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.
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|
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|