Green light to market Hemlibra for hemophilia A with inhibitors in the US

This article is a Clarivate Analytics Market Insight report, an ongoing series featuring expert reviews of hot topics in the pharma/biotech field, with analysis and discussion on the factors currently affecting the industry.


Roche Holding’s Hemlibra (emicizumab-kxvh) has been approved in the U.S. for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A developing factor VIII (FVIII) inhibitors. The innovative therapy, which mimics the function of FVIII, is the first to be approved in close to 20 years to prevent or reduce bleeding in this setting.  The agent was approved by the FDA in November 2017, almost three months ahead of the PDUFA date scheduled for Feb. 23, 2018, and is set to challenge standard of care FVIII replacement therapy with its novel action, self-administration and weekly injection profile.


Long-awaited anti-hemorrhagic therapy


Hemophilia A is a rare genetic disorder caused by missing or defective FVIII, a blood clotting protein. Approximately one in three people with severe hemophilia A can develop inhibitors to FVIII replacement therapies, resulting in risk of repeated bleeds and life-threatening bleeding. For decades, and prior to the introduction of long-acting recombinant clotting factors in 2014, hemophilia patients have relied upon recombinant replacement therapy that needs to be administered as often as every other day.


Hemlibra was conceived as a once-weekly, subcutaneous approach to tackle and circumvent the immunogenicity arising from standard recombinant FVIII therapy. The humanized bispecific monoclonal IgG4 antibody against factors IXa and X, initially discovered by Roche’s subsidiary Chugai and jointly advanced with Roche and Genentech, is designed to mimic FVIII and activate the natural coagulation cascade to restore the blood clotting process. The completely new mechanism to hemophilia treatment could drive a major switch from older products. Additionally, positive top line data released at the time of approval have shown Hemlibra’s superiority versus standard FVIII prophylaxis in hemophilia A without inhibitors, which could be a potential trigger for Hemlibra to become a disruptive treatment and change the hemophilia A landscape


According to Cortellis Consensus sales forecasts (source Thomson Reuters I/B/E/S), the drug could potentially reach sales of $3.8 billion in 2023. (See Figure 1.)



Figure 1. Actual sales and forecasts of drugs competing in the hemophilia A landscape. Source: Cortellis Consensus sales forecasts (via Thomson Reuters I/B/E/S)


Hemlibra for treating hemophilia A


The BLA for Hemlibra was filed in June 2017 seeking market approval for hemophilia A with inhibitors. The filing was based on data from two large ongoing pivotal studies that already demonstrated the treatment’s safety and efficacy. In the 109-patient, phase III HAVEN 1 trial, assessing the drug in hemophilia A sufferers aged 12 years or older and developing FVIII inhibitors, the prophylactic treatment resulted in an 87% reduction in bleed rate compared with on-demand bypassing agent (BPA) with no prophylaxis. After a median observation time of 31 weeks, 62.9% of patients receiving Hemlibra experienced zero treated bleeds compared with 5.6% of those receiving on-demand treatmentsAdditionally, a first-of-its-kind intra-patient comparison demonstrated a 79% decline in number of bleeds compared with previous treatment with BPA prophylaxis collected in a non-interventional study prior to enrollment.


The second pivotal trial, HAVEN 2, assessing Hemlibra prophylactic treatment in hemophilia A pediatric patients with inhibitors began in June 2016, and results reported to date are consistent with HAVEN 1 data. According to interim data reported in June 2017, only one of 19 children experienced a bleeding episode that required treatment while on Hemlibra. Additionally, an intra-patient analysis of 13 children who had participated in the non-interventional study demonstrated a 99% decline in treated bleeds for patients receiving Hemlibra prophylaxis compared with previous treatment with a BPA either as prophylaxis (n = 12) or on demand (n = 1). Most importantly, no thrombotic adverse events have been observed in this trial so far. Injection site reactions, headache and arthralgia were the most common adverse events occurring in 10% or more of patients receiving Hemlibra prophylaxis in pooled studies. Data from the HAVEN 1 and 2 studies are being reviewed under accelerated assessment by the European Medicines Agency and updated data from both trials with six-month follow-up are expected at the 59th Annual Meeting and Exposition of the American Society of Hematology (ASH) in December. A Japanese filing is also under review.


Key positive top line data from the HAVEN 3 trial in hemophilia A patients without inhibitors were reported following the FDA approval. This trial compared Hemlibra prophylaxis once weekly or once every other week versus on-demand therapy in 152 patients aged 12 years or older who were previously treated with FVIII therapy either episodic or for prophylaxis. The trial met both primary and key secondary endpoints, demonstrating that once-weekly Hemlibra led to a reduction in the number of treated bleeds over time versus patients receiving no prophylaxis. Notably, an intra-patient comparison showed superiority of once-weekly Hemlibra versus prior VIII prophylaxis. Patients did not experience thrombotic microangiopathies (TMA) or thrombotic events and the most common adverse events were injection site reactions, with no new safety signals observed.


A further trial, HAVEN 4, is evaluating Hemlibra prophylaxis dosed every four weeks in patients aged 12 years or older with hemophilia A with or without inhibitors. The trial is expected to be completed in July 2018.


Approval with a safety warning                                  


Despite the FDA’s nod to market Hemlibra based on superior efficacy in reducing the number of bleeds versus on-demand treatment, the U.S. regulatory body has decided to place a black-boxed safety warning on the U.S. label due to unexpected thrombotic events experienced during the rescue therapy to treat bleeds for 24 hours while on Hemlibra.


In the HAVEN 1 trial, a total of five patients who, in addition to Hemlibra, were receiving prothrombin treatment for breakthrough bleeds, developed blood clots; three of these were associated to TMA, an uncommon adverse event in this population. However, all the events occurred in patients that had used Shire’s FEIBA or Novo Nordisk’s NovoSeven (eptacog alfa) activated prothrombin complex concentrate as bypassing agents at higher-than-recommended doses for multiple days, potentially predisposing to an hypercoagulable state. Remarkably, one of the three subjects experiencing TMA died of rectal hemorrhage in the registrational trial, although the reason was attributed to the patient’s decline of a blood transfusion following hemorrhage. In essence, the combination of Hemlibra prophylaxis plus FEIBA or NovoSeven aimed to stop breakthrough bleeds in these five patients due to the lack of efficacy of Hemlibra prophylaxis alone appears to have resulted in increased levels of thrombin causing excess clotting and ultimately triggering the thromboembolic events. Controversially, Shire filed an injunction accusing Roche of unlawful disparagement of its BPA FEIBA, and of inaccurate communication and misleading characterization of the serious adverse events that occurred in the phase III trial.


Hemophilia A landscape


FVIII deficiency is the type of hemophilia disorder with the largest market opportunity, affecting around 320,000 people worldwide, approximately 50% to60% of whom suffer from the severe form of the disorder. About 20,000 people are estimated to have hemophilia in the U.S. The current standard therapies for hemophilia A, already in the market for more than 15 years, are recombinant versions of FVIII. These include Shire’s Advate (octocog alfa) and Recombinate (recombinant human FVIII), and Bayer’s next-generation Kogenate (octocog alfa) formulations. Improved FVIII versions offering dosing benefits versus older replacement therapies started to enter the market in July 2014 with Bioverativ’s Eloctate (efmoroctocog alfa), followed by others including Shire’s Adynovate (rurioctocog alfa pegol) and CSL’s Afstyla (lonoctocog alfa). Although patients now have these extended half-life formulations within reach, high pricing has likely increased the barrier to switching, in addition to other factors such as strong brand loyalty and the fact that well-treated patients are less likely to switch to new products if their current factor replacement therapy is working well. Shire’s FEIBA, an activated prothrombin complex concentrate, is the current leading prophylactic treatment for hemophilia A patients with inhibitors.


According to Cortellis total Consensus forecast sales, Advate is expected to maintain its market leader status over the next three years, although analysts predict a bearish tendency starting in 2018. Extended half-life products are anticipated to increase their share over the next decade, commencing with strong performances for Bioverativ’s Eloctate and followed by Shire’s Adynovate and CSL’s Afstyla. NovoSeven is also expected to cede significant share to Hemlibra, which is predicted to lead sales in 2021, becoming a longer-term rival to Advate. Other longer-term players gaining share within this market include Novo Nordisk’s N8-GP (sustained-release turoctocog alfa), which is expected to be filed in 2018, and once-weekly damoctocog alfa pegol, already filed for approval in major markets.


While treatment of hemophilia A with inhibitors has lacked in innovation, Hemlibra’s early approval now makes solid the expectations of Roche’s bispecific FIXa/X antibody becoming the one agent that has the potential in the near term to change inhibitor treatment. And most importantly, following positive topline data from the HAVEN 3 trial, the potential for Hemlibra to gain access to the broader hemophilia A market has grown considerably. Additionally, the drug’s once-weekly dosing would also provide a more pronounced advantage over short-acting rFVIII products than the current longest half-life products Eloctate (once-every-three to five-day dosing) or Adynovate and Afstyla (twice-weekly dosing). In fact, longer-acting treatment is one of the biggest unmet needs for hemophilia, and Hemlibra’s half-life and dosing frequency could leverage convenience advantages and increase patient/caregiver satisfaction. Additionally, the HAVEN 4 trial testing once-monthly dosing of Hemlibra in hemophilia A with or without inhibitors is ongoing, and if successful, this would significantly differentiate the drug from current therapies. However, more likely than not, the impending launch of Roche’s drug will initially encounter big barriers to drive drug switching from fierce old competitors such as Advate. With an expected annual price of around $482,000 for the first year and $448,000 for subsequent years, payers may prefer existing options in patients without inhibitors based on cost, such as first-line BPA therapies for bleeding control, including Novo Nordisk’s recombinant activated FVII product NovoSeven and Shire/Baxalta’s activated prothrombin complex concentrate FEIBA VH.


Further competition to Hemlibra is expected to come from Bayer’s next-generation Kogenate formulations, in particular the twice-weekly, unmodified, full-length rFVIII product, Kovaltry. Although efficacy is still to be proved in late-stage trials, competition from next-generation extended half-life FVIII products such as Shire/Baxalta’s BAX-826 and Bioverativ/Swedish Orphan Biovitrum’s FVIII-VWF-XTEN with once-weekly or once-monthly dosing profiles could represent a longer-term threat for Hemlibra. Likewise, potential future competition from disruptive  gene therapy approaches could arise, such as Alnylam Pharmaceutical’s RNAi therapeutic against antithrombin mRNA, fitusiran, although  its phase II/III development for once-weekly, once-monthly or twice-monthly treatment of hemophilia A and B is currently on hold after a patient death, or from BioMarin Pharmaceutical’s valoctocogene roxaparvovec  (BMN-270), an AAV5-based gene therapy, which has shown positive preliminary phase II data and phase III studies are planned later this year.


A number of legal disputes between the Irish company and Roche are ongoing in addition to the accusation of misleading statements with regard to the HAVEN 1 serious adverse events. In an effort to preserve its dominant share in the hemophilia space, Shire’s owner, Baxalta, has sued Chugai over U.S. and Japanese patent infringement, seeking to prevent commercialization of Hemlibra. While non-infringement is still to be proved, the Swiss company is bustling to bring the drug to the U.S. market promptly.




While many patients suffering from Hemophilia A still rely on well-established standard factor replacement or bypassing therapy, these products possess huge limitations in terms of convenience of administration that Hemlibra could overcome. The recent approval of Roche’s drug in conjunction with positive top line HAVEN 3 data generates good prospects for Roche to ultimately revolutionize the hemophilia A competitive space and grasp a substantial share of this multibillion-dollar market. At the same time, it may benefit all people with hemophilia A regardless of inhibitor status while enhancing their quality of life. However, further clinical evidence will be required.


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