Therapeutic focus – Faster-acting factor VIIs seek to unseat Novo

Analysis

Novo Nordisk does not only dominate in diabetes. The Danish company has also built a strong position in haemophilia through its NovoSeven product, a rescue clotting factor used when patients stop responding to factor VIII and factor IX replacement factors.

Sales of NovoSeven reached $1.6bn last year and the product is forecast to remain one of the largest haemophilia factors until at least 2018, despite a number of companies working on longer and faster-acting factor VIIs – including Novo itself with vatreptacog alfa. Pivotal data on vatreptacog are due next month, although the Danish company’s recent announcement that patients in the study had developed antibodies to the product represents a serious concern. With Baxter and Bayer both pushing ahead with late-stage products, a setback for Novo could present a way in to this section of the haemophilia market (see tables).

Treatment advance

Factor VII is the protein that initiates the coagulation cascade in combination with another molecule called tissue factor. Factor VII replacement products and their analogues are used primarily to stop bleeding in patients who develop inhibitors to two other key proteins that aid in blood clotting – factor VIII in haemophilia A and factor IX in haemophilia B.

Inhibitors are antibodies that occur when the body essentially rejects the replacement clotting factor. It is thought that inhibitors occur in almost a third of patients using recombinant factor VIII, while incidence is much lower with factor IXs, at around 5%.

In first-line treatment of haemophilia A and B, specialists are moving towards prophylactic use of recombinant factor VIIIs and IXs to prevent joint bleeds, which can lead to arthritis and other complications. NovoSeven is used only as needed after a bleed, mainly owing to its short half life of just a few hours.

Fresh frozen plasma or plasma-derived products can be used to replace factor VII. However this can lead to blood volume overload. Thus the launch of the recombinant NovoSeven was a treatment advance when this became available 15 years ago, and it remains the only approved recombinant factor VIIa product on the market,

Evolving options

Just as advances are being made with other clotting factors, a number of companies have been working on improvements to recombinant factor VIIs (Therapeutic focus - Long-acting haemophilia agents set to shake things up, July 26, 2011).

Novo is most advanced with vatreptacog alfa, which it hopes to sell as a much faster-acting agent than NovoSeven. Phase II data presented at the 2010 Ash conference showed that 96% of joint bleeds were well controlled using vatreptacog alfa, in a head-to-head trial that showed a 90% rate of controlled bleeds with NovoSeven.

Novo is due to release results from the 72-patient phase III trial of vatreptacog alfa shortly, most likely in October. However alongside annual results earlier in August the company said anti-drug antibodies were observed in a few patients and, in one patient, a potentially neutralising effect was observed in one sample.

Novo has yet to determine what this means for the project and today confirmed to EP Vantage that the findings continued to be analysed. Analysts believe the finding could raise serious question marks over the product. At the time of the Deutsche Bank described the finding as a “major risk” to the development of the compound.

Admittedly, the product is not seen as a huge contributor to the franchise in the future. Analysts at JP Morgan had pencilled in a launch in 2014 and peak sales of $168m by 2020, while EvaluatePharma consensus has risk-adjusted sales of $33m by 2018. NovoSeven, meanwhile, is still predicted to be a $1.6bn product in 2018.

However, the Danish company will not want to lose a follow-on product that could help protect NovoSeven against competition from other more advanced factor VIIs in development.

Factor VIIa pipeline
Status Product Company Trial ID
Phase III Vatreptacog Alfa/NN1731 Novo Nordisk NCT01392547
BAY 86-6150 Bayer NCT01625390
Phase II BAX 817 Baxter International -
Phase I CSL689 CSL NCT01542619
PF-05280602 Pfizer NCT01439971

Many believe that Bayer’s activated factor VII candidate BAY 86-6150 holds the most potential to eat Novo’s lunch in this area, with the potential for faster and longer clotting action. The German company has already established itself in the haemophilia A space with the factor VIII Kogenate, a product of similar size to NovoSeven with annual sales seen staying steady around $1.5bn out to 2018.

A phase II/III dose-ranging and efficacy trial started in June this year, seeking to recruit 65 patients, comparing BAY 86-6150’s ability to control bleeding episodes against NovoSeven. The 10-hour time frame for bleeding control measured in the primary endpoint makes it competitive with vatreptacog alfa, which measures bleeding control at 12 hours in its pivotal trial.

Assuming the study takes around the same time as the vatreptacog pivotal trial to generate data on the primary endpoint, data could emerge later next year. In a phase I study that recruited 16 patients, no subject developed neutralising antibodies during a 50-day follow-up. The company says the product also has the advantage of a tissue-factor-independent “thrombin burst” that can lead to formation of a stable clot.

Other competitors

At a similar stage in development is Baxter, which has said that a phase III trial with BAX 817 will start by the end of the year. The company has released little information on the product to date.

A bit further back is the Australian blood-products specialist CSL with CSL-689. With the longest half-life of the products in waiting, with up to 20 hours’ extension over NovoSeven, this has the potential to be used just three times weekly against daily doses of the competition, and is hoped to have decreased immunogenicity.

But as it is in phase I, much remains to be proved. Its first-in-man safety trial in 40 healthy volunteers began earlier this year, but the company has disclosed little beyond that.

Meanwhile, in January Pfizer initiated a phase I trial of PF-05280602, looking to recruit 36 male patients with severe hemophilia A or B, with or without inhibitors to factors VIII or IX.

Little change for now?

As the table below shows, analysts' sales forecasts suggest that few are modelling huge swings in the haemophilia market in the next few years.

However, this picture could easily change in the coming months, as a host of data appears on newer clotting factors designed to improve on the incumbents that have dominated the market for years. Biogen Idec for example is due to reveal pivotal results by the end of the year for much longer-acting factor VIII and factor IX agents, which could extend dosing intervals from every other day to as infrequently as once weekly (Event – Biogen's long-acting haemophilia agents near clinical validation, August 14, 2012).

These also hold the promise of much lower rates of antibody formation – if the 30% incidence of inhibitors seen with the current factor VIII agents can be halved, for example, the need for costly treatment with factor VIIs would be much reduced.

So while faster and longer acting factor VII products do hold the potential to challenge NovoSeven, perhaps a greater threat to the franchise lies in the development of these more advanced recombinant VIII and IX factors.

Top 10 haemophilia products in 2018 Annual sales WW ($m)
Rank Product Company Pharmacological Class 2011 2018
1 Advate Baxter International Factor VIII 1,911 1,995
2 Kogenate Bayer Factor VIII 1,496 1,613
3 NovoSeven Novo Nordisk Factor VIIa 1,559 1,572
5 BeneFIX Pfizer Factor IX 693 813
6 ReFacto AF/Xyntha Pfizer Factor VIII 506 764
7 Humate P CSL Factor VIII 542 599
9 Alphanate Grifols Factor VIII & von Willebrand factor 232 340
10 Helixate CSL Factor VIII 512 279

To contact the writers of this story email Jonathan Gardner at jonathang@epvantage.com or Joanne Fagg at joannef@epvantage.com.

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