The haemophilia drug market

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Haemophilia is a monogenic X-linked recessive disease characterized by a disrupted clotting cascade. Deficiency of procoagulant factor VIII (FVIII) in haemophilia A, or FIX in haemophilia B, results in uncontrolled bleeding episodes. Intra-articular and intramuscular bleeding are the major clinical manifestations of haemophilia. Recurrent joint bleeding causes synovial proliferation and inflammation that contribute to haemophilic arthropathy. Over the long term, the resulting permanent joint deformation is painful and limits motion, which severely affects quality of life.

Haemophilia is classified as severe, moderate or mild, depending on the patient's residual plasma levels of clotting factor. There are ~39,000 patients with haemophilia A (approximately 40% severe) and ~10,000 patients with haemophilia B (approximately 30% severe) across the EU5 countries (France, Germany, Italy, Spain and the United Kingdom) plus the United States.

The drug market for haemophila is undergoing major changes, owing to advances in gene therapy and protein engineering and to novel strategies that target negative clotting regulators.

Current treatment

Factor replacement therapy is a life-saving treatment for individuals with haemophilia. Key current treatments are plasma-derived or recombinant in nature, and can be used prophylactically or on demand (when a bleed occurs). Recombinant FVIII (rFVIII) or rFIX can have either a standard half-life (SHL), similar to their plasma-derived counterparts, or an extended half-life (EHL). EHL products can allow for less frequent dosing.

Although the majority of patients with haemophilia can be managed by replacing the missing clotting factor, development of inhibitors (anti-drug antibodies) to the injected factor is one of the most serious complications of haemophilia treatment. Patients with inhibitors are treated on demand with immune tolerance induction (ITI), which uses high levels of factor to saturate the inhibitor. If ITI is inappropriate or fails, patients can be treated with a bypass agent — such as recombinant FVIIa (NovoSeven; Novo Nordisk) or anti-inhibitor coagulant complex (FEIBA; Shire) — that directly activates FX, in effect bypassing the need for FVIII or FIX.

Key unmet needs in haemophilia include prophylactic treatments for patients with inhibitors, a means to reduce dosing burden and a way to eliminate large fluctuations in factor levels between doses. Keeping factor levels above a certain threshold could lessen the severity of the disease phenotype.

Emicizumab (Hemlibra; Roche/Chugai), the first new agent in nearly 20 years for patients with haemophilia A with inhibitors, launched in the United States in November 2017. Emicizumab is a bispecific antibody that binds to FIXa and FX to mimic the function of FVIII. Emicizumab is the first subcutaneously administered haemophilia treatment to be approved, and is also the first non-factor agent for haemophilia.

Therapies in clinical development

Gene therapies. Several therapies in development aim to restore the expression of endogenous FVIII or FIX to reduce bleeding events, negate the need for prophylaxis and reduce the amount of injected replacement factor required (Table 1). Gene therapies, such as BioMarin Pharmaceutical's phase III candidate valoctocogene roxaparvovec (BMN 270), deliver the gene encoding the missing factor to the nucleus of liver cells through a non-replicating, non-integrating viral delivery vector such as adeno-associated viruses (AAVs). Gene-editing therapies, such as Sangamo Therapeutics' phase I/II zinc finger nuclease-based agent SB-FIX, alter specific sites within the endogenous gene.

Table 1 Selected agents in clinical development for haemophilia

Haemophilia gene therapy is being hailed as a potential cure, but responses are variable, with no clear relationship between vector dose and factor response. Importantly, if the first infusion fails, data suggest that the same vector cannot be used for a second infusion. Gene therapy is not suitable for patients with inhibitors to FVIII or FIX, nor those with neutralizing antibodies to AAV. Immune responses to the AAV capsid have been observed and the duration of effect is not fully established. The lack of long-term safety data is also likely to impact patients' willingness to try gene therapy. Owing to such issues, development risks are high. Recently terminated programmes that have been unsuccessful include Dimension Therapeutics' DTX101 and Shire's BAX 335.

Non-factor, non-gene therapy. Emicizumab is in phase III trials that could provide the basis for an additional approval in patients with haemophilia A without inhibitors. Bioverativ (which has recently been acquired by Sanofi) is also developing a bispecific antibody and Apitope is developing an antigen-specific immunotherapy (ATX-F8-17) for patients with haemophilia A with inhibitors; these agents are in the early stages of development.

Fitusiran (Alnylam/Sanofi) is currently in phase II/III trials and, like emicizumab, is subcutaneously administered. Fitusiran is a small interfering RNA (siRNA) that targets antithrombin III (ATIII), an endogenous coagulation inhibitor. By reducing the production of ATIII, fitusiran should increase the clotting capacity of the blood. Unlike emicizumab, fitusiran is being developed as a treatment for patients with haemophilia A or B, with or without inhibitors. There are concerns, however, for the thrombogenic potential of an agent targeting ATIII. In September 2017, fitusiran clinical trials were suspended by the FDA after a patient died after developing a blood clot. The trials resumed in December 2017.

Similarly, drugs targeting tissue factor pathway inhibitor (TFPI) are being developed for the treatment of patients with haemophilia A or B, with or without inhibitors. The most advanced anti-TFPI therapy, concizumab (Novo Nordisk), is a humanized monoclonal antibody that enhances thrombin generation potential by inhibiting TFPI.

Factor replacement therapy. EHL factor agents have been developed using various approaches, including PEGylation (which is used in marketed agents such as Shire's Adynovate/Adynovi for haemophilia A) and protein fusion (which is used in marketed agents such as Bioverativ's Eloctate/Elocta for haemophilia A and CSL Behring's Idelvion for haemophilia B). Irrespective of the protein engineering approach, attempts to substantially extend the half-life of FVIII have underwhelmed so far; some patients have to inject these EHL products every other day. Conversely, FIX half-life has been extended substantially through PEGylation or protein fusion, with some patients able to inject every 10-14 days.

Bayer's BAY 94-9027 and Novo Nordisk's N8-GP are both PEGylated recombinant FVIII molecules that are in phase II development for patients with haemophilia A. They could be the second and third PEGylated EHL FVIII products to reach the market. Novo Nordisk is also developing a subcutaneous version of N8-GP, NN7170, which is currently in phase I trials.

The haemophilia pipeline has moved away from PEGylated and protein fusion formulations; new methods for extending factor half-life are being explored. For example, Bioverativ/Amunix's BIVV 001 for haemophilia A and BIVV 002 for haemophilia B are recombinant EHL factor agents in early-stage development that use XTENylation, a novel method of half-life prolongation.

Extending half-life is also being tried for bypass agents. OPKO is developing OPK88005, a C-terminal-peptide-modified FVIIa, for haemophilia A and B with inhibitors, for potential prophylactic use.

Rani Therapeutics and Shire are evaluating the use of the Rani Pill technology for the oral delivery of FVIII. The efficacy and bioavailability of this approach compared to intravenous formulations is unknown.

Market outlook

In 2017, the EU5 and United States haemophilia drug market achieved combined annual sales in excess of US$6 billion. The market value is forecast to substantially increase, reaching $10 billion by 2027 (Fig. 1). The strong performance of the haemophilia pipeline, particularly of therapies for haemophilia A, is expected to contribute substantially to this sales growth. Haemophilia A is a more commercially attractive area than haemophilia B, as it has a larger patient population and current treatments have not dramatically improved the treatment landscape. Haemophilia B agents coming to the market will face tough competition, as efficacious FIX EHLs are already in use. Although non-factor agents are expected to capture a major share of the market, factor replacement therapies are forecast to remain the dominant treatment option. Non-factor agents could elicit immune responses, and factor replacement may still be required in breakthrough bleeding or surgical procedures. These reasons, along with physician and patient familiarity and satisfaction with factor agents, spur their continued use and development.

Figure 1: Current sales and 2027 market forecast for the haemophilia market.

Sales data are for the EU5 countries (France, Germany, Italy, Spain and the United Kingdom) plus the United States. *Emicizumab, the only non-factor, non-gene therapy available in 2017 (launched November 2017), contributed non-significant sales to 2017 market value. Source: Decision Resources Group.

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