REGENX BioSciences and Asklepios BioPharmaceutical Enter into Agreement for the Development of Treatments for Hemophilia A using NAVTM rAAV8 Vectors

 WASHINGTON, DC March 8, 2012 — REGENX BioSciences, LLC announces that it has entered into an agreement with Chatham Therapeutics, LLC, an affiliate of Asklepios BioPharmaceutical, Inc. (AskBio), for the development and commercialization of products to treat Hemophilia A using NAVTM rAAV8 vectors.

Under the terms of the agreement, Chatham and REGENX entered into a research collaboration, and REGENX provided Chatham with a non-exclusive license to use REGENX’s NAV rAAV8 in Chatham’s research and pre-clinical development of therapeutics that deliver DNA, RNA or other sequences for treatment of hemophilia A. The rights granted to Chatham include, but are not limited to, use in methods for protein replacement, modulation of gene expression, as well as gene editing approaches. Additionally, Chatham has the exclusive right to exercise an option for an exclusive worldwide license, with rights to sublicense, to REGENX’s NAV rAAV8 vectors for the treatment of Hemophilia A in humans, subject to certain limitations. In return for these rights, REGENX receives payments in the form of up-front and on-going fees and is eligible to receive future payments beginning at the exercise of the license option including up-front and on-going fees, certain milestone fees and royalties on net sales of products incorporating NAV rAAV8. REGENX would also receive a share of any sublicensing revenues.

“We believe that this collaboration and license option with Chatham is important and will enable the development of NAV rAAV8-based gene delivery treatments for hemophilia,” said Ken Mills, President and Chief Executive Officer of REGENX. “Chatham’s development programs combine the outstanding proprietary technologies and expertise of REGENX and AskBio. This agreement represents the continued interest of REGENX to ensure access to our NAV technology for partners that evidence expertise and commitment to development of novel therapies.

“We are excited to build upon our extensive IP platform with this new license, adding to our preexisting exclusive rights to rAAV8 for the field of treating Hemophilia B. We are on track to advance our rAAV8-based Hemophilia B therapeutic into clinical testing later this year,” said Scott McPhee, Vice President at AskBio and Co-Founder of Chatham Therapeutics. “We are confident that the science and synergy supporting these Hemophilia A & B programs will result in efficient clinical development and product approval processes.”

Hemophilia A is caused by a deficiency of the clotting factor designated Factor VIII. The main symptom is uncontrolled, often spontaneous bleeding. Internal bleeding into the joints can result in pain, swelling and, if left untreated, can cause permanent damage. The worldwide incidence of hemophilia A is one case per 5,000 male births, translating to 700,000 cases in all, with approximately 17,000 of those cases in the US. A recently published clinical study in the New England Journal of Medicine reported correction in patients with hemophilia B using NAV rAAV8 vectors, demonstrating the utility and safety of the platform.

About REGENX BioSciences, LLC

REGENX BioSciences, LLC is leading the effort to translate promising gene delivery applications into a pipeline of next generation personalized therapies for a range of severe diseases with serious unmet needs. We believe that the NAVTM technology to which we have exclusive rights represents the potential promise of curing the root cause of disease rather than the symptoms. We are committed to establishing best in class standards for our NAV vectors. Our intent is to initially develop treatments for a number of rare, genetic diseases including hypercholesterolemias, the mucopolysaccharidoses, and retinitis pigmentosa and to ensure continuing access to our NAV technology through innovative partnerships, license opportunities, as well as the expansion of our growing team of global collaborators. REGENX holds exclusive rights to a portfolio of over 100 patents and patent applications pertaining to its NAV technology and related applications. Visit www.regenxbio.com to learn more.

About Asklepios BioPharmaceutical, Inc.

Asklepios BioPharmaceutical, Inc. (AskBio) is a private clinical development-stage biotechnology company engaged in the development of novel, gene therapy mediated protein therapies using a proprietary Biological Nano Particle (BNPTM) technology platform. BNPs may be used to deliver a broad variety of biological material to a cell, including therapeutic genes, monoclonal antibodies, RNAi, and vaccines, among others. Chatham Therapeutics, LLC is a subsidiary of AskBio focusing on a potential cure for hemophilia, thru the use of the BNP platform technologies. The company is currently engaged in gene therapy based therapeutic programs for both hemophilia A and B and will commence a Phase I/II clinical trial for its Hemophilia B program in 2012. For additional information, visit AskBio’s Web site at http://www.askbio.com.

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Contact:

REGENX BioSciences
Vit Vasista, 202-785-7438
vvasista@regenxbio.com

Chatham Therapeutics & Asklepios BioPharmaceutical
Jade Samulski
jsamulski@askbio.com

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.

Alnylam Provides Key 2012 Goals for RNAi Therapeutics Pipeline

– Focuses Near-Term ‘Alnylam 5×15’ Efforts on Highest Value Opportunities in Transthyretin-Mediated Amyloidosis and Hemophilia with Accelerated Clinical Development –

For complete New Release click here.

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Jan. 8, 2012– Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today its key “Alnylam 5×15” and partner program goals for 2012.

• Advance ALN-APC Program for Hemophilia into Clinical Studies. ALN-APC is an RNAi therapeutic targeting protein C, a genetically defined target, for the treatment of hemophilia. By reducing levels of protein C, a natural anticoagulant protein, ALN-APC is intended to act by increasing thrombin generation and reducing the frequency of bleeding in hemophilia patients, including those more severe patients with inhibitors against their replacement factors. Alnylam is exploring both systemically delivered LNP and subcutaneously delivered GalNAc-conjugate approaches for ALN-APC with the goal of selecting the clinical candidate in the first half of 2012. Alnylam plans to advance its ALN-APC program toward the clinic with a goal of initiating a Phase I clinical trial in the first half of 2013 with data expected in the second half of 2013.

“We believe that ALN-TTR, our lead ‘Alnylam 5×15’ program, has the potential to become the leading innovative medicine for the treatment of transthyretin-mediated amyloidosis. In 2012, we aim to advance ALN-TTR02 through an initial Phase I study and then into the start of a Phase II study in ATTR patients, positioning our program for the start of pivotal trials in 2013. Further, we also intend to advance our subcutaneous TTR program, ALN-TTRsc, with an IND filing this year, as we view this program as a differentiated opportunity for additional applications in the ATTR disease setting,” said Barry Greene, President and Chief Operating Officer of Alnylam. “We also view our ALN-APC hemophilia program as an exciting opportunity to fundamentally change the management of this genetic disease where new approaches for patients are greatly needed. Clinical data showing a markedly reduced bleeding phenotype in hemophilia patients who have co-inherited pro-thrombotic gene mutations greatly support our enthusiasm for this program.¹ Accordingly, we aim to advance both lipid nanoparticle and conjugate versions of ALN-APC toward final candidate selection, with an IND filing targeted in 2013. Thereafter, we expect this program to advance rapidly toward pivotal trials.”

“While we focus Alnylam resources on our ALN-TTR and ALN-APC programs, we will also advance additional ‘Alnylam 5×15’ and partner programs through existing alliances and new partnerships that we aim to form in 2012 and beyond. In this regard, we believe our recent clinical successes greatly strengthen the attractiveness of many of our programs for partnership,” saidLaurence Reid, Ph.D., Senior Vice President and Chief Business Officer of Alnylam. “We are also pleased to announce today the designation of our fifth ‘Alnylam 5×15’ program, ALN-TMP, an RNAi therapeutic targeting Tmprss6 for the treatment of hemoglobinopathies. Based on its performance in pre-clinical models, we believe that ALN-TMP could become a disease modifying therapy for both beta-thalassemia and sickle cell anemia, areas of enormous unmet medical need. Along with other programs, we will look to advance this new program with a new partnership.”

FDA grants orphan designation for AMT’s hemophilia gene therapy program

 Amsterdam, The Netherlands – January 4, 2011 – Amsterdam Molecular Therapeutics (Euronext: AMT), a leader in the field of human gene therapy, announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to its gene therapy program for the treatment of hemophilia B. Orphan designation in the U.S. could provide up to seven years market exclusivity on regulatory approval. Orphan designation for AMT’s hemophilia program in the European Union was granted in November 2011.
 
AMT’s hemophilia B program, which consists of an adeno-associated viral (AAV) vector containing the human factor IX gene, is being investigated in a Phase I/II study conducted by St. Jude’s Children’s Research Hospital (Memphis, USA) and University College London (UK). Promising data from an initial 6 patients, recently published in the New England Journal of Medicine (N Engl J Med 2011; 365:2357-2365), shows that gene therapy administration resulted in a reduced need for protein replacement treatment, the standard care for hemophilia patients.  AMT is preparing for additional clinical development work to establish safety, tolerability and proof-of-concept with a factor IX gene therapy produced using its proprietary AAV production system.

“U.S. orphan designation provides additional support for our hemophilia B gene therapy program and supplements the designation in the EU received in November,” said Jörn Aldag, CEO of AMT. “The early clinical success seen with the program to date by our partners is very encouraging. We will build on this success in the coming months.”

About Amsterdam Molecular Therapeutics
AMT is a world leader in the development of human gene based therapies. AMT has a product pipeline of gene therapy products in development for hemophilia B, acute intermittent porphyria, Parkinson’s disease and SanfilippoB. Using adeno-associated viral (AAV) derived vectors as the delivery vehicle of choice for therapeutic genes, the company has been able to design and validate probably the world’s first stable and scalable AAV manufacturing platform. This proprietary platform can be applied to a large number of rare (orphan) diseases caused by one faulty gene and allows AMT to pursue its strategy of focusing on this sector of the industry.  AMT was founded in 1998 and is based in Amsterdam. Further information can be found at www.amtbiopharma.com.

For further enquiries:
Jörn Aldag                                       Mike Sinclair
CEO                                                     Partner
AMT                                                    Halsin Partners
Tel : +31 20 566 7394                 Tel : +44 20 7318 2955
j.aldag@amtbiopharma.com  msinclair@halsin.com

Gene therapy proves effective for hemophilia B

SAN DIEGO | Sat Dec 10, 2011 3:42pm EST By Deena Beasley

(Reuters) – A single treatment with gene therapy, an experimental technique for fixing faulty genes, has been shown for the first time to boost output of a vital blood clotting factor, possibly offering a long-term solution for people with hemophilia B.

Researchers said the same technology was also being studied as a treatment for hemophilia A, the far more common type of the inherited bleeding disorder.

“It is a technique for potentially permanently curing patients,” said Dr. Charles Abrams, American Society of Hematology secretary and associate chief of hematology/oncology at the University of Pennsylvania in Philadelphia.

The strategy involves replacing the defective gene that causes the bleeding disorder with a correct version delivered via a virus to the patient’s liver cells — the only cells in the body capable of producing certain clotting factors missing or deficient in people with hemophilia.

The factors are numbered using Roman numerals. The two main forms of the disease are hemophilia A, caused by a lack of clotting factor VIII, and hemophilia B, caused by a lack of clotting factor IX.

Researchers from the University College London Cancer Institute and St. Jude Children’s Research Hospital in Memphis, Tennessee, studied six men with severe hemophilia B who were producing clotting factor IX, also called FIX, at less than 1 percent of normal levels. The general goal of current treatment with manufactured FIX is to achieve factor levels greater than 1 percent of normal.

Four of the six trial participants have stopped routine treatment and remain free of spontaneous bleeding. The other two have increased the interval between FIX infusions to once every 10 days to two weeks from two to three times a week, said Dr. Andrew Davidoff, chairman of the department of surgery at St. Jude’s and co-author of the study.

HIGH COST FOR CURRENT TREATMENT

Frequent treatments with manufactured FIX can cost hundreds of thousands of dollars a year, making hemophilia a tempting target for gene therapy.

The trial “is truly a landmark study,” Dr. Katherine Ponder, hematology and oncology professor at Washington University in St. Louis, said in a New England Journal of Medicine editorial.

“If further studies determine that this approach is safe, it may replace the cumbersome and expensive protein therapy currently used for patients with hemophilia B,” she wrote.

The trial results were published in the NEJM and reported on Saturday at a meeting of the American Society of Hematology in San Diego.

The approach involved the use of a novel viral “vector,” designed to target the liver specifically.

The six trial subjects were broken into three groups with each group receiving a different concentration of new genes.

FIX levels in the first subject have remained at 2 percent for nearly two years, while the two patients treated with the highest dose have seen FIX levels rise to between 3 and 12 percent, researchers said.

One high-dose subject developed elevated levels of transaminases, an indicator of possible liver damage, and another had a slight increase in liver enzymes. Both cases were resolved with steroids, the researchers said.

Plans are to treat more patients with the highest dose used so far, and if research continues to succeed, the treatment could be widely available “in the next five years or so,” said Dr. Amit Nathwani, co-lead study author of the Department of Hematology at UCL Cancer Institute in London.

He also said the team was working to use the technique for treating hemophilia A.

ISI Group analyst Mark Schoenebaum said the gene therapy could pose big competition for companies such as Biogen Idec that are producing recombinant factor concentrates.

“This clearly presents a curveball to our (and much of Wall Street’s) assumptions around the future of the hemophilia market,” he said in an email to investors.

The analyst said estimated sales of the hemophilia factors accounted for between $10 and $17 of his $125 price target for shares of Biogen, which closed at $112.95 on Friday.

People with hemophilia bleed more following trauma than people without the disease, and those with severe disease may bleed spontaneously.

Hemophilia B is much less common than hemophilia A. About one in five hemophilia patients has hemophilia B, according to the National Institutes of Health.

The global market for Factor VIII products is about $5 billion, while the market for Factor IX is worth about $1 billion.

Hemophilia is an inherited condition that affects men more frequently. Worldwide, about one in 5,000 men is born with hemophilia A and 1 in 25,000 men is born with hemophilia B each year.

(Reporting by Deena Beasley)

Amsterdam Molecular Therapeutics Receives Orphan Designation in the EU for Hemophilia B Gene Therapy

AMSTERDAM, November 16, 2011 /PRNewswire/ –

Amsterdam Molecular Therapeutics (Euronext: AMT), a leader in the field of human gene therapy, announced today that the European Medicines Agency (EMA) has granted orphan designation for its gene therapy program for the treatment of hemophilia B. Orphan designation in the European Union provides several benefits including 10 years of market exclusivity from product launch and access to the central authorization procedure.

AMT’s hemophilia B program, which consists of an adeno-associated viral (AAV) vector containing the human factor IX gene, is being investigated in a Phase I/II study conducted by St. Jude’s Children’s Research Hospital (Memphis, USA) and University College London (UK). Promising data from an initial 6 patients shows that gene therapy administration resulted in a reduced need for protein replacement treatment, the standard care for hemophilia patients.  AMT is preparing for additional clinical development work to establish safety, tolerability and proof-of-concept with a factor IX gene therapy produced using its proprietary AAV production system.

“Orphan designation is an important milestone for our hemophilia B gene therapy program and will provide additional support to our negotiations as we seek potential licensing partners,” said Jörn Aldag, CEO of AMT. “A successful gene therapy for hemophilia could dramatically change not only the lives of patients but also the current hemophilia market that is dominated by protein replacement therapies.”  

About Amsterdam Molecular Therapeutics

AMT is a world leader in the development of human gene based therapies. AMT has a product pipeline of gene therapy products in development for hemophilia B, acute intermittent porphyria, Parkinson’s disease and SanfilippoB. Using adeno-associated viral (AAV) derived vectors as the delivery vehicle of choice for therapeutic genes, the company has been able to design and validate probably the world’s first stable and scalable AAV manufacturing platform. This proprietary platform can be applied to a large number of rare (orphan) diseases caused by one faulty gene and allows AMT to pursue its strategy of focusing on this sector of the industry.  AMT was founded in 1998 and is based in Amsterdam. Further information can be found at http://www.amtbiopharma.com.

Certain statements in this press release are “forward-looking statements” including those that refer to management‘s plans and expectations for future operations, prospects and financial condition. Words such as “strategy,” “expects,” “plans,” “anticipates,” “believes,” “will,” “continues,” “estimates,” “intends,” “projects,” “goals,” “targets” and other words of similar meaning are intended to identify such forward-looking statements. Such statements are based on the current expectations of the management of AMT only. Undue reliance should not be placed on these statements because, by their nature, they are subject to known and unknown risks and can be affected by factors that are beyond the control of AMT. Actual results could differ materially from current expectations due to a number of factors and uncertainties affecting AMT’s business. AMT expressly disclaims any intent or obligation to update any forward-looking statements herein except as required by law. 

SOURCE Amsterdam Molecular Therapeutics (AMT) B.V

Gene Therapy Shows Promise as Hemophilia Treatment in Animal Studies

ScienceDaily (Nov. 3, 2011) — For the first time, researchers have combined gene therapy and stem cell transplantation to successfully reverse the severe, crippling bleeding disorder hemophilia A in large animals, opening the door to the development of new therapies for human patients.

Researchers at Wake Forest Baptist Medical Center’s Institute for Regenerative Medicine, collaborating with other institutions, report in Experimental Hematology that a single injection of genetically-modified adult stem cells in two sheep converted the severe disorder to a milder form. The journal is a publication of the Society for Hematology and Stem Cells

“A new approach to treating severe hemophilia is desperately needed,” said lead author Christopher D. Porada, Ph.D., associate professor of regenerative medicine at Wake Forest Baptist. “About 75 percent of the world doesn’t have access to the current treatment — therapy to replace missing clotting factors. This puts patients in most of the world at risk of severe and permanent disabilities.”

Porada cautioned that challenges will need to be overcome before the treatment can be applied to humans, including that the sheep developed an immune response to the therapy that could decrease its effectiveness and duration.

There is currently no cure for the rare bleeding disorder hemophilia. People with this genetic disorder lack a protein, known as a clotting factor, needed for normal blood clotting. As a result, they may bleed for a longer time than others after an injury, as well as bleed internally, especially in joints such as the knees, ankles, and elbows. This bleeding can damage the organs and tissues and be life threatening. Even when life-threatening bleeds are prevented with replacement therapy, it doesn’t prevent smaller bleeds within the joints that can cause pain and decreased mobility.

People with hemophilia A, the most common type, are missing clotting factor VIII. For the study, the researchers used a combined stem cell/gene therapy approach to increase levels of factor VIII produced by the animals.

The scientists first inserted a gene for factor VIII into engineered mesenchymal stem cells, a type of adult stem cell. The cells — acting as a carrier for the gene — were then injected into the abdominal cavity of the sheep. The scientists selected mesenchymal stem cells to carry the gene because they have the ability to migrate to sites of injury or inflammation.

In the treated animals, the cells migrated to the joints and stopped ongoing bleeding.In addition, all spontaneous bleeding events ceased, and the existing joint damage was completely reversed, restoring normal posture and gait to these crippled animals, and enabling them to resume a normal activity level.

However, a paradox of the treatment was that while the symptoms were eliminated, the sheep developed an immune response to factor VIII, suggesting that the treatment’s effects would be reduced or shorter in duration. The scientists are currently working to learn why the immune response occurred and to develop strategies to prevent it.

“While preliminary, these findings could pave the way for a new therapy for hemophilia patients who experience debilitating bleeding in their joints,” Porada said.

The research was supported by the National Institutes of Health.

Co-authors were Graça Almeida-Porada (senior author) and Chung-Jung Kuo , both with Wake Forest Baptist; Chad Sanada, Evan Colletti, Esmail D. Zanjani, Walter Mandeville and John Hasenau, all with the University of Nevada at Reno; Robert Moot, Aflac Cancer Center and Blood Disorders Service; Christopher Doering, Emory Children’s Center Pediatrics; and H. Trent Spencer, Emory University School of Medicine.

Factor VIII Biopump

 From Reuters

Medgenics says in talks with Baxter on collaboration

Fri Oct 14, 2011 10:49am EDT

Oct 14 (Reuters) – Medgenics Inc said on Friday it is in active discussions with Baxter International Inc regarding a possible further collaboration on a medical device.

Medgenics and Baxter had an agreement, which expired on Sept. 30, 2011, for the joint development of the Factor VIII Biopump, a proprietary tissue-based platform technology that delivers therapeutic proteins using the patient’s own skin biopsy.

The pump would be used to treat a range of chronic diseases including anemia, hepatitis C and hemophilia, Medgenics said.

No further information was provided and Baxter was not immediately available to comment.

Another post from Bleedingdisorder about Medgenics and their “Biopump” can be found here.

FIV Vectors for the Treatment of Hemophilia A

Company Information:
VIROGENICS, INC.
PO BOX 2702 DEL MAR, CA 92014
EIN/Tax ID: 421578027
DUNS: 146101196

Phase II

Abstract: DESCRIPTION (provided by applicant): Although several labs including ours have demonstrated the feasibility of gene therapy for hemophilia A in animal models, long-term expression of the transgene at therapeutic levels was not observed in the clinic. The l ack of sufficient expression levels Factor VIII (FVIII) in hemophilic patients indicates that further improvements of the current gene delivery systems are needed to generate a therapeutic product. In the Phase I of this project we initiated a study to add ress the issues of FVIII expression level and duration based on findings showing that FVIII expression is limited by unstable mRNA, interaction with endoplasmic reticulum (ER) chaperones, and a requirement for facilitated ER to Golgi transport through inte raction with the mannose- binding lectin LMAN1. Vectors for FVIII expression in gene therapy applications typically have used a B domain deleted (BDD) cDNA in which the coding sequence for this domain is removed to yield a shorter construct for protein pro duction and gene transfer. Of note, the expression of BDD FVIII within the cell has the same limitations as the whole FVIII molecule. However, the inclusion of several asparagine-linked oligosaccharides within a short B-domain spacer increased ER to Golgi transport resulting in secretion of functional FVIII at levels 15- to 25-fold higher than full-length or B domain deleted FVIII both in vitro and in vivo. Phase I initiated the testing of the hypothesis that therapeutic FVIII production can be significantl y enhanced by addition of parts of the B domain in hemophilic dogs, the most relevant animal model to the human disease and a prerequisite test for clinical studies, Two FIV vectors were constructed and tested which contain canine FVIII with different leng ths of the B domain added. The constructs were prepared with the canine FVIII genetic sequence to reduce complicating cross-species factors when introduced into the hemophilic dog. Also, in Phase I the parameters for preparing high titer virus were optimiz ed and the innate immune response to VSV- G and GP64 pseudotyped vectors were analyzed. The completion of the Phase I aims puts the project in position to conduct the FVIII expression level and duration studies in hemophilic mice and dogs and to select the most favorable FVIII cDNA for safe and long term expression. In this Phase II study the aims are to evaluate expression level, duration and clinical benefit from FIV delivery of canine FVIII with no B domain or with two different lengths of the B domain i ncluded. Also, additional elements that may further enhance FVIII production significantly from transduced cells will be incorporated into the transfer vector and tested. This Phase II also includes the development of methods to provide increased productio n of the virus vector for these and subsequent studies, which will require large amounts of the vector. PUBLIC HEALTH RELEVANCE: Clinical application of Factor VIII gene therapies to hemophilia A patients have suffered from insufficient production o f Factor VIII. Using an FIV lentiviral vector capable of long-term expression in host cells, Factor VIII gene sequences with improvements designed to overcome the problem of poor expression will be tested in hemophilic dogs, the animal model which closely resembles the human disease. The goal is to advance the best product as determined from this study toward application in the clinic to human patients.

For more information about phase I, click here.

For more information about other projects, click here.

New Gene Therapy Corrects Hemophilia in Mice

Sangamo BioSciences Announces Publication of First Demonstration of In Vivo Correction of Hemophilia Gene via Systemic Delivery of a ZFP Therapeutic®

Groundbreaking Nature Publication Demonstrates Direct In Vivo Correction of a Defective Gene and Highlights Potential Use of ZFN Technology for Treatment of Hemophilia and Other Monogenic and Rare Diseases

Sangamo Press Release

RICHMOND, Calif., June 27, 2011 /PRNewswire/ – Sangamo BioSciences, Inc. (Nasdaq:SGMO – News) announced today the publication of a groundbreaking preclinical study demonstrating permanent functional correction of the gene that causes hemophilia B by the systemic delivery of zinc finger nucleases (ZFNs) .  The study, published in Nature, represents a significant advance in the development and systemic delivery of ZFP Therapeutics® and proof of concept for ZFN-based gene-editing for the treatment of hemophilia and other monogenic diseases.  

The work was carried out in the laboratory of Katherine High, M.D., Investigator, Howard Hughes Medical Institute, Professor of Pediatrics, University of Pennsylvania School of Medicine and Director, Center for Cellular and Molecular Therapeutics at The Children’s Hospital of Philadelphia, in collaboration with Sangamo scientists and was published as an Advance Online Publication in Nature http://dx.doi.org/10.1038/nature10177.

“These data represent a significant advance in realizing efficient, systemic, therapeutic gene repair – the ‘holy grail’ of genetic medicine,” said Dr. High, “With a single systemic administration of ZFNs and a donor sequence in a mouse model of hemophilia B, we demonstrated permanent correction of a defective human gene encoding the clotting factor, Factor IX, resulting in restoration of normal clotting times in the animal.  ZFN-mediated gene-editing provides a new approach to monogenic disease and circumvents the problems of traditional gene-addition strategies that result in random insertion that may lead to malignancy or other unintended consequences. Genome editing also reinstates the wild-type sequence under the control of the endogenous regulatory sequences, assuring restoration of this critical aspect of normal gene expression.  The study also demonstrated that permanent correction of the disease-related gene in situ can be achieved with therapeutically meaningful correction efficiencies.”

“This is an important step forward in our goal to broaden the application of ZFN gene-editing via in vivo administration,” stated Edward Lanphier, Sangamo’s president and chief executive officer. “These data highlight the therapeutic potential of our ZFN technology and enable us to expand our ZFP Therapeutic pipeline to a growing number of monogenic and rare diseases.”

The paper entitled “In vivo Genome Editing Restores Hemostasis in a Mouse Model of Hemophilia” described highly specific and efficient ZFN-mediated correction of a defective human Factor IX gene in a mouse model of hemophilia B by the delivery of ZFNs directly into animals.  Stable levels of Factor IX protein made from the corrected human gene were measured in the plasma of the treated animals and resulted in the restoration of normal rates of blood clotting for the eight-month duration of the study.  Moreover, the treatment was well tolerated as there were no deleterious effects on growth or liver function in the animals.

About Sangamo

Sangamo BioSciences, Inc. is focused on research and development of novel DNA-binding proteins for therapeutic gene regulation and modification.  The most advanced ZFP Therapeutic® development program is currently in a Phase 2b clinical trial for evaluation of safety and clinical effect in patients with diabetic neuropathy. Sangamo also has a Phase 1 / 2 clinical trial and two ongoing Phase 1 clinical trials to evaluate the safety and efficacy for the treatment of HIV/AIDS as well as a Phase 1 trial for the treatment for recurrent glioblastoma multiforme. Other therapeutic programs are focused on Parkinson’s disease, monogenic diseases, neuropathic pain and nerve regeneration.  Sangamo’s core competencies enable the engineering of a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs).  By engineering ZFPs that recognize a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TFs) that can control gene expression and, consequently, cell function.  Sangamo is also developing sequence-specific ZFP Nucleases (ZFNs) for gene modification.  Sangamo has established strategic partnerships with companies in non-therapeutic applications of its technology including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the company’s website at www.sangamo.com.

ZFP Therapeutic® is a registered trademark of Sangamo BioSciences, Inc.

This press release may contain forward-looking statements based on Sangamo’s current expectations. These forward-looking statements include, without limitation, the potential of ZFNs to treat human monogenic diseases such as hemophilia and other rare diseases, research and development of novel ZFP TFs and ZFNs and therapeutic applications of Sangamo’s ZFP technology platform. Actual results may differ materially from these forward-looking statements due to a number of factors, including uncertainties relating to the initiation and completion of stages of our clinical trials, whether the clinical trials will validate and support the tolerability and efficacy of ZFNs, technological challenges, Sangamo’s ability to develop commercially viable products and technological developments by our competitors. For a more detailed discussion of these and other risks, please see Sangamo’s SEC filings, including the risk factors described in its Annual Report on Form 10-K and its most recent Quarterly Report on Form 10-Q. Sangamo assumes no obligation to update the forward-looking information contained in this press release.