Looking beyond factors in haemophilia

Next-generation projects, including gene therapies, could soon be shaking up the haemophilia market.

The haemophilia market is set for a shake-up – in the near term with Roche’s bispecific antibody emicizumab and in the longer term with even more convenient, longer-lasting options. These projects could put a squeeze on the makers of traditional factor-replacement products, with Shire having the most to lose.

Of the emerging pipeline, Alnylam’s RNA interference therapy fitusiran holds promise, while further into the future one-off gene therapy could finally become a reality, with Spark Therapeutics and Biomarin leading the charge (see table below). However, with the long-term safety of gene therapy still unknown and price a potential sticking point, these contenders might have a tough time gaining traction if the first wave of new therapies succeeds.

That wave is led by Roche’s emicizumab, which is awaiting approval in haemophilia A patients with inhibitors, antibodies rendering front-line factor VIII clotting factors ineffective (Vantage Point – Does Roche have the haemophilia X factor?, August 09, 2017).

And data later this year from the Haven 3 trial could give it a shot in non-inhibitor patients even though this population is already effectively treated by factor-replacement therapy. All else being equal, convenience will be key: emicizumab is a once-weekly subcutaneous injection while prophylactic factor VIII therapy is given intravenously several times a week.

Selected haemophilia pipeline
Project Company Mechanism Indication Trial(s)
Emicizumab Roche Anti-factor IXa/X bispecific MAb Haemophilia A, inhibitors (filed) Haven 1 (NCT02622321); Haven 2 (NCT02795767)
Haemophilia A, no inhibitors (phase III) Haven 3 (NCT02847637)
Fitusiran Alnylam Anti-thrombin III RNAi therapeutic Haemophilia A & B, inhibitors (phase III) Atlas-INH; Atlas-PPX (recently initiated)
Haemophilia A & B, no inhibitors (phase III) Atlas-A/B; Atlas-PPX (recently initiated)
BMN 270  Biomarin AAV-factor VIII gene therapy Haemophilia A, no inhibitors (phase II) NCT02576795
SPK-8011 Spark Factor VIII gene therapy Haemophilia A, no inhibitors (phase II) NCT03003533
SPK-9001 Spark/Pfizer Factor IX gene therapy Haemophilia B, no inhibitors (phase II) NCT02484092
AMT-060 Uniqure Factor IX gene therapy Haemophilia B, no inhibitors (phase II) NCT02396342
SB-525 Sangamo/Pfizer Factor VIII gene therapy Haemophilia A, no inhibitors (phase I/II) NCT03061201
SB-FIX Sangamo Factor IX gene therapy Haemophilia B, no inhibitors (phase I/II) NCT02695160
SHP654 Shire Factor VIII gene therapy Haemophilia A, no inhibitors (phase I) -
Source: EvaluatePharma.

Alnylam and Sanofi’s fitusiran, a subcutaneous once-monthly project, is more convenient still. In addition, the volume of injection is smaller, which could mean less painful administration, and it does not need to be refrigerated. “These things are not nearly as important as safety and efficacy,” says Guy Young of the Children’s Hospital Los Angeles. “But they are additional advantages.”

The companies believe that it is not just convenience where fitusiran might have an edge, however. “Whether it’s factor replacement or a bispecific antibody, patients still have peaks and troughs [in factor activity],” Baisong Mei, Sanofi's senior global project head, Alnylam portfolio, tells EP Vantage. “We have thrombin generation consistently coding to a normal range – this way we’ll eliminate the peak-and-trough issue and hopefully will see some benefit to patients, although that remains to be seen.”

Dr Young is “very impressed” with the data seen with fitusiran so far, but with phase III trials only just about to start – in haemophilia A and B patients both with and without inhibitors – Alnylam and its partner Sanofi are some way behind Roche.

Like emicizumab, fitusiran should find it easier to penetrate the underserved inhibitor segment, but gaining market share will be trickier in non-inhibitor patients, where any new products will need to show efficacy and safety comparable to existing factor-replacement therapies.

Unlike emicizumab, fitusiran could also be used in haemophilia B patients, who account for around 20% of cases of haemophilia.

Just the once?

The more distant future holds the prospect of gene therapy, where Biomarin and Spark are the leading contenders. Both groups presented phase I/II data at last month’s International Society on Thrombosis and Haemostasis (ISTH) meeting; the former with its haemophilia A candidate BMN 270 and the latter with SPK-9001 in haemophilia B, which is being developed in collaboration with Pfizer.

“Biomarin has shown full correction in haemophilia A, and Spark has shown very significant correction in haemophilia B,” summarises Johannes Oldenburg of the University of Bonn.

Since then, Biomarin has announced plans to begin two separate phase III trials by the end of the year, each testing a different dose of BMN 270. And Spark has reported encouraging early results with its haemophilia A candidate SPK-8011, albeit only in three patients so far (Snippet roundup: Two approvals, two setbacks and a price war, August 4, 2017). 

Others involved in the haemophilia gene therapy space include Sangamo, which is enrolling patients into a phase I/II trial of its haemophilia A candidate SB-525 after signing up Pfizer as a partner in May, and Uniqure, whose haemophilia B project AMT-060 appears to fall short of Spark's SPK-9001 on factor IX activity. Uniqure presented updated results from its 10-patient phase I/II study presented at ISTH and plans to meet regulators by the end of the year to discuss further trials of AMT-060. 

“Gene therapy for haemophilia is now almost in place from a proof-of-principle [perspective],” says Professor Oldenburg.

Dr Young concludes: “I was a gene therapy sceptic for a while, but the data I’ve seen recently look quite promising. I’m more optimistic about gene therapy than I ever have been, but I think we’re at least five to seven years away from a commercial product.”

He adds that with such a novel approach safety will be paramount, and it is unclear how many years of follow-up regulators will need to see before granting approval.

Meanwhile, Professor Oldenburg says that even if a gene therapy reaches the market safety worries could hinder uptake. “There might be patients who fear very late-onset side effects. You never know what might happen in 20-30 years with these therapies.” After previous safety scandals, haemophilia patients are notoriously conservative and reluctant to switch therapies, making this a particularly relevant issue in this market.

Another problem for gene therapy developers could be enrolling patients into pivotal trials if and when emicizumab and fitusiran become available. “It’s entirely possible that patients will be perfectly satisfied with those, and won’t even want to participate in gene therapy trials,” says Dr Young.

Unlike emicizumab and fitusiran, gene therapy is only being developed for non-inhibitor patients so will be fighting for a foothold in this already crowded market. If its developers can convince regulators, doctors and patients on safety, they might win out with the promise of a treatment that could last a lifetime.


The promise of a once-and-done treatment raises the issue of how these products will be priced, with payers needing to balance the up-front cost of gene therapy with its longer-lasting effects.

“I think there’s going to have to be a shared-risk model,” says Dr Young. “If the payer pays $2m for a gene therapy product, which is not out of the realm of possibility, and it fails and the patient has to go back to factor therapy, the payer’s not going to want to be on the hook.”

Professor Oldenburg believes that uptake will vary by country and, somewhat counterintuitively, thinks that developing nations are more likely to embrace gene therapy to avoid the cost of long-term factor replacement products. “The average cost of a haemophilia patient is around €100,000-250,000 ($118,000-290,000) per year, so the cumulative effect over time is very significant.”

Gene therapy will obviously have a larger up-front cost, but “in principle, can be offered at a much lower cost than the classical substitution therapies”, he adds.

Meanwhile, gene therapy’s task could be harder in developed countries where older products are more entrenched. “You have resources for the classical products now, and the other treatment options at that time will also be excellent,” Professor Oldenburg says.

In spite of these issues, the haemophilia market could change significantly in the next few years. And this fact will not have escaped Shire, the maker of the number one factor-replacement therapy, Advate. The company has its own gene therapy candidate, SHP654, in phase I and also recently licensed a preclinical bispecific antibody from Novimmune, putting it some way behind the competition.

Ultimately, if the likes of emicizumab and fitusiran and, later on, gene therapies, can show similar efficacy and safety to current treatments, their convenience could help them win a chunk of the market.

Sanofi’s Mr Mei concludes: “Longer-acting factors have really benefitted patients but still have limitations and people are looking for new [treatments]. People are looking beyond factors.” The strength of the data will dictate whether the current crop of candidates meets their expectations.

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow @ByMadeleineA on Twitter

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