Therapeutic focus - Long-acting haemophilia agents set to shake things up

The staid, stable world of haemophilia treatment is due for a shakeup. Biogen Idec and Swedish Orphan Biovitrum’s rFVIIIFc, a long-acting recombinant factor VIII, has reported detailed early-stage data showing it could significantly reduce treatment frequency for patients with the genetic platelet deficiency.

rFVIIIFc has raced to the front of the field for long-acting factor VIIIs, with launch projected for 2013 in haemophilia A if pivotal trials are successful (see tables). Blockbuster sales are being mooted but it is still considered a high-risk play; the holy grail would be a product that could be infused just once a week for prophylaxis against uncontrolled bleeding, compared with three times or more a week for the most severely ill patients today. Whilst development is progressing for many aspects of haemophilia – such as the rarer factor IX deficiency and combating resistance – the biggest excitement surrounds the promise of a long-acting treatment in haemophilia A, which could radically shift the treatment of this condition.

Frequent dosing

The reason recombinant and plasma-derived factor VIIIs on the market today must be dosed so frequently is that they have a short half-life of between eight and 12 hours. As a large protein, factor VIII cannot be prepared for subcutaneous injection; thus patients must undergo IV infusion.

Prophylactic infusion, as opposed to on-demand care, is a relatively recent innovation in treating the most severe haemophiliacs. However, it has necessitated the use of central IV lines in many patients, particularly children. Thus reducing the frequency of infusions in prophylactic treatment protocols could eliminate the need for the IV line and reduce the chances of complications such as infection and thromboses.

Available for eight years, market leader Advate is one of the youngest products for treating haemophilia and is forecast for steady sales growth – rising from $1.8bn in 2010 to $2.6bn in 2016 (see table). But as a sign of both the stability of the market and the changing treatment protocols, even Bayer’s recombinant Kogenate, nearly 20 years on since launch, is a blockbuster expected to expand sales through 2016.

Thus, it is a rich vein to mine by an innovative product promising to reduce the burden of the evolving treatment practices.

Factor VIII market Annual Sales WW - ($m)
Product Generic Name Details Company First Introduction 2008 2010 2012 2014 2016
 Advate  factor VIII (procoagulant)  First fully non-human product  Baxter International  2003  1,497  1,800  2,078  2,352  2,629
 Kogenate  octocog alfa  Recombinant; derived from baby hamster kidney cells  Bayer  1993  1,246  1,332  1,593  1,708  1,612
 Humate P  factor VIII  human plasma derived  CSL  1987  524  573  588  650  712
 ReFacto AF/Xyntha  moroctocog alfa  recominant; derived from chinese hamster ovary cells   Pfizer  2008  363  404  477  535  582
 Helixate  octocog alfa  Recombinant; derived from baby hamster kidney cells  CSL  1994  440  529  559  612  443
 Alphanate  factor VIII; von Willebrand factor (human)  human plasma derived  Grifols  1994  178  207  244  272  307
 Hemofil M  factor VIII   human plasma derived  Baxter International  1966  265  258  261  270  280
 Recombinate  antihemophilic factor (recombinant)  recominant; derived from chinese hamster ovary cells   Baxter International  1992  469  295  227  192  155
 Haemoctin SDH  factor VIII  human plasma derived  Biotest  1993  119  119  125  129  132
 Koate-DVI  factor VIII  human plasma derived  Grifols/Talecris  1999  40  57  76  87  98
Total 5,153 5,573 6,226 6,814 6,983


Enter rFVIIIFc. The detailed data from a phase I/II trial disclosed by Biogen and Swedish at the International Society on Thrombosis and Haemostasis congress showed that rFVIIIFc had a half-life 1.7 times that of Advate.

Whilst that might not necessarily lead to a once-a-week treatment, many observers believe a product with a half-life 1.75 times that of current therapies would be a step forward – for a patient now undergoing 150 infusions a year, such an extension in half life would reduce the frequency to 85, according to analysts from Deutsche Bank.

It is telling that George Scangos, Biogen Idec's chief executive, recently admitted that he doubts the product will allow weekly dosing, although they expect "substantial prolongation", he told the Goldman Sachs Healthcare Conference last month. The widespread appearance of neutralising antibodies, which would indicate a patient is becoming immune to the treatment, remains the biggest threat to the products success, he said. Along with more conclusive data on the half life, this will be the main focus when late-stage data emerges on the product.

Biogen and Swedish already have rFVIIIFc in a pivotal trial called Along expected to report data in the second half of 2012 or early 2013. It is an open-label trial in 150 patients testing low and high dose prophylaxis, along with an on-demand arm.

As a sign of the high-risk nature of rFVIIIFc, few analysts are willing to forecast annual sales for the product yet; if successful, it will have a clear run at the market, however. Deutsche Bank predicts peak sales of $3.2bn in 2026, signifying how long, as with the current market, the product’s tail may be. Likewise, ISI Group forecasts $3bn in peak sales, and the group's analysts do include sales in their models, pencilling in $220m in 2016 for Biogen’s market of North America and all countries other than Europe, Russia and the Middle East.


As the tabel below shows, the most immediate pipeline threat, in that it is also forecast to launch in 2013, appears to be Novo Nordisk’s NN7008; however, it is essentially a biosimilar not considered a long-acting factor VIII.

On the other hand, there are commercial implications: the Danish group has commercial experience in the haemophilia field, as its NovoSeven, a factor VIIa, is used to prevent and treat bleeding episodes in patients whose haemophilia A or B has developed inhibitors, or resistance, to factor VIII or XI treatment. Thus Novo has an established and experienced sales force, which Biogen and Swedish will need to develop in order to advance rFVIIIFc.

With the exception of Bayer’s BAY 81-8973, none of the products in phase III are considered long acting. Bay 81-8973 is being trialled at two to three times a week, compared with the every-other-day dosing of predecessor product Kogenate.

Phase I holds greater threats: All are tabled as long-acting alternatives from established haemophilia players Novo, Bayer, and Baxter International. The Novo and Bayer products all rely on pegylation, the attachment of a methoxy polyetheyline glycol, to the protein factor VIII to extend half-life.

Sustained success for these R&D products will likely have analysts reassessing the persistence of options currently on the market. Patients and physicians will clearly welcome a product that reduces the burden of treatment; a stumble from the Biogen and Swedish therapy, however, will only reinforce the relative durability of the currently marketed factor VIIIs.

Selected Factor VIII pipeline
Product Generic Name Company Originator First Introduction Details Ongoing studies
Phase III rFVIIIFc factor VIII Biogen Idec/Swedish Orphan Biovitrum Syntonix Pharmaceuticals  2013 Fully recombinant, Fc fusion technology, long acting NCT01181128 (phase II/III)
NN7008 factor VIII Novo Nordisk Novo Nordisk  2013  Essentially a biosimilar; not considered long acting NCT01138501, NCT00840086, NCT00984126
Human-cl rhFVIII factor VIII Octapharma Octapharma  2014 Recombinant; derived from human embryonic kidney cell line, not considered long acting NCT00989196, NCT01125813
OBI-1 factor VIII (recombinant) Inspiration Biopharmaceuticals/Ipsen Emory University  2014 Recombinant porcine factor VIII; not considered long acting NCT01178294 (phase II/III)
BAY 81-8973 factor VIII Bayer DIREVO Biotech  - Kogenate follow on; slightly longer acting  NCT01233258, NCT01029340, NCT01311648
Phase I NN7088  GlycoPEGylated Factor VIII Novo Nordisk Neose Technologies  - Long acting NCT01205724
 BAY94-9027 PEGylated BDD-rFVIII  Bayer Bayer Long acting  NCT01184820
ARC19499  subcutaneous rFVIII Baxter International Archemix Long acting  NCT01191372

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