesterolemia in the US and the EU. Hypercholesterolemia is a major risk of cardiovascular disease,the leading cause of death worldwide, accounting for more than 30% of deaths annually. Inclisiran is a small interfering RNA (siRNA) that silences the expression of a gene encoding for PCSK9, an enzyme that promotes the breakdown of LDL receptors in the liver. By silencing PCSK9 expression, LDL receptors are not degraded and become widely available on the cell surface, resulting in improved ingestion of LDL particles into the liver cells, thus reducing LDL levels in blood. It will face competition mainly from generic statins and PCSK9 inhibitor monoclonal antibodies. Inclisiran must leverage its strong efficacy and twice-a-year dosing to succeed. If approved, Inclisiran will be the first and only cholesterol-lowering siRNA product with forecast sales of $40.21m for this year, rising to $1.16bn by 2024.
9. Immunomedic’s sacituzumab govitecan initial target market is metastatic triple negative breast cancer in patients who have failed at least two prior therapies. Due to the lack of optimal targeted therapies and the modest efficacy of chemotherapy, it has the potential to be broadly adopted and become the standard of care. It is an antibody-drug conjugate (ADC) consisting of an anti-tumour-associated calcium signal transducer 2 (Trop2) monoclonal antibody bound to a moderately toxic drug, SN-38, an active metabolite of the topoisomerase inhibitor irinotecan. Trop2 is a transmembrane glycoprotein overexpressed in many epithelial cancer cells, including TNBC. The monoclonal antibody allows greater and more specific delivery of the toxin to tumour cells expressing Trop2, allowing for greater delivery over repeated cycles of therapy, thereby improving the therapeutic index of the drug. The FDA is reviewing a filing in this setting, and has set a PDUFA date of 2 June 2020. Sales of $45m are forecast for this year, rising to $1.27bn in 2024.
10. Daiichi Sankyo and AstraZeneca’s Enhertu (trastuzumab deruxtecan) is also an ADC that targets HER2. It is approved in the US for the treatment of unresectable or metastatic HER2-positive breast cancer in the third-line-plus setting. It has entered into a market dominated by Herceptin and other HER2-targeted therapies such as Perjeta and Tykerb. Kadcyla, the only other anti-HER2 ADC in this market, is a direct competitor and differentiation versus this established drug will be key. Enhertu must secure approvals in earlier settings to realise its maximal revenue potential. Sales of $50.17m are forecast for this year, rising to $2.02bn by 2024.
11. Liso-cel for large B-cell lymphoma is being developed by Bristol-Myers Squibb to treat large B-cell lymphomas, and a filing in the third-line setting is being reviewed by the FDA, with a PDUFA date of 17 August 2020. Liso-cel (lisocabtagene maraleucel, JCAR-017) is an immunotherapy comprised of autologous T cells genetically modified (via lentiviral vector) to express an anti-CD19 chimeric antigen receptor (CAR). CD19 is a target ubiquitously expressed in a number of B-cell malignancies. Thanks to the CAR construct, the engineered T cells can recognise and attack the CD19-expressing cancer cells. Liso-cel can potentially be the best-in-class anti-CD19 based on its differentiated profile compared with other cell therapies: the therapy is manufactured in a defined 1:1 ratio of CD4+ helper T cells and CD8+ cytotoxic T cells. This composition could confer efficacy and safety advantages, including fewer adverse effects such as cytokine release syndrome (CRS) and neurotoxicity, which are very common with other CAR T-cell therapies such as Kymriah and Yescarta. Sales of $43.25m are forecast for this year, rising to $1.089bn by 2024.
No matter the fate of the drugs on this year’s list, it’s likely that the messy tension among scientific innovation, commercial motive and public goods will continue to be at the top of people’s minds in the year ahead, as medical research and the pursuit of innovative medicines continues to accelerate.