Approval of IB1001 would offer people with hemophilia B a choice of recombinant therapies

Inspiration Biopharmaceuticals Announces Filing of Biologics License Application (BLA) for IB1001, a Recombinant Factor IX Product for People with Hemophilia B

Approval of IB1001 would offer people with hemophilia B a choice of recombinant therapies

Cambridge, Mass., April 17, 2012 – Inspiration Biopharmaceuticals, Inc. today announced that it has submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for the approval of IB1001, an intravenous recombinant factor IX (rFIX) protein for the treatment and prevention of bleeding in individuals with hemophilia B. 

Based on the terms of its agreement with Ipsen (Euronext: IPN; ADR: IPSEY), Inspiration will receive a $35 million milestone payment associated with its filing of the BLA.  In return, Inspiration will issue a convertible note to Ipsen, bringing Ipsen’s fully diluted equity ownership position in Inspiration to approximately 43.5%.

Approval of IB1001 would represent a significant advance for the hemophilia community, including the estimated 75% of people living with hemophilia worldwide who do not have adequate access to currently available treatments. IB1001 would be the first recombinant therapy for people with hemophilia B introduced in more than 15 years.

Regulatory review is now pending in both the U.S. and Europe. Inspiration’s Marketing Authorization Application for IB1001 was accepted by the European Medicines Agency in September 2011.  The company is currently finalizing plans for additional regulatory filings and preparing for the commercial launch of IB1001.

“The introduction of recombinant factor IX was an important step forward in the treatment of hemophilia B, but a single product is not sufficient to meet the needs of all people affected by this disease,” said John P. Butler, Inspiration’s Chief Executive Officer. “At Inspiration, we are solely focused on the needs of people with hemophilia, and we are proud of the progress we have made towards bringing forward a new choice of treatment for patients. We plan to work closely with regulatory authorities both here in the U.S. and around the world to make IB1001 available as broadly and rapidly as possible.”

The IB1001 BLA filing includes a comprehensive set of pharmacokinetics safety, and efficacy data from a Phase 3 clinical trial in people affected by hemophilia B.  A surgery substudy was also included.

John Taylor, Co-Founder and Chairman of Inspiration, stated, “With sons affected by hemophilia B, Inspiration co-founder Scott Martin and I are acutely aware of the impact of limited treatment options on families. We believe more choice can help us achieve our mission to broaden access to care—increasing the supply of products, driving healthy competition, and supporting prophylaxis, which is rapidly becoming the standard of care in hemophilia. We believe that the approval of IB1001 will be the first step in our journey to make broader access to care a reality for thousands of individuals with hemophilia.”
About IB1001
IB1001 is an intravenous rFIX product being developed for the treatment and prevention of bleeding in individuals with hemophilia B.  IB1001 has completed pivotal Phase 3 clinical studies that support the filling of the BLA, conducted at study sites in the U.S., Europe and India.

To date, IB1001 has been well tolerated by patients and pharmacokinetic (PK) analyses have demonstrated non-inferiority to the one approved rFIX product currently marketed for the treatment of hemophilia B.  Confirmatory PK studies reported at the 53rd Annual Meeting of the American Society of Hematology showed no evidence of development of inhibitors during treatment periods ranging from 4 to 18 months.

Results recently presented at the 5th Annual Congress of the European Association for Haemophilia and Allied Disorders demonstrated that IB1001 provided effective surgical hemostasis in study participants with hemophilia B undergoing major surgical procedures.

About Inspiration Biopharmaceuticals
Inspiration Biopharmaceuticals is exclusively dedicated to developing treatments for hemophilia, with a primary mission to broaden access to care by providing safe and effective recombinant therapies and advancing innovation for people living with hemophilia. Inspiration has a broad portfolio of recombinant hemophilia product candidates, which includes one under review by the FDA and EMA for marketing approval in the U.S. and Europe, one in late-stage clinical development, and two preclinical programs.

Inspiration’s lead product candidates are IB1001 and OBI-1, an intravenous recombinant porcine factor VIII (FVIII) product being developed for the treatment of individuals with congenital hemophilia A who have developed inhibitors against human FVIII, and for individuals with acquired hemophilia.  Inspiration has earlier-stage development programs focused on human recombinant factor VIIa (rFVIIa) for individuals with either hemophilia A or hemophilia B who have developed inhibitors or those with factor VII deficiency, and human recombinant FVIII for individuals with hemophilia A.

Inspiration’s senior management team has broad experience and expertise in hemophilia product development, biologics manufacturing and the successful commercialization of products to treat hemophilia and other rare diseases.

In January 2010, Inspiration entered into a strategic agreement with Ipsen (EURONEXT: IPN; ADR: IPSEY), leveraging the combined expertise and resources of the two companies, to develop a broad portfolio of hemophilia products. As announced in late August 2011, Ipsen and Inspiration extended their agreement to create a hemophilia business unit structure that will act as the exclusive sales organization for all hemophilia products commercialized under the Inspiration brand in Europe. For further information on Inspiration, please visit http://www.inspirationbio.com.
Contacts:
Media
Kate Lewis
Dan Quinn
Feinstein Kean Healthcare
Tel: +1-617-577-8110
Email: kate.lewis@fkhealth.com
dan.quinn@fkhealth.com

Company
Gordon H. Busenbark
Senior Vice President, Chief Financial Officer
Tel: +1-617-588-1802

More new drugs are in the pipeline now than in past decades

By Sarah Aldridge | 02.09.2012  by Hemaware

The marketing terms “new and improved” and “longer lasting” are not limited to the latest brand of chewing gum. They also apply to a long list of therapies now in clinical trials for people with bleeding disorders. Some people have waited years for a new recombinant product; others a lifetime for any factor product to treat their rare condition. For many, their patience is about to pay off.

There are more drugs in the pipeline now than in the past few decades. “The companies’ commitment to continue to work on behalf of patients with bleeding disorders is what’s driving it,” says Val D. Bias, CEO of the National Hemophilia Foundation (NHF). The dilemma facing many patients in the future won’t be a lack of medications, but a plethora of products that act in a variety of ways. (See table “Bleeding Disorders Drugs in Human Clinical Trials.”)

For drugs to be approved and licensed by the US Food and Drug Administration (FDA), they have to go through a series of clinical trials. First they are tested on animals, such as mice; then they are tested on humans. Each phase of a clinical trial helps determine the drug’s safety, efficacy, optimal dosage and side effects. (See sidebar, “Clinical Trial Phases.”) The National Institutes of Health clinical trials registry at clinicaltrials.gov lists more than 250 trials on hemophilia and more than 60 on von Willebrand disease (VWD). (See “Clinical Trials 101.”).)

Tried and True vs. Something New

Prophylactic medications to treat hemophilia have given patients a new degree of freedom. They can self-infuse whenever and wherever it’s convenient.

“In terms of hemophilia A and B, I feel that the products we have right now are really good,” says Marion Koerper, MD, NHF medical advisor. She is also director emerita of the hemophilia treatment center at the University of California, San Francisco, where she practices pediatric hematology and oncology. “The factors do work to stop bleeding or, in the case of prophylaxis, prevent bleeding.”

However, prophylaxis is not perfect. “It’s only efficacious if the patient takes it the prescribed way,” Koerper says. The best time to give factor is in the morning before school or work, often the most hectic time of day. For busy families who delay treatment until bedtime, there are consequences. “That is not optimal because the child’s highest levels are while he’s asleep, rather than when he’s running around with his pals on the playground,” says Koerper.

Further, taking a product two or three times a week means that clotting strength can plummet on the off days. “When we give prophylaxis right now for a hemophilia A patient, we’re resolved to the fact that before their next prophy dose, their level in plasma could be as low as about 1% to 2%,” says Steven W. Pipe, MD, medical director, Pediatric Hemophilia and Coagulation Disorders Program, University of Michigan, Ann Arbor. That puts patients at risk for bleeding, especially if there is trauma. “Clearly, that’s not correction of their hemostasis.”

Products With Staying Power

To remedy that risk, pharmaceutical companies are creating new products that last longer in the bloodstream. The amount of factor VIII (FVIII) or factor FIX (FIX) in the blood is measured by its half-life, the time it takes for the amount of factor to be reduced by half. There are many variables involved, including blood type, but FVIII’s half-life is about 8–12 hours; FIX’s is about 18–24 hours. One option is to increase the interval between prophylactic doses, ideally to once a week for FIX products and twice a week for FVIII products. 

Another option is to retain the current prophylactic regimen, but avoid the precipitous drop in clotting factor as the next dosing time approaches. “We may be able to maintain much higher plasma levels than we’ve been able to previously with the same intervals that we’re currently using,” says Pipe.

One way to prevent factor products from degrading too quickly is to attach them to the chemical compound polyethylene glycol (PEG). This process, called PEGylation, increases the size of the factor protein molecule so that it circulates in the blood longer and is not cleared by the kidneys prematurely.

“Another strategy is to fuse the recombinant factor protein molecule to a partner protein that already has a long half-life,” says Pipe. Two naturally occurring partner proteins being fused to the FVIII or FIX molecule are albumin, which moves small molecules through the bloodstream, and Fc, a protein fragment that facilitates binding and recycling of immunoglobulin G (IgG).

Data from early clinical trials on Biogen Idec’s recombinant FVIII and FIX Fc fusion products, rFVIIIFc and rFIXFc, look promising. The A-LONG study on patients with severe hemophilia A showed a 1.7-fold increase in half-life during phase 1/2a clinical trials. B-LONG studies on patients with severe hemophilia B showed a nearly threefold increase in half-life during phase 1/2 trials. (See “Long Strides,” HemAware Summer 2011, p. 14.)

Adjunctive therapies, or drugs that are added to the primary factor product, are also being tested in clinical trials. Some use molecules that bind to tissue factor pathway inhibitor (TFPI), preventing it from hindering the action of FXa and thrombin, necessary for clot initiation and formation. Baxter’s BAX513 uses fucoidan, a seaweed extract being tested on healthy volunteers without hemophilia.

“If you block the proteins that are slowing down coagulation, you can actually restore normal clotting in hemophilic plasma without replacing the missing clotting factor,” says Pipe. For some patients, the adjunctive therapy may become the primary therapy, reducing the number of infusions needed, he says. A bonus is that some TFPI antagonists could be taken orally, such as the capsule form that delivered fucoidan to trial subjects.

“Compliance with bleeding disorders’ treatment is always an issue,” says Bias. “A drug that works better, faster and that you have to take less often can only improve that.”

Innovations for Inhibitors

An estimated 25% of patients with severe hemophilia A develop antibodies, called inhibitors, to the infused factor. Currently, patients undergo immune tolerance therapy to desensitize their immune systems or take a bypassing agent, such as FVIIa. The main drawbacks of the recombinant FVIIa product are that its half-life is only two hours and it is very expensive.

Inspiration Biopharmaceuticals is developing a recombinant porcine (pig) FVIII product for patients with inhibitors. “You can give a dose and get the measurable level of FVIII. That’s a distinct advantage when there’s a life-threatening­ bleed, like a head bleed (intracranial hemorrhage), or a limb-threatening bleed in someone with a compartment syndrome (increased pressure in a muscle in an enclosed space),” Koerper says. But because 80% of patients developed antibodies to plasma-derived pig factor within five days or after five doses, it is possible that a similar scenario might occur with the recombinant product. Results of the clinical trials will provide more data, but its use will probably be restricted.

The longer-lasting products may have an added benefit for inhibitor patients. “Some forms of PEGylation strategy and possibly even some of the fusion proteins may result in reduced risk for inhibitors,” says Pipe. Another product now being tested, Octapharma’s recombinant human-cl rhFVIII, may reduce the rate of inhibitor development because it uses proteins from human cells, not the typical hamster cells.

Recombinant VWD Product at Last

Recombinant products to treat FVIII and FIX were approved in 1992 and 1998, respectively; not so for von Willebrand factor (VWF). “It has bothered me for almost 20 years that I couldn’t offer a recombinant VWF product to my VWD patients,” says Koerper. That need will be fulfilled once Baxter’s recombinant VWF product goes through FDA approval and licensure. It will be targeted to patients with type 3 VWD, the most severe form, and those unresponsive to DDAVP, a synthetic hormone used to prevent or stop bleeds.

Gene Therapy Revisited

Researchers can now create precision drugs that treat diseases caused by specific genetic mutations. One such drug in phase 2 trials is Ataluren (PTC 124^®), manufactured by PTC Therapeutics Inc. It will be used for the approximately 10%–15% of patients with hemophilia A and B with a nonsense mutation, which halts factor production early. Ataluren introduces a molecule that allows the cell to read through the stop signal, making more clotting factor. It comes in a powder that is mixed in water. “Something that you can swallow is going to be a huge advantage because there are no needles involved,” Koerper says. (See sidebar “The Allure of Ataluren” in “What’s Your Genotype?” HemAware Spring 2010, p. 29.)

Rare Bleeding Disorders on the Radar

Patients with rare factor deficiencies know that being one in a million is hardly a cause for celebration. “People forget that there are other clotting factor deficiencies that, in some cases, have no treatment,” says Bias.

But hope is on the horizon. Companies that fractionate, or separate, plasma are interested in getting as many products out of it as they can, says Pipe. “Developing new markets for new plasma derivatives, such as the new FXIII product Corifact™ (approved by the FDA in March 2011), and RiaSTAP^®, a fibrinogen concentrate to treat FI deficiency (indicated for patients with congenital fibrinogen deficiency including afibrinogenemia and hypofibrinogenemia only), increases the sustainability and viability of the plasma fractionation industry.” Both products are manufactured by CSL Behring. Currently, Novo Nordisk has applied for a license for its recombinant FXIII product. British Plasma Laboratories has a plasma-derived FX product in phase 3 clinical trials.

“NHF is most supportive of new products for rare disorders or categories where products don’t currently exist, like the recombinant VWD product,” Bias says. “It’s important that people have access to a product that’s made for them.”

Time Frame for Trials

For drugs now in clinical trials, that access may take a few years. “From initiation of clinical trials to approval, it’s about a five-year window,” says Pipe. Drugs nearing the finish line—those in phase 3 or moving to FDA licensing—still have between 18 and 30 months, he says.

New Era of Optimism

Patients awaiting better, more effective or first-time products to treat their bleeding disorders have many reasons to be optimistic. “For the first time we’re now going to be offering agents that clearly behave differently. We’re not going to be faced with just a single-breed entity to choose from,” Pipe says.

The idea of having more distinct options may be foreign to some, but should be very welcome. New products with different mechanisms mean that treatments may soon be given in a more targeted, personalized manner. “When you have multiple choices it’s going to take some time for the clinicians and families to figure out what’s best for individual patients,” Pipe says.

When recombinant FVIII and FIX drugs came out two decades ago, Koerper thought they were the “ultimate products.” But with all of these recent innovations, she’s changed her thinking. “Now I realize there is so much more that can be done.”

—————————————————————————

Clinical Trial Phases

A drug must go through several stages of testing, called “phases” in clinical trials, before it can seek approval review by the Food and Drug Administration (FDA) for use in the US. Depending on how well things go in each phase, the drug progresses from one phase to the next. However, some drug trials are halted voluntarily or by the FDA at certain stages because of concerns about safety or efficacy, for instance. It can take up to five years or more for a new drug to pass muster and make it to the marketplace.

Phase 1

An experimental drug is given to a small number of people (20–100*) to test its safety, tolerability, pharmacokinetics (absorption, distribution, metabolism and excretion) and pharmacodynamics (biochemistry and physiology). Dose-escalating studies are done during this phase to find the optimal dosage.

Phase 2

The drug is given to a larger number of people (100–300*) to evaluate its effectiveness and safety.

Phase 3

The drug is tested in an even larger group of people (1,000–3,000*) at multiple centers across the country to confirm its effectiveness and safety compared with current treatments. During this phase, side effects are also monitored. The studies are randomized and controlled, meaning some patients receive the drug and others get a placebo. Once this “pivotal phase” is successfully completed, the manufacturer can apply for licensing review by the FDA.

Phase 4

Once a drug is licensed for sale, post-marketing surveillance trials are required by the FDA. These trials provide important information on risks, including less common side effects, benefits and optimal use.

*Note: these figures are for standard clinical trials. For bleeding disorders products, the number of trial subjects is often much smaller.

Information partially adapted from clinicaltrials.gov.

Bleeding Disorders Drugs in Human Clinical Trials*

Bleeding Disorder	Drug Name	Company	Clinical Trial
Hemophilia A	Recombinant FVIII-Fc Fusion	Biogen Idec	Phase 3
	NN7088 Recombinant FVIII, third generation	Novo Nordisk	Phase 3
	Human-cl rhFVIII (recomb FVIII, human cell line)	Octapharma	Phase 3
	OBI-1 Recombinant Porcine FVIII	Inspiration	Phase 2/3
	ARC 19499 PEG-conjugated aptamer	Archemix	Phase 1/2
	BAX499 FVIII, subcutaneous	Baxter	Phase 1
	CSL627 Recombinant FVIII-single chain	CSL Behring	Phase 1
Hemophilia B	BAX326 Recombinant FIX	Baxter	Phase 3
	Recombinant FIX-Fc Fusion	Biogen Idec	Phase 3
	OB1001 Recombinant FIX	Inspiration	Phase 2/3
	NN7999 Glyco-PEGylated Recombinant FIX	Novo Nordisk	Phase 3
	ARC 19499 PEG-conjugated aptamer	Archemix	Phase 1/2
	BAX499 FIX, subcutaneous	Baxter	Phase 1
	CSL654 Recombinant FIX-Albumin Fusion	CSL Behring	Phase 1/2
Hemophilia A & B Nonsense mutation	PTC 124 Ataluren	PTC	Phase 2
Inhibitors	rFVII analog	Novo Nordisk	Phase 3
	CSL689 Recombinant FVII-Albumin Fusion	CSL Behring	Phase 2
	GlycoPEG-rFVIIa	Novo Nordisk	Phase 2
	SQ GlycoPEG-rFVIIa	Novo Nordisk	Phase 1
Von Willebrand Disease	BAX 111, rVWF	Baxter	Phase 3
Rare Factor Deficiencies	Recombinant FXIII	Novo Nordisk	License applied for
	Plasma-derived FX	BPL	Phase 3

*This table provides a sampling of drugs now in clinical trials to treat various bleeding disorders. It is by no means comprehensive. NHF does not endorse or recommend any of the products or manufacturers listed. To check the status of drugs now in clinical trials, visit clinicaltrials.gov.

Search this blog for more information on individual press releases form Baxter, Novo Nordisk, CSL Behring,  OctaPharma, Biogen Idec, and Isporation Biopharmaceuticals.

CSL Behring Receives FDA Orphan Drug Designation for rVIIa-FP

KING OF PRUSSIA, Pa., Feb. 16, 2012 /PRNewswire/ – CSL Behring announced today that the company has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) for its novel recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP). The Orphan Drug Designation is granted for the treatment and prophylaxis of bleeding episodes in patients with congenital hemophilia and inhibitors to coagulation factor VIII or IX. CSL Behring is developing this therapy in collaboration with its parent company CSL Limited (ASX: CSL).

The CSL Behring rVIIa-FP clinical program will soon be initiated and intends to demonstrate that an extended half-life rVIIa-FP will result in a requirement for fewer doses while providing adequate therapeutic response in patients who have hemophilia A and B with inhibitors.

“CSL Behring’s albumin fusion technology uses albumin as the ideal recombinant genetic fusion partner for coagulation factor proteins because of its high tolerability, inherently long half-life, low potential for immunogenic reactions and known mechanism of clearance,” said Russell Basser, M.D., Senior Vice President, Global Clinical R&D at CSL Behring. “CSL Behring’s rVIIa albumin fusion protein is expected to exhibit a good tolerability profile and improved pharmacokinetics that may enable prophylaxis. We welcome Orphan Drug Designation for our rVIIa-FP and will work closely with the FDA to make this important therapy available for people in the U.S. with hemophilia A and hemophilia B with inhibitors.”

The FDA’s Orphan Drug Designation program provides orphan status to unique drugs and biologics, defined as those intended for the safe and effective treatment or prevention of rare diseases that affect fewer than 200,000 people in the U.S. Orphan designation qualifies the sponsor of the product for important tax credits, elimination of FDA license application fees and certain marketing incentives.

CSL Behring’s rVIIa-FP was granted Orphan Drug Designations (ODD) by the European Commission in May, 2011.

About Hemophilia
Hemophilia is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. In nearly all cases, it affects only males. The disease is caused by deficient or defective blood coagulation proteins known as factor VIII or IX. The most common form of the disease is hemophilia A, or classic hemophilia, in which the clotting factor VIII is either deficient or defective.  Hemophilia B is characterized by deficient or defective factor IX. Hemophilia A affects approximately 1 in 5,000 to 10,000 people. Hemophilia B affects approximately 1 in 25,000 to 50,000 people. The recommended treatment for patients who are factor deficient is to treat by replacement factor therapy. A complication in some patients is the development of inhibitory antibodies (inhibitors) to FVIII or FIX which renders replacement therapy ineffective.  This can occur in up to 25 percent of hemophilia A patients and around 5 percent of hemophilia B patients.  One treatment option for these patients is recombinant activated factor VII (called a bypassing agent) which can be used to achieve hemostasis without the need for factor VIII or IX. 

About the recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP)
Preclinical studies have confirmed that CSL Behring’s rVIIa-FP has favorable pharmacokinetic properties compared with the existing recombinant FVIIa product. Significant increases in half-life have been observed across all animal species. The use of a bypassing agent with an extended half-life could offer significant benefit to those affected by hemophilia A or B with inhibitors and may offer patients the opportunity to be treated less frequently than with currently available product.

About CSL Behring
CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide. CSL Behring therapies are indicated for the treatment of coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in newborns. CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited (ASX:CSL), a biopharmaceutical company headquartered in Melbourne, Australia. For more information, visit www.cslbehring.com.

For Press release click here.

SOURCE CSL Behring

Activated Protein C Inhibitor for Correction of Thrombin Generation in Hemophilia A Blood and Plasma

By: K. E. Brummel-Ziedins¹, M. F. Whelihan¹, G. E. Rivard², S. Butenas¹

^{From: Journal of Thrombosis and Haemostasis  Sept 15, 2011}
DOI: 10.1111/j.1538-7836.2011.04504.x

Specific activated protein C inhibitor PNASN-1 significantly increases thrombin generation in the blood and plasma of individuals with congenital hemophilia A, with and without factor VIII deficiency, according to a study published online Sept. 15 in the Journal of Thrombosis and Haemostasis.

Summary

Background: The replacement therapy for hemophilia patient treatment is costly due to the high price of pharmacologic products and is not affordable for the majority of patients in developing countries. Objective: To generate and evaluate low molecular weight agents useful for hemophilia treatment. Methods: Potential agents were generated by synthesizing specific inhibitors (PNASN) for activated protein C (APC) and tested in plasma and fresh blood from hemophilia A patients. Results: In the APTT-based APC-resistance assay, inhibitor PNASN-1 partially neutralized the effect of APC. In calibrated automated thrombography, PNASN-1 neutralized the effect of APC on thrombin generation in normal and congenital factor (F)VIII-deficient plasma (FVIII:C<1%). The addition of PNASN-1 to tissue factor-triggered (5 pM) contact pathway-inhibited fresh blood from 15 hemophilia A patients with various degrees of FVIII deficiency (FVIII:C<1-51%) increased the maximum level of thrombin generated from 78 nM to 162 nM, which approached that observed in blood from a healthy individual (201 nM). PNASN-1 also caused a 47% increase in clot weight in hemophilia A blood. Conclusion: Specific APC inhibitors compensate to a significant extent for FVIII deficiency and could be used for hemophilia treatment.

Inspiration Biopharmaceuticals Announces Data from OBI-1 Pivotal-Stage Program in Hemophilia

KYOTO, Japan, July 28, 2011 /PRNewswire/ – Inspiration Biopharmaceuticals, Inc. (Inspiration) today announced data from its clinical development program for OBI-1, an intravenous (IV) recombinant porcine factor VIII product (rpFVIII), intended for the treatment of bleeding in people with hemophilia A with inhibitors and in people with acquired hemophilia. The data were presented in a Scientific Session held in conjunction with the 23rd Congress of the International Society on Thrombosis and Haemostasis (ISTH), which was chaired by Amy Shapiro, M.D., Co-Medical Director at the Indiana Hemophilia and Thrombosis Center (IHTC).

During the Scientific Session, Anne Greist, M.D., Co-Medical Director at IHTC, presented interim results from the first registration study in the OBI-1 Accur8 clinical trial program. A total of three patients with acquired hemophilia, who had experienced severe bleeds not controlled with by-passing agents, were treated with OBI-1; in all three patients, treatment with OBI-1 stopped the bleeding. Further data on hemostatic efficacy and safety are being collected as part of the Accur8 clinical trial program, designed to study OBI-1 in acquired hemophilia. A second study in individuals with congenital hemophilia A who have developed inhibitors against FVIII is set to commence later this year.

Additional reports from the Scientific Session confirmed findings from the Phase 2 study in congenital hemophilia A with inhibitors; that OBI-1 effectively resulted in hemostasis, and controlled all non-life/non-limb threatening bleeding episodes in individuals with congenital hemophilia A and inhibitors, even in the presence of high inhibitor levels. All 25 bleeds in the study were controlled, and twenty out of 25 bleeds (80%) were controlled with two infusions. In over 40 infusions administered, OBI-1 was well tolerated by all participants and no drug-related serious adverse events were observed.

Dr. Greist commented, “Acquired hemophilia can be a life-threatening crisis in which individuals develop antibodies against their own coagulation factor. Unfortunately, current therapies for inhibitors do not provide the same level of hemostatic efficacy as do human FVIII therapies for non-inhibitor patients. Further limitations include the inability to guide dosing and monitor treatment efficacy using established laboratory parameters. OBI-1 represents a potential alternative treatment, which allows established laboratory parameters to guide dosing and monitor efficacy, in addition to clinical outcome. I am happy to report the progress that has been seen in this development program.”

Nonclinical findings were also presented at the ISTH Congress, showing that OBI-1 corrected biomarkers of blood coagulation in vitro in a dose-dependent, anti-OBI-1 inhibitor titer-dependent fashion, including in plasma taken from individuals with congenital hemophilia A who have inhibitors. The data were presented in Poster # No. 01829: “In vitro correction of thrombin generation and improvement of clot structure by recombinant porcine factor VIII in plasma containing anti-factor VIII inhibitory antibodies.” According to Claude Negrier, M.D., author on the poster and head of the Hematology Department at Edouard Herriot University Hospital (Lyon, France), “The study demonstrated that recombinant porcine FVIII has the potential to correct surrogate markers of haemostasis, depending on the anti-porcine FVIII titre and on dose, which would likely translate into in vivo effectiveness.”

About Hemophilia and Acquired Hemophilia

Hemophilia is a bleeding disorder caused by low levels or the absence of a protein called a coagulation factor, essential for blood clotting. The two most common forms of hemophilia are types A and B. Hemophilia A is caused by a factor VIII deficiency and the congenital form occurs in – 1 out of every 5,000 male births. Hemophilia B is caused by factor IX deficiency and occurs in – 1 out of every 30,000 male births. Approximately 60% of persons with hemophilia have a severe condition, which results in frequent spontaneous bleeding episodes, in addition to serious bleeding after injuries. The annual market for hemophilia treatments is estimated at $8 billion worldwide.

Acquired hemophilia is a rare, though potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) against coagulation factors. Unlike congenital hemophilia, acquired hemophilia is typically a disorder of older adults, and occurs equally in both males and females. Also, the pattern of bleeding seen in acquired hemophilia is different from that observed in the more common congenital form. In acquired hemophilia, individuals typically bleed into the skin, muscles and soft tissues, as opposed to bleeding into joints, which is more typical in congenital hemophilia.

In addition, approximately one-third of individuals with hemophilia A develop an immune reaction (inhibitors) to human FVIII (hFVIII), and can no longer respond to replacement treatment with the coagulation factor. Current therapies, specifically human factor VIIa (NovoSeven®) and FEIBA, work by bypassing the natural hemostatic pathway and forcing coagulation with much higher levels of FVIIa than normal.

About OBI-1 and the Clinical Development Program

In the fourth quarter of 2010, the Accur8 clinical trial program started, and OBI-1 entered pivotal clinical testing in individuals with acquired hemophilia (Accur8 Auto-antibody clinical trial). Inspiration plans to initiate a second Phase 3 clinical trial before the end of this year, in individuals with congenital hemophilia A who have developed inhibitors against FVIII (Accur8 Allo-antibody clinical trial).

OBI-1, a recombinant form of porcine FVIII which typically possesses low cross reactivity to anti-human FVIII antibodies, is a replacement therapy, activating the natural hemostatic pathway. This should allow clinicians to correlate activity and efficacy with a biomarker, and therefore guide dosing to better monitor and predict treatment outcomes. OBI-1 presents a unique and alternative approach to address the needs of individuals who have developed inhibitors to FVIII and is highly desired by the medical community.

For more information about enrolling in one of Inspiration’s clinical trials, please visit www.hemophiliaregistry.com or call 1-800-361-3227. For more information on the ongoing clinical studies, please visit http://www.clinicaltrials.gov.

About Inspiration Biopharmaceuticals

Inspiration Biopharmaceuticals is the only company exclusively dedicated to developing treatments for hemophilia, with a primary mission to broaden access to care, including prophylactic therapy, and to improve the treatment of individuals with inhibitor complications. Inspiration has a broad portfolio of recombinant hemophilia products, which includes two late-stage products in clinical development and two pre-clinical programs.

Inspiration’s lead product candidates are IB1001, an intravenous recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with hemophilia B, and OBI-1, an intravenous recombinant porcine factor VIII (FVIII) for the treatment of individuals with hemophilia A who have developed inhibitors against human FVIII, and for individuals with acquired hemophilia. Both products are in clinical development. Earlier-stage preclinical programs at Inspiration are focused on human recombinant factor VIIa (FVIIa), for individuals with either hemophilia A or hemophilia B who have developed inhibitors, and for individuals with factor VII deficiency; and human recombinant FVIII, to treat individuals with hemophilia A.

Inspiration has extensive expertise and experience in hemophilia product development, biologics manufacturing, and global commercialization. The Company’s senior leadership was directly responsible for the development and commercialization of the majority of hemophilia products currently on the market. In January 2010, Inspiration entered into a long-term strategic partnership with Ipsen SA, leveraging the combined expertise and resources of the two companies. As part of that transaction, Inspiration in-licensed OBI-1 from Ipsen. For further information on Inspiration, please visit http://www.inspirationbio.com.

SOURCE Inspiration Biopharmaceuticals, Inc.
Source: PR Newswire

CSL Behring Receives EU Orphan Drug Designations for rVIIa-FP for Hemophilia A and B Treatment

KING OF PRUSSIA, PA — 31 May 2011

CSL Behring announced today that it has been granted Orphan Drug Designations (ODD) by the European Commission for the development of its recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP), a novel therapy to treat hemophilia A and hemophilia B patients with inhibitors. The designations would entitle CSL Behring to exclusively market recombinant factor VIIa fused with albumin in Europe for a period of 10 years if the product at the stage of license application fulfils the orphan drug requirements. Based on the submission of data from the company’s Pediatric Investigation Plan, once available, the 10-year market exclusivity may be extended to 12 years.

Under these designations European Medicines Agency (EMA) will also provide CSL Behring with development assistance and with reductions in certain regulatory fees.

“CSL Behring welcomes Orphan Drug Designation for rVIIa-FP as support of our ongoing commitment to developing, manufacturing and marketing products for the treatment of rare and serious diseases, such as hemophilia with inhibitors,” said Val Romberg, Senior Vice President, Global Research & Development. “We will continue to work closely with the EMA to make this important therapy available to patients as soon as possible.”

An orphan drug designation application has not yet been submitted in the United States.

By providing incentives to the pharmaceutical industry, the EU legislative framework for orphan medicines encourages the development of products intended to diagnose, prevent and treat life-threatening or chronically-debilitating conditions that impact up to 5 in 10,000 people in the European Union. The initiative helps improve access to quality medical care for patients who have rare diseases for which there are few, if any, approved treatments.

About Hemophilia
Hemophilia is an inherited bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. The disease is caused by deficient or defective blood coagulation proteins known as factor VIII or IX. The most common form of the disease is hemophilia A, or classic hemophilia, in which the clotting factor VIII is either deficient or defective. Hemophilia B is characterized by deficient or defective factor IX. Hemophilia A affects approximately 1 in 5,000 to 10,000 people. Hemophilia B affects approximately 1 in 25,000 to 50,000 people. The recommended treatment for patients who are factor deficient is to treat by replacement factor therapy.

Some patients develop inhibitors, factor VIII or IX neutralizing antibodies which render further replacement therapy ineffective. It has been reported that up to 33% of all severe hemophilia A and up to 6% of all severe hemophilia B patients develop inhibitors.

Patients who have become refractory to replacement factor therapy can be treated with recombinant human factor VIIa. Factor VIIa is an enzyme that can both initiate blood clotting and, at high dose, “bypass” the factor VIII and IX dependent steps involved in effective coagulation. With the current commercially available recombinant product, frequent injections are needed to adequately control or prevent bleeding due to its inherent short half-life.

About the recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP)
Using a proprietary genetic fusion technology (patents pending), CSL Behring is in the pre-clinical phase of developing a novel fusion protein formed by linking recombinant Factor VIIa with albumin. Because albumin is the most abundant natural protein in plasma and has a very long half-life (i.e., more than 20 days), the CSL Behring fusion protein is expected to exhibit a good tolerability profile and improved pharmacokinetics that may allow for less frequent dosing.

Preclinical studies have confirmed that CSL Behring’s rVIIa-FP has favorable pharmacokinetic properties compared to the existing recombinant product. A half-life extension of greater than 8-fold has been observed. The use of a bypassing agent with an extended half-life could offer significant benefit to those affected by hemophilia A or B with inhibitors and may offer patients the opportunity to be treated less frequently than with the currently available product.

CSL Behring’s clinical program intends to demonstrate that an extended half-life rVIIa-FP will result in a requirement for fewer doses while providing adequate therapeutic response in patients with hemophilia A and B with inhibitors.

About CSL Behring
CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide. CSL Behring therapies are indicated for the treatment of coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in newborns. CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited (ASX: CSL), a biopharmaceutical company headquartered in Melbourne, Australia. For more information, visit www.cslbehring.com.

Major Factor VIII Infusions Linked to Inhibitor Development

Inhibitor Development In Patients with Mild and Moderate Hemophilia A : Results From a Single Centre

See review at end of post.

Oral and Poster Abstracts
Poster Session: Disorders of Coagulation or Fibrinolysis: Poster I

Saturday, December 4, 2010, 5:30 PM-7:30 PM

Hall A3/A4 (Orange County Convention Center)
Poster Board I-387

Yohann Repesse^*, Philippe Gautier^* and Annie Borel-Derlon, MD, PhD

Laboratoire d’hématologie, CHU de Caen, Caen, France

The development of factor VIII (FVIII) inhibitors is usually considered uncommon among patients with mild and moderate hemophilia A (HA) and less frequent than in patients with severe HA. We report here the prevalence of FVIII inhibitors and their caracteristics in 167 patients with mild and moderate HA followed in Caen Hemophilia Treatment Centre (Table). FVIII molecular defects were identified by direct sequencing in 167 patients including 30 and 137 with mild and moderate HA, respectively. Following FVIII concentrates infusions, FVIII inhibitors occured in 7.8% of patients (13/167). Fifteen percent (2/13) were low-responding inhibitors. The risk of inhibitor development appeared to be associated with high-risk FVIII genotypes clustered in the A2 and C2 domains, especially p.Arg2150His (50%) and p.Arg593Cys mutations. Interestingly, we described inhibitor development associated with novel missense-mutations (p.Tyr1786Ser, p.Asp115Tyr and -219C>T substitutions in FVIII gene promoter). In addition, high regimen infusion of FVIII concentrates appeared as risk factor for FVIII inhibitors development. Indeed, 60% (8/13) developped FVIII inhibitors following massive infusion of FVIII concentrates associated with FVIII:C levels above 1.2 UI/dL. Inhibitors in mild HA usually cross-react with endogenous factor VIII reducing the circulating basal FVIII:C level and are associated with more bleeding events. Similarly, we observed the evolution of bleeding patterns in our cohort to severe phenotypes. Bleedings were treated with FVIII concentrates and bypassing therapies (activated FVII and activated-prothrombin complex). About 25% (3/13) of these inhibitors disappeared spontaneously. Induction of Immune Tolerance (ITI) protocoles with high doses of FVIII were initiated for 7 high-responding patients with a success rate of 85 % (6/7). However, inhibitors persisted long-term and remained troublesome in 1 of these patients despite of ITI protocole. For two patients, immunosuppressive treatment with corticosteroids was started. Inhibitors disappeared and the levels of FVIII:C became detectable within 6 months. Development of FVIII inhibitors, their disappearance and the efficacy of ITI regimen seem to be different from our experience between patients with mild or moderate HA and severe HA.

Patients	FVIII:C (UI/dL)	FVIII gene mutation	Treatment at time of FVIII inhibitor development	Inhibitor status	Treatment
1	0.02	p.Arg2150His	High regimen infusion	HR	ITI
2	0.03	p.Arg2150His	FVIII infusion for a mild bleed	LR	FVIII
3	0.04	p.Arg2150His	High regimen infusion	HR	FVIII
4	0.04	p.Tyr2105Cys	High regimen infusion	LR	ITI
5	0.04	p.Arg2150His	FVIII infusion for a mild bleed	HR	ITI
6	0.04	p.Arg2150His	FVIII infusion for a mild bleed	HR	ITI
7	0.05	p.Arg2150His	High regimen infusion	HR	FVIII
8	0.05	p.Arg593Cys	FVIII infusion for a mild bleed	HR	ITI
9	0.1	p.Tyr1786Ser	High regimen infusion	HR	ITI
10	0.12	p.Val2016Ala	FVIII infusion for a mild bleed	HR	ITI
11	0.14	-219 C>T	High regimen infusion	HR	IS
12	0.18	p.Val2016Ala	High regimen infusion	HR	IS
13	0.35	p.Asp115Tyr	High regimen infusion	HR	ITI

LR: Low Responder, HR: High Responder, IS: immunosuppressive treatment

Disclosures: No relevant conflicts of interest to declare.

_______________________________________________
Review by: By Ed Susman, Contributing Writer, MedPage Today

Major infusions of factor VIII appear to be associated with development of inhibitors against the clotting factor — which can complicate treatment of patients with hemophilia A, researchers reported here.Genotypic testing of 167 patients diagnosed with mild to moderate hemophilia A at a single center in France found that 13 patients exhibited genetic mutations correlating to inhibitor status. Eight of those patients had high regimen infusions of factor VIII concentrates, said Yohann Repesse, MD, associate professor of hemostasis at the Centre Hopitaliers Universitaire de Caen.

“Although the development of inhibitors is most frequently developed in patients with severe hemophilia,” Repesse told MedPage Today at his poster presentation at the annual meeting of the American Society of Hematology, “the development of antibodies against factor VIII in mild hemophilia A may induce considerable clinical problems because the inhibitor, directed against both endogenous and exogenous factor VIII, usually changes the bleeding type from a mild to a severe form.”

In this study, about 7.8% of the mild to moderate hemophilia A patients — all followed at the Caen Hemophilia Treatment Centre in France — developed inhibitors against factor VIII.

Inhibitor development is estimated to occur between 3% and 15% of the time, so he said his population appears to be similar to other cohorts in the medical literature.

Repesse and colleagues performed genetic and other tests to determine the inhibitor-related mutations and also whether the patients were high responders or low responders.

Of the 13 patients with factor VIII inhibitor status, two were classified as low responders; 11 were high responders. Eight of these patients who exhibited inhibitors were being treated with high infusion doses of factor VIII at the time their inhibitor status became apparent; the other five patients were undergoing factor VIII infusion for a mild bleed.

“High regimen infusion of factor VIII concentrates appeared as a risk factor for factor VIII inhibitors development,” he said. “About 60% — eight of 13 patients — developed factor VIII inhibitors following massive infusion of factor VIII concentrates for surgical procedures,” he noted.

“What this study may be telling us is that we may want to be more conservative in administering factor VIII in patients with mild disease,” Lindsey Greene, MD, a resident in pediatrics at the Weill-Cornell Medical Center, New York, told MedPage Today.

David Kuter, MD, chief of hematology at Massachusetts General Hospital, Boston, remarked that the “study tells us that when you start giving patients factor VIII you may induce development of antibodies or inhibitors. Doctors should avoid, if possible, giving patients with mild disease factor VIII infusions.”

Repesse suggested that the type of clotting factor used in treatment of patients with mild to moderate hemophilia might contribute to the development of inhibitors.

“However,” he said, “inhibitor formation has been reported in patients receiving a large variety of plasma derived of recombinant factor VIII concentrates, and none of them appeared clearly associated with a higher rate of inhibitor development,” he said.

Repesse said that the bleeding episodes experienced by patients who developed antibodies were treated with factor VIII and with bypassing agents, such as activated factor VII and activated prothrombin complex.

In three of the 13 patients the inhibitors disappeared without further treatment. In six of the other seven high-responding patients, treatment with induction of an immune tolerance protocol using high doses of factor VIII was successful in eradicating the inhibitors. “Nevertheless,” he said, “inhibitors persisted long-term and remained troublesome in one of these patients despite induction of immune tolerance protocol.”

Repesse noted that a variety of eradication treatments are available in addition to induction of immune tolerance. They include immunomodulatory agents such as corticosteroids, cyclophosphamide and rituximab (Rituxan).

Aquired Hemophilia – Clinical Trial Phase III

Ipsen’s Partner Inspiration Biopharmaceuticals Announces The Treatment Of The First Patient In Phase III Pivotal

From MedicalNewsToday – Article Date: 20 Nov 2010

Ipsen (Euronext: IPN, ADR: IPSEY) announced that its partner Inspiration Biopharmaceuticals, Inc. (Inspiration) has initiated treatment of patients in the first of two phase III pivotal clinical studies of OBI-1, an intravenous recombinant porcine factor VIII (FVIII) product, for the treatment of acquired hemophilia A, a rare, though potentially life-threatening bleeding disorder. Under the terms of their partnership agreement signed in January 2010, Inspiration in-licensed OBI-1 from Ipsen, and is responsible for the clinical development, regulatory process and commercialization of the product. In the context of this first phase III clinical study initiation, Ipsen has subscribed to a US$50 million newly issued convertible note by Inspiration, bringing its fully diluted share ownership position in Inspiration to about 34.0%.

About the study (acquired hemophilia A)

The pivotal phase III study is a prospective, non-randomized, open-label study evaluating the efficacy of OBI-1 for the treatment of serious bleeding episodes in individuals with acquired hemophilia caused by development of autoimmune inhibitory antibodies to human FVIII. Serious bleeding episodes include those that are a threat to a patient’s life or vital organs or limbs, or which require a blood transfusion. In addition, the study will obtain data about the pharmacokinetic behavior of OBI-1.

About Hemophilia and Acquired Hemophilia

Hemophilia is a group of bleeding disorders caused by low levels or absence of proteins called a coagulation factors, essential for blood clotting. The two most common forms of hemophilia are types A and B. Hemophilia A is caused by a factor VIII deficiency and the congenital form occurs in ~1 out of every 5,000 male births. Hemophilia B is caused by factor IX deficiency and occurs in ~1 out of every 30,000 male births. Approximately 60% of individuals with hemophilia have a severe condition, which results in frequent spontaneous 2/3 bleeding episodes, in addition to serious bleeding after injuries. The annual market for hemophilia treatments is c. $7.5 billion worldwide.

Acquired hemophilia is a rare, though potentially life-threatening, bleeding disorder caused by the development of autoantibodies (inhibitors) against coagulation factors. Unlike congenital hemophilia, acquired hemophilia is typically a disorder of older adults, and occurs in both males and females. Also, the pattern of bleeding seen in acquired hemophilia is different from that observed in the more common congenital form. In acquired hemophilia, individuals typically bleed into the skin, muscles and soft tissues, as opposed to bleeding into joints, which is more typical in congenital hemophilia.

About OBI-1

Approximately one-third of individuals with hemophilia A develop an immune reaction (inhibitors) to human FVIII (hFVIII) and can no longer respond to treatment with the coagulation factor. Current therapies, specifically human factor VIIa (NovoSeven®) and FEIBA, work by bypassing the natural hemostatic pathway and forcing coagulation with much higher levels of FVIIa than normal. In contrast, OBI-1, a recombinant form of porcine FVIII that typically possesses low cross reactivity to anti-hFVIII antibodies, is a replacement therapy, activating the natural hemostatic pathway. This should allow clinicians to correlate activity and efficacy with a biomarker, and therefore guide dosing to better predict treatment outcomes. OBI-1 presents a unique and alternative approach to address the needs of individuals who have developed inhibitors to hFVIII and is highly desired by the medical community.

OBI-1 has been evaluated in a Phase 2 study in patients with congenital hemophilia A who have developed inhibitors to hFVIII, and who presented with a non-life/non-limb threatening bleed. The Phase 2 study demonstrated OBI-1 was well-tolerated and can be given over a short infusion time. In addition to the recently initiated pivotal trial of OBI-1 in individuals with acquired hemophilia A, Inspiration expects to initiate a separate pivotal trial in individuals with congenital hemophilia A who have developed inhibitors against hFVIII.

About Ipsen

Ipsen is a global biopharmaceutical group, with sales exceeding 1 billion euros in 2009. The Group has total worldwide staff of more than 4,400 employees, of which nearly 900 contribute to the discovery and development of innovative drugs for patient care. Ipsen’s development strategy is based on fast growing specialty care drugs in oncology, endocrinology, neurology and hematology, and on primary care drugs. This strategy is supported by an active policy of partnerships. Ipsen’s research & development (R&D) centers and its peptide & protein engineering platform give the Group a strong competitive edge. In 2009, R&D expenditure totaled close to €200 million, representing nearly 20% of Group sales. Ipsen’s shares are traded on segment A of Euronext Paris (stock code: IPN, ISIN code: FR0010259150) and eligible to the “Service de Règlement Différé” (“SRD”). The Group is part of the SBF 120 index. Ipsen has implemented a Sponsored Level I American Depositary Receipt (ADR) program, which trade on the over-the-counter market in the United States under the symbol IPSEY.

Forward Looking Statement

The forward-looking statements, objectives and targets contained herein are based on the Group’s management strategy, current views and assumptions. Such statements involve known and unknown risks and uncertainties that may cause actual results, performance or events to differ materially from those anticipated herein. Moreover, the targets described in this document were prepared without 3/3 taking into account external growth assumptions and potential future acquisitions, which may alter these parameters. These objectives are based on data and assumptions regarded as reasonable by the Group. These targets depend on conditions or facts likely to happen in the future, and not exclusively on historical data. Notably, future currency fluctuations may negatively impact the profitability of the Group and its ability to reach its objectives. Actual results may depart significantly from these targets given the occurrence of certain risks and uncertainties. The Group does not commit nor gives any guarantee that it will meet the targets mentioned above. Furthermore, the Research and Development process involves several stages each of which involve the substantial risk that the Group may fail to achieve its objectives and be forced to abandon its efforts with regards to a product in which it has invested significant sums. Therefore, the Group cannot be certain that favorable results obtained during pre-clinical trials will be confirmed subsequently during clinical trials, or that the results of clinical trials will be sufficient to demonstrate the safe and effective nature of the product concerned.

The Group also depends on third parties to develop and market some of its products which could potentially generate substantial royalties; these partners could behave in such ways which could cause damage to the Group’s activities and financial results.

The Group expressly disclaims any obligation or undertaking to update or revise any forward looking statements, targets or estimates contained in this press release to reflect any change in events, conditions, assumptions or circumstances on which any such statements are based, unless so required by applicable law. The Group’s business is subject to the risk factors outlined in its registration documents filed with the French Autorité des Marchés Financiers.

Source: Ipsen

Harnessing the power of plants to fight hemophilia

Original Article: University of Florida Health Science Center
By Czerne M. Reid • Published: March 30th, 2010

Hemophilia, a disease linked with legends of European monarchs, frail heirs and one flamboyant charlatan called Rasputin, still afflicts many people today.

And the very treatments that can help can also put patients’ lives at risk.

The standard treatment is infusion with an expensively produced protein that helps the blood to clot. But in some patients the immune system fights the therapy, and in a subset of those, it sets off an allergic reaction that can result in death.

Now researchers at the University of Florida and the University of Central Florida have devised a way that potentially could help patients develop tolerance to the therapeutic protein before they are in need of treatment.

They genetically modified plants to encapsulate the tolerance-inducing protein within cell walls so that when ingested, it can travel unscathed through the stomach and be released into the small intestines where the immune system can act on it. The low-cost plant-based system, now being tested in mice, eventually could help improve the lives of many people who have hemophilia and dramatically reduce related health-care costs. The approach also has the potential for use with other conditions such as food allergies and autoimmune diseases.

“We’re hoping that our research will, in the future, result in better and more cost-effective therapies,” said Roland Herzog, an associate professor of pediatrics, molecular genetics and microbiology in the UF College of Medicine and a member of the UF Genetics Institute, who was one of the study’s leaders.

The findings were published Monday in the Proceedings of the National Academy of Sciences.

Hemophilia is characterized by defects in the gene that produces a protein required for blood to clot. People with hemophilia can suffer from spontaneous internal bleeding or severe bleeding resulting from minor injuries. Males get the disease, which is linked to the X chromosome, while females are “carriers” who rarely exhibit symptoms. The two forms of the disease — hemophilia A and B — are associated with the absence of proteins called factor VIII and factor IX, respectively.

Many people around the world have the disease — 1 in 5,000 boys are born with hemophilia A, the more common of the two forms.

Hemophilia treatment consists of infusing the missing protein into a patient’s blood. But in 25 percent of patients, the immune system rejects the therapy and makes inhibitors that stop the clotting factor from taking effect.

In hemophilia B, up to 4 percent of patients develop inhibitors to the protein therapy and many develop severe systemic allergic reactions, called anaphylaxis, which can be life-threatening.

“If the very protein that you administer to the patient is neutralized, it’s as if you haven’t administered any protein at all,” said Thierry Vandendriessche, an associate professor of medicine at the University of Leuven in Belgium, and president of the European Society of Gene Cell Therapy. He was not involved in the study.

Because treatment itself poses a potential threat to life, it has to be done in a hospital setting under supervision. That makes it an expensive enterprise that often includes blood transfusions and hospital stays costing up to $1 million. Average treatment costs are $60,000 to $150,000 a year, according to the National Hemophilia Foundation.

To help patients tolerate therapy, doctors try to exhaust patients’ immune systems by administering the therapeutic protein intravenously at frequent intervals and for long periods until the body no longer responds by producing inhibitors. While that brute force approach works for hemophilia A, it often doesn’t for hemophilia B, in which patients risk death from anaphylactic shock if exposed to the protein therapy.

To find a new, gentler approach to developing tolerance, Herzog teamed with Henry Daniell, a Pegasus professor and University Board of Trustees Chair in the College of Medicine at the University of Central Florida, who has spent the last two decades developing transgenic plants for producing and delivering oral vaccines and immune-tolerant therapies.

They inserted the gene responsible for producing the therapeutic protein into the genome of plants. To maximize the amount of protein produced, they inserted thousands of copies of the genes into chloroplasts — the energy-producing centers of plants — using a gene gun.

The research team, including first authors Dheeraj Verma, and Dr. Babak Moghimi, fed the encapsulated protein to hemophilic mice for an extended period. Surrounded by the hardy plant cell walls, the protein was protected from digestive acids and enzymes while traveling through the stomach. Once it arrived safely in the small intestines, however, surrounding bacteria chewed on the cell walls, causing the protein to be released and acted on by the immune system to induce tolerance.

When the mice were later treated intravenously with the clotting factor therapy, they produced little or no inhibitors, and none developed anaphylactic shock.

“We have made them develop tolerance, and removed the allergic part of this treatment,” Daniell said.

Not only did the pretreated mice survive the once-deadly treatment — they also had a greater positive effect from therapy than did other mice.

“You may wonder, ‘why hasn’t this happened before,’” Vandendriessche said. “It’s because it was difficult to administer a high amount of protein in the right place and at the right time. I think this is a milestone — nobody has previously achieved such levels of robust immune tolerance by any means using a noninvasive procedure.”

The researchers will continue to study how their method works, extend the approach to treating hemophilia A in mice and, ultimately, conduct trials in humans. Protein used in the human trials will be produced in lettuce and formulated to allow delivery of standard doses.

FDA Approves 8 mg Vial of NovoSeven® RT

FDA Approves 8 mg Vial of NovoSeven® RT for the Treatment of Hemophilia A or B with Inhibitors and Enhanced Shelf Life for All Vial Sizes

 New 8 mg vial will save reconstitution time and when treating a bleed, every second counts

PRINCETON, N.J., Aug. 10 /PRNewswire-FirstCall/ — Novo Nordisk announced today that the U.S. Food and Drug Administration (FDA) has approved NovoSeven® RT (Coagulation Factor VIIa [Recombinant] Room Temperature Stable) in an 8 mg vial size, making the hemophilia A or B with inhibitors treatment available in 1, 2, 5 and 8 mg vials. The 8 mg vial allows a rapid initiation and administration of this medication for those patients who need a larger dose. In addition, FDA has also approved the extension of shelf life for all vial sizes from 24 months to 36 months at room temperature (at or below 77 degrees Fahrenheit).

NovoSeven® RT is specially formulated to treat people with hemophilia A or B with inhibitors. Hemophilia, which is typically diagnosed in childhood, is a chronic, inherited bleeding disorder that occurs when certain blood clotting factors are missing or do not work properly, resulting in easy bruising and prolonged bleeding from trauma. Spontaneous internal bleeding can occur as well, particularly in the joints and muscles. Inhibitors, a serious complication that can occur after treatment, develop in as many as 30 percent of those with hemophilia. In these cases, antibodies form that neutralize or attack the blood coagulation agents contained in the treatment, resulting in joint disease and making it more difficult to manage bleeds.

“When I get a bleed, I want to infuse my treatment right away. The faster I treat a bleed, the sooner I can continue with my daily routine,” said Bob Hoyt, a member of the Novo Nordisk Changing Possibilities Coalition. “Using fewer vials will be a positive change for patients.” Hoyt has been living with hemophilia with inhibitors most of his life.

For many people living with hemophilia with inhibitors, the 8 mg vial will allow for faster reconstitution – the time it takes to prepare the injection – than their current NovoSeven® RT regimen. Those who previously had to use three vials to deliver an 8 mg dose will now have to reconstitute only one vial. Though the amount of powder in the 8 mg vial is larger than the 5 mg vial, the vial will be the same size and will have a yellow cap to distinguish it from the smaller dose.

“We have heard from patients and physicians alike that when they are treating a bleed, every second counts. We at Novo Nordisk are committed to improving the lives of people living with hemophilia with inhibitors,” said Eddie Williams, Vice President, Biopharmaceuticals, at Novo Nordisk. “The NovoSeven® RT 8 mg vial will allow patients to get the medicine they need much faster when experiencing a bleed, without having to manage multiple vials. We’re also pleased that it will have a positive environmental impact as well – fewer vials may mean less waste.”

The new vial size is expected to be available by November.

The enhanced stability of all vial sizes will allow for more flexibility when managing treatment supplies – another important aspect of hemophilia treatment.

About NovoSeven® RT

Indications and Usage

NovoSeven® RT (Coagulation Factor VIIa [Recombinant] Room Temperature Stable) is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to FVIII or FIX and in patients with acquired hemophilia; prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to FVIII or FIX and in patients with acquired hemophilia; treatment of bleeding episodes in patients with congenital Factor VII deficiency and prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency.

Important Safety Information

Warning: Serious thrombotic side effects are associated with the use of NovoSeven® RT outside of uses approved by the FDA. These thrombotic side effects are blood clots that form in arteries and veins and can cause harm and may lead to death. Your doctor should discuss the risks and explain the signs and symptoms of thrombotic side effects to you. Your doctor should monitor you for blood clots during treatment with NovoSeven® RT.

Thrombotic side effects following the use of NovoSeven® RT occurred in 0.28% of all bleeds that were treated for FDA-approved uses. The rate of 0.20% was observed in hemophilia patients with inhibitors, and the rate was higher in patients with acquired hemophilia (4%). Thrombotic events (fatal and non-fatal) have been reported following use of NovoSeven® RT for all FDA-approved uses.

Some patients have conditions that may increase the risk of thrombotic events. These include clogged arteries, blood clots that form throughout the body instead of at the place of injury (called disseminated intravascular coagulation), a type of blood poisoning called septicemia, and crush injury, which is when a body part is crushed or squeezed between heavy or immobile objects. Also, people taking aPCCs/PCCs (activated or nonactivated prothrombin complex concentrates) at the same time they are taking NovoSeven® RT may be at increased risk for thrombotic side effects. NovoSeven® RT should be used with caution in patients who have an increased risk for thrombotic side effects. These include, but are not limited to, patients with a history of heart disease, liver disease, patients who have limited movement following surgery, elderly patients, and neonates (babies who are 4 weeks old or younger). In each of these situations, the potential benefit of treatment with NovoSeven® RT should be weighed against the risk of these complications.

Some patients with Factor VII deficiency have developed resistance (antibodies) to Factor VII after treatment with NovoSeven® RT. Factor VII-deficient patients should be monitored for antibody formation before and after administration of NovoSeven® RT.

People who have ever had a bad reaction to NovoSeven® RT or to proteins from mice, hamsters, or “bovines” (such as an ox or cow) should consult their physician prior to using NovoSeven® RT.

The most common side effects during clinical trials in people taking NovoSeven® RT were fever, bleeding, injection site reaction, joint pain, headache, high or low blood pressure, nausea, vomiting, pain, swelling, and rash.

Please visit www.novosevenrt.com for Prescribing Information.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088

NovoSeven® RT is a prescription medicine.

NovoSeven® is a registered trademark of Novo Nordisk Health Care AG.

About Novo Nordisk

Novo Nordisk is a global healthcare company with more than 87 years of innovation and leadership in diabetes care. The company also has leading positions within hemophilia care, growth hormone therapy and hormone therapy for women. Novo Nordisk’s business is driven by the Triple Bottom Line: a commitment to social responsibility to employees and customers, environmental soundness and economic success. Headquartered in Denmark, Novo Nordisk employs more than 29,650 employees in 76 countries, and markets its products in 179 countries. Novo Nordisk’s B shares are listed on the stock exchange in Copenhagen and its ADRs are listed on the New York Stock Exchange (NVO). For more information, visit novonordisk-us.com.

SOURCE Novo Nordisk

RELATED LINKS
http://www.novosevenrt.com