Therapeutic Focus – is longer action the X factor for factor IXs?

Analysis

Baxter’s US filing of BAX 326 yesterday puts the drug in pole position among several recombinant factor IX treatments expected to enter the market in the next couple of years, with some holding the promise of a less frequent dosing schedule for patients trying to prevent damaging and life-threatening bleeding episodes.

The new longer-acting factors being developed by companies such as Novo Nordisk, CSL and Biogen Idec – the last of which is to release phase III results towards the end of this year – have treatment durations of three to five times that of the current market leader, BeneFIX, an edge that could help them leapfrog the Pfizer product. However, with a clinical hold on the most advanced next-generation factor IX, safety concerns will have to be dispelled to renew confidence in these products (see table).

Uncontrolled bleeding

Haemophilia B is a hereditary blood disorder caused by a lack of blood clotting factor IX. It is a recessive X chromosome-linked disease, so many more males than females suffer from the disorder. Worldwide one in 20,000 males are born with haemophilia B.

This lack of factor IX leads to haemorrhaging in joints or muscles, either spontaneously or in response to trauma. One of the major complications of haemophilia B is chronic joint disease and the leading cause of death related to uncontrolled bleeding is intracranial haemorrhage. Treatment with recombinant factor IX allows patients a life expectancy of around 60 years.

The severity of haemophilia B depends on plasma levels of factor IX. As such severe haemophilia is defined as having less than 1% of the normal level of functional factor IX in the blood; moderately severe patients have 2-5%, and mild 6-30%. The current standard of care for those with severe disease is prophylactic infusions of factor IX two to three times a week, with the aim to maintain factor IX activity above 1% and prevent spontaneous bleeding. Patients can also have episodic treatment of one to three injections to treat spontaneous bleeding episodes.

Pfizer's recombinant factor IX product BeneFIX, which came off patent last year, is the current market leader. It is indicated for the control and prevention of bleeding episodes in adult and paediatric patients, and had sales in 2011 of $693m. But its mean half-life is just 18.8 hours, so longer-lasting products with the potential to improve dosing convenience could steal BeneFIX’s crown.

Regulatory fears

Before they can do that, though, they need the regulators' blessing. Ahead of them in the regulatory queue are two drugs awaiting approval, and one of them might have to wait a little bit longer. IB1001 was filed with the FDA by Ipsen and Inspiration Biopharmaceuticals in April, but in July the agency placed a clinical hold on the drug after unusually high levels of antibodies to proteins from the cells used to manufacture IB1001 were seen in patients (Ipsen follows woeful first half with sentiment-battering clinical hold, July 10, 2012). Further testing is ongoing, with results expected towards the end of this year.

IB1001 is essentially a biosimilar version of BeneFIX, and is therefore likely to have the same dosing schedule. Sales of BeneFIX are expected to flatten out over the next few years, according to EvaluatePharma – biologicals rarely suffer from the same sales erosion as small-molecule drugs when they lose patent protection. Should IB1001 finally gain approval, a smart pricing strategy will be needed to see it take share from the tried and tested leader, but first the FDA's safety fears must be allayed.

Last month, Ipsen and Inspiration renegotiated their partnership, with Inspiration granting Ipsen commercial rights for IB1001 in territories including Europe, Russia, China and Australia, in return for up-front and milestone payments, investment, and a higher royalty on IB1001 sales. Inspiration remains responsible for the worldwide development of IB1001. The drug is also awaiting approval in Europe, and the European Medicines Agency is due to make a recommendation towards the end of this year.

A more recent development is Baxter's FDA filing of its recombinant factor IX, BAX 326, which is also expected to be submitted to European regulators. Like IB1001, BAX 326 is not clinically differentiated from BeneFIX, according to analysts at UBS. If Baxter is to remain competitive in the factor IX space, though, it will have to produce a longer-acting factor IX to compete with the likes of Biogen, CSL and Novo Nordisk, which are snapping at its heels in phase III.

In with the new

Biogen’s longer acting recombinant factor IX, rFIXFc, is leading the way in phase III, with data expected to report by the end of the year (Event- Biogen’s long acting haemophilia agents near clinical validation, August 14, 2012).

Alongside its European partner Swedish Orphan Biovitrium, Biogen is aiming to extend the dosing intervals for haemophilia from every other day to once weekly. In a phase I/II trial rFIXFc had a half-life three times greater than exisiting therapies such as BeneFIX, and was well tolerated. There were no signs of injection site reactions or antibody development.

Analysts at RBC expect market entry mid-2013, while EvaluatePharma forecasts $120m sales by 2018. rFIXFc is also being tested in pediatric patients up to 11 years old, with data expected 2014-15.

Novo Nordisk’s pegylated recombinant factor IX N9-GP is next in line with a phase III trial slated to complete in mid-2013. In a phase I trial in 16 patients, the half-life of the N9-GP was 93 hours, better than that of Biogen’s rFIXFc and a fivefold improvement over BeneFIX. There were no reported incidences of inhibitor development; however, one patient developed transient hypersensitivity symptoms during administration of the drug and was excluded from the pharmacokinetic analysis.

The ongoing phase III trial in 74 male patients 13-70 years old is testing two doses prophylactically once weekly, plus on-demand treatment. Primary outcomes will measure the incidence of inhibitory antibodies.

Analysts at RBS forecast market entry in 2014, with sales of $47m expected in 2018 according to EvalulatePharma data. Again the drug is to be trialled in pediatric patients and those undergoing surgical procedures with haemophilia B.

Following Novo is CSL654 from the Australian blood products specialist CSL. CSL654 is a fusion protein linking recombinant factor IX with recombinant human albumin. In phase I the half-life of the drug was more than five times longer than current recombinant factor IX therapy. There were no reported incidences of inhibitors to factor IX or antibodies to the drug.

A phase II/III study is to recruit 60 male patients between the ages of 12 and 65 with severe haemophilia B. Its primary outcomes include change in frequency of spontaneous bleeding events and number of patients developing inhibitors against factor IX. Testing prophylaxis and on-demand treatment, the trial will report toward the end of 2013.

Analysts at RBS expect market entry in 2015, while EvaluatePharma forecasts sales of $92m in 2018. Another phase III study is planned to examine the drug in male patients under 12 years old.

Gene target

In a completely different approach, ReGenX Biosciences is attempting to combat haemophilia B using gene therapy. Its product, known simply as the hemophilia B program, involves delivery of the Factor IX gene to the liver using recombinant adeno-associated viral vectors, and is currently in phase II trials. If successful the advantage of ReGenX's therapy will be its permanence: rather than the regular infusions most haemophiliacs must endure, transfection of the healthy copy of the gene into the liver is a one-off, enabling patients to produce Factor IX themselves for the rest of their lives.

No gene therapy has yet made it to market anywhere in the world, but the positive opinion for UniQure's Glybera (Glybera gets happy surprise in form of European backing, July 20, 2012) shows that regulatory authorities are at least open to persuasion. However, Glybera treats an extremely rare and underserved condition, lipoprotein lipase deficiency; with effective haemophilia B treatments already available, ReGenX will have to demonstrate an extraordinary advantage to get the regulators on side.

Factor IX pipeline
Status Product Generic name Company Trial ID
Filed IB1001 trenonacog alfa Ipsen/Inspiration Biopharmaceuticals Clinical hold
NCT01271868
NCT00768287
Immunine/BAX 326 factor IX concentrate (purified; virus-inactivated) Baxter International NCT01174446
Phase III CSL654 - CSL NCT01496274
N9-GP factor IX Novo Nordisk NCT01333111
rFIXFc factor IX Biogen Idec/Swedish Orphan Biovitrum NCT01027364
Phase II Hemophilia B Program (Factor IX gene therapy) - ReGenX Biosciences -

To contact the writers of this story email Elizabeth Cairns at elizabethc@epvantage.com or Joanne Fagg at joannef@epvantage.com

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