With Roche’s bispecific antibody emicizumab on the horizon, Shire’s haemophilia business is facing the squeeze. While concerns have been voiced in the market, Shire is maintaining a positive line, claiming that it can keep its lead position in this sector.
Juliana Dierks, head of Shire’s global haematology franchise, declines to give any specific details on how it plans to do this, apart from saying that the group is “always interested in innovation”. In-house, early-stage work is approaching the clinic, but Shire needs to make bolder moves if it wants to remain a dominant force in this space (see table below).
Since Roche presented impressive phase III results with emicizumab in June Shire’s stock has fallen 17%, with investors all but writing off the value of its haemophilia franchise, Deutsche Bank analysts believe.
Not that the company should be discounted yet – so far, emicizumab has only succeeded in patients with inhibitors, antibodies rendering front-line factor VIII ineffective. But, if Roche’s project also prevails in the non-inhibitor population, it could emerge as a huge threat to Shire’s factor VIII franchise.
Ms Dierks, however, brushes aside any suggestion that Shire needs to defend its haemophilia base, saying: “We have the broadest portfolio of factor therapy in haemophilia. Factor products will remain a necessary option for the foreseeable future.”
Still, the proportion of Shire’s sales coming from its haemophilia products is forecast to shrink over the next few years, according to EvaluatePharma sellside consensus – and expectations could fall further still if emicizumab takes off.
|Shire's haemophilia products/pipeline|
|Global sales ($m)|
|Advate||Haemophilia A||Factor VIII||1,438||1,859|
|Adynovate||Haemophilia A||Factor VIII||81||518|
|Feiba VH||Haemophilia A||Anti-inhibitor coagulant complex||435||303|
|Rixubis||Haemophilia B||Factor IX inhibitor||43||216|
|Recombinate||Haemophilia A||Factor VIII||105||155|
|Obizur||Haemophilia A||Factor VIII||20||115|
|Hemofil M||Haemophilia A||Factor VIII||63||89|
|Proplex-T||Haemophilia B||Factor IX inhibitor||25||45|
|Xyntha||Haemophilia A||Factor VIII||-||-|
|Autoplex T||Haemophilia A||Anti-inhibitor coagulant complex||-||-|
|Prothromplex||Haemophilia A & B||Prothrombin complex||-||-|
|Feiba NF||Haemophilia A & B||Anti-inhibitor coagulant complex||-||-|
|Immunine||Haemophilia B||Factor IX inhibitor||-||-|
|Immunine VH||Haemophilia B||Factor IX inhibitor||-||-|
|Kryobulin||Haemophilia A||Factor VIII||-||-|
|Immunate Stim Plus||Haemophilia A||Factor VIII||-||-|
|Factor VII||Haemophilia A||Factor VII||-||-|
|SHP654||Haemophilia A||Factor VIII gene therapy||-||-|
|SHP648||Haemophilia B||Factor IX gene therapy|
|NIBX-2101||Haemophilia A||Anti-factor IXa bispecific MAb||-||-|
|Total Shire sales||10,886||18,883|
The initial indication for Roche’s candidate is likely to be haemophilia patients who have developed inhibitors, who currently have few options. This would hit Shire’s bypassing agent Feiba, which can be given as a rescue therapy or prophylactically; however, in the latter use it does not appear to be as effective as emicizumab at preventing bleeding (Vantage Point – Does Roche have the haemophilia X factor?, August 9, 2017).
In spite of the falling forecasts for Feiba Ms Dierks is bullish, “particularly given some of the safety issues we’ve seen in clinical trials with emicizumab”.
As for the non-inhibitor population, where factor VIII therapies like Shire’s Advate currently dominate, Roche’s chances depend on the Haven 3 trial, due to be completed next year.
While on the surface Shire appears unruffled by the prospect of a new rival, it has been spurred into action in the bispecific antibody arena, licensing NIBX-2101 from Novimmune in July. But this project is still in preclinical development, and Ms Dierks will not say when it is set to enter human trials.
Bruce Ewenstein, a senior fellow of clinical development in Shire’s haematology division, says NIBX-2101 is “distinct” from other bispecific antibodies, but will not go into more detail. “I think it’s fair to say that the first-generation product [emicizumab] leaves room for some improvement. It’s not clear how much factor VIII activity it has. But I think it’s possible to develop a molecule that might have more.”
He concludes: “We’re trying to make [NIBX-2101] even more safe and effective.”
Emicizumab’s safety record is not perfect: when used in combination with Feiba, the project has been linked with an increased rate of thromboembolic events. While some investigators have blamed high doses of Feiba over a prolonged time, Mr Ewenstein hints at problems with the Roche bispecific, saying: “These patients were not getting [Feiba] doses that are outside of our label.”
As for what Shire could do to shore up its franchise in the near term, targets already in the clinic are few and far between.
Biogen's spin-off Bioverativ, with a market cap of around $6bn, appears to be in the M&A sweet spot. But its marketed products, Eloctate for haemophilia A and Alprolix for haemophilia B, are factor-replacement therapies, an area where Shire is already well represented.
Bioverativ claims to have the first factor products with prolonged circulation in the body, which technically represent an advance on Shire’s franchise. And it is working on even longer-acting factor therapies that promise once-weekly or less frequent dosing. But even these could be threatened by emicizumab, which has a more convenient subcutaneous delivery.
|Unpartnered novel haemophilia projects in the clinic|
|SB-FIX||Factor IX gene therapy||Sangamo Therapeutics|
|BMN 270||AAV-factor VIII gene therapy||Biomarin Pharmaceutical|
|SPK-8011||Factor VIII gene therapy||Spark Therapeutics|
|Haemophilia B Gene Therapy||Factor IX gene therapy||Freeline Therapeutics|
Shire could acquire a more advanced player in haemophilia gene therapy – its own gene therapy assets are at an earlier stage. Mr Ewenstein tells EP Vantage that Shire has two active projects: SHP654, which is set to start human trials in haemophilia A by the end of the year, and SHP648, in preclinical trials in haemophilia B.
Biomarin and Spark are among the most advanced in this area, with projects in phase II (Vantage Point – Looking beyond factors in haemophilia, August 10, 2017). However gene therapy has much to prove, and represents a very long-term bet.
Shire's chief executive, Flemming Ornskov, has made it clear that rare diseases will remain central to Shire’s strategy, and haemophilia, where it is already strong, is surely a field it needs to defend.
Emicizumab is a huge cloud on the horizon, and to date Shire’s defence has been a follow-on bispecific antibody that is years behind Roche’s candidate. Investors are right to wonder about the longevity of this franchise – but it’s hard to see an easy move for Shire to stem the bleeding in the immediate term.