Lettuce Pills May Help Treat Haemophilia

Leave a comment

Dec 16, 2014 |By Elie Dolgin

The food in Anita’s bowl is not your average dog chow. Although the dish contains pellets and wet food, there is also a sprinkling of green powder—the product of a trailblazing experiment to address a potentially lethal complication of haemophilia treatment. Anita, so named because her red coat reminded breeders of the character from the animated film One Hundred and One Dalmatians, is a keagle (a mix of a beagle and a Cairn terrier) with haemophilia B.

Like people with this rare genetic disorder, Anita is naturally deficient in factor IX, a protein that helps the blood to form clots. When treated with replacement coagulation proteins, the dog naturally develops antibodies, or inhibitors, against the therapy—a problem that is also seen in some 5% of humans with haemophilia B. In these people, the immune system identifies the therapeutic protein as dangerous, causing the body to stop accepting the protein as a normal part of the blood, and destroys it before it can stop the bleeding. Continuing to take factor-replacement therapies can result in life-threatening allergic reactions, such as anaphylaxis.

The problem is even worse with haemophilia A, a disease that is four times more common than haemophilia B and in which the missing link in the coagulation chain is a protein called factor VIII. Around 30% of people with haemophilia A develop antibodies against replacement factor VIII.

Therapies are available to eliminate these antibodies. Some people, for example, undergo an intensive treatment called immune tolerance induction therapy, which involves regular intravenous administration of coagulation factors. But this is time consuming and costly (around US$1 million for an average five-year-old patient), and the treatment works in only about three-quarters of patients. “The challenges of treating haemophilia with inhibitors are just staggering,” says Timothy Nichols, director of the Francis Owen Blood Research Laboratory at the University of North Carolina at Chapel Hill, which maintains the colony of haemophiliac dogs to which Anita belongs.

Inducing immune tolerance in people who have developed inhibitors is one approach. But avoiding the problem altogether would be even better. “If you can prevent antibody formation in the first place, by finding some way of producing immunological tolerance that gets around that type of protocol, that would be a major advantage,” says David Lillicrap, a clinician and researcher who specializes in bleeding disorders at Queen’s University in Kingston, Ontario, Canada.

The green powder in Anita’s dish might do just that. The oral treatment is a concentrate of freeze-dried lettuce-leaf cells, each containing around 10,000 chloroplasts—the organelles responsible for photosynthesis—that have been genetically engineered to produce factor IX. These proteins cannot themselves be used to prevent bleeding episodes, because the cellular machinery found in plants cannot package the human clotting factors into the biologically active form. What they can do, however, is prevent the immune system from mounting an attack against subsequent therapy.

The researchers behind the bioengineered lettuce have shown that inhibitor formation and severe allergic reactions can be prevented in mice by feeding the animals with a product based on these plants. If the strategy also works in Anita and her kennel mates—and ultimately in humans—it could form the basis of the first product to protect against the immune responses associated with haemophilia treatment.

Anita is one of only two dogs to have received the bioengineered lettuce. “So far, it’s going very well,” says lead researcher Henry Daniell, director of translational research at the University of Pennsylvania School of Dental Medicine in Philadelphia.

An act of tolerance
In 2006, Lillicrap demonstrated that a simple oral treatment could train the immune system not to produce inhibitors. Working with a mouse model of haemophilia A, he and his colleagues gave the mice a purified fragment of the human factor VIII protein, through the nose or mouth. The researchers found that the treatment afforded some protection against antibody development after factor VIII replacement therapy. But the approach did not deliver sufficient amounts of the factor to immune cells in the gut or nasal passage to fully quash inhibitor formation.

Daniell came up with an improved delivery system. He focused first on haemophilia B. Adapting a technique that he had previously developed to delay the onset of type 1 diabetes, Daniell and his group genetically modified tobacco plants to express human factor IX in their chloroplasts. (Daniell has since switched to using lettuce.)

Chloroplast DNA is separate from the genome DNA in the plant nucleus, and the large numbers of these tiny organelles in the cell allow huge volumes of the coagulation protein to accumulate in each tobacco leaf. Once ingested, the plant cell wall protects the coagulation protein from being destroyed by stomach acid. Gut microorganisms farther down the digestive tract then chew away at the cell wall, releasing the clotting-factor protein.

To target the proteins to the immune system, Daniell then attached a second protein that has high binding affinity for a receptor found on the inside of the human gut. With this fused construct tethered to the intestinal wall, the coagulation protein could be absorbed into the body and processed by the specialized cells in the immune system that induce tolerance.

Working with Roland Herzog, a molecular biologist at the University of Florida in Gainesville, Daniell then tested the plant-based product in animal models. In 2010, they showed that oral delivery of factor IX expressed in chloroplasts in this way led to almost undetectable inhibitor levels in mice, and no sign of anaphylactic shock. “The mice are healthy, they show no allergic responses and they don’t form the inhibitors,” Herzog says. “That’s pretty exciting.”

Daniell then modified the tobacco leaves to express factor VIII and shipped powders of the leaves to Herzog. Earlier this year, the two researchers and their teams documented suppression of inhibitor formation and even reversal of pre-existing inhibitors in mouse models of haemophilia A.

Inhibitory control
Other strategies being pursued to prevent the formation of inhibitors of clotting-factor therapy include immunosuppressants and drugs that deplete specific immune cells. However, these therapies have many side effects, including increased susceptibility to infection.

A potentially safer option comes from Selecta Biosciences, a company in Watertown, Massachusetts. Selecta has developed a nanoparticle delivery system in which an immune-modifying compound is contained in biodegradable plastic particles just 150 nanometres across. When injected together with factor VIII into mouse models of haemophilia A, the nanoparticles deliver their payload to cells in the lymphoid tissue that are responsible for initiating immune responses. These cells, in turn, instruct factor-VIII–specific immune cells to become tolerant to the coagulation protein, resulting in suppression of misdirected antibody responses to the replacement therapy—all without affecting the rest of the immune system.


Green power: from leaf to powder to capsule.
Credit: Kwang-Chul Kwon, Jin Su & Henry
Daniell, Univ. Pennsylvania

David Scott and his colleagues at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, teamed up with Selecta to show that inhibitors remained undetectable for at least six months after treatment with the nanoparticle formulation. “This underscores the point that we’re actually teaching the immune system to become tolerant to factor VIII,” says Selecta’s chief scientific officer, Takashi Kei Kishimoto.

The nanotechnology approach that is being tested for inhibitor control could also improve the haemophilia treatment that is now at the cutting edge of clinical research: gene therapy. Using the standard gene-therapy approach, researchers have shown that they can achieve long-term expression of factor IX in adults with haemophilia B at sufficiently high levels to convert the bleeding disorder into a mild disease (see page S6). There has so far been no reported evidence of inhibitor formation in the small number of human participants in clinical trials for this viral therapy.

Still, the standard form of liver-targeted gene therapy carries a range of potential complications, including the risk of harmful mutations and of the body mounting an immune response against the viral vectors used to carry the correct forms of the defective genes responsible for haemophilia. That is why several research groups are attempting to replace viral vectors with nanoparticles that can deliver gene therapies as ‘DNA pills’.

Pill protection
DNA pills combine DNA plasmids—circular pieces of bacterial DNA containing the gene encoding either factor VIII or factor IX—with nanoparticles made of chitosan, a tough polymeric carbohydrate found in the exoskeleton of crustaceans. Chitosan protects the therapeutic gene product and chaperones it through the gut. “The oral route has significant appeal,” says Gonzalo Hortelano, a gene-therapy researcher at McMaster University in Hamilton, Canada. “The key is to achieve a system of delivery that’s persistent, effective and completely safe.”

Independent studies by Hortelano’s group and other research teams in Germany and the United States have shown that this oral gene therapy does not activate the immune system. Indeed, exposure of the protein produced by the nanoparticle-based gene therapy to the gut mucosa prevents inhibitor development and restores clotting-factor activity in mouse models of both haemophilia A and B. “This approach really could hold big benefit for patients,” says Jörg Schüttrumpf, a transfusion-medicine specialist who led one of the studies performed at the German Red Cross Blood Donor Service in Frankfurt.

Kam Leong, a biomedical engineer at Columbia University in New York City whose team was the first to demonstrate success with this approach in mice, has even tried feeding the chitosan–DNA nanoparticles to dogs with haemophilia A. Leong found some evidence of gene transfer and a reduction in inhibitors in the animals. But bleeding times were not reduced, which would be expected if sufficient levels of factor VIII were being produced. “It is still a very inefficient process,” Leong says, “so it requires continued optimization.”

Although the ideal remains a gene therapy that both corrects the disease and offers immune tolerance, some scientists have focused on treating inhibitor formation, without worrying about fixing the disease. Under this strategy, people would still need to take factor-replacement therapies, but they could do so without fear of inhibitor development.

With this in mind, independent teams led by Scott and Herzog took the conventional viral-vector approach to inducing tolerance through gene therapy. But rather than delivering the entire gene for the clotting-factor proteins to cells, as most gene therapies do, the researchers used the viruses to engineer immune-regulating B cells to express a fragment of the clotting factor fused to an immune molecule called an immunoglobulin. This led to long-lived tolerance in mouse models of haemophilia A and B.

Pursuing such gene-therapy approaches offers a degree of bet hedging, says Herzog. “Each strategy has potential advantages and disadvantages,” he points out, “and we do not really know yet what will work or may work best in people.” With so many therapeutic tactics moving through the preclinical pipeline, scientists and clinicians remain hopeful that at least one will ultimately succeed, eliminating the problem of inhibitor formation for people with haemophilia altogether.

MORE TO EXPLORE1. Verma, D. et al. Proc. Natl Acad. Sci. USA 107, 7101-7106 (2010).

2. Sherman, A. et al. Blood 124, 1659-1668 (2014).

3. Rawle, F.E. et al. J. Thromb. Haemost. 4, 2172-2179 (2006).

4. Ruhlman, T., Ahangari, R., Devine, A., Samsam, M. & Daniell, H. Plant Biotechnol. J. 5, 495-510 (2007).

5. Zhang, A.-H.A. et al. Blood 122, 2337 (2013).

6. High, K.A. Blood 120, 4482-4487 (2012).

7. Bowman, K., Sarkar, R., Raut, S. & Leong, K.W. J. Control. Release 132, 252-259 (2008).

8. Dhadwar, S.S., Kiernan, J., Wen, J. & Hortelano, G. J. Thromb. Haemost. 8, 2743-2750 (2010).

9. Quade-Lyssy, P. et al. J. Thromb. Haemost. 12, 932-942 (2014).

10. Lei, T.C. & Scott, D.W. Blood 105, 4865-4870 (2005).

11. Wang, X. et al. Mol. Ther. 22, 1139-1150 (2014).

This article was originally published with the title “Immunology: Oral solutions.”

For original article, click here.

CSL Behring Submits Biologics License Application for FDA Approval of Recombinant Fusion Protein Linking Coagulation Factor IX with Recombinant Albumin (rIX-FP) for Hemophilia B Patients

Leave a comment

KING OF PRUSSIA, Pa. — 16 December 2014

CSL Behring announced today it has submitted a biologics license application (BLA) to the United States Food and Drug Administration (FDA) for the marketing authorization of its long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP). Once approved by the FDA, rIX-FP (Coagulation Factor IX {Recombinant}, Albumin Fusion Protein) will provide people with hemophilia B and their physicians a long-acting treatment option with dosing intervals up to 14 days.

“As we mentioned at our recent R&D investor briefing, submission of our BLA to the FDA for rIX-FP is a significant milestone for CSL Behring’s recombinant factor IX development program and moves us one step closer to bringing this innovative therapy to hemophilia B patients in the U.S.,” said Dr. Andrew Cuthbertson, Chief Scientific Officer and R&D Director, CSL Limited. “Our strong partnership with and commitment from the hemophilia community led us to develop rIX-FP based on novel recombinant albumin fusion technology. This technology has led to a long-acting treatment candidate that continues our legacy of improving the well-being of patients with bleeding disorders and other rare diseases.”

About PROLONG-9FP Clinical Development Program

CSL Behring’s BLA is based on the results from the PROLONG-9FP Phase II/III (patients ages 12 to 61 years) study. The Phase II/III pivotal study was an open-label, multicenter, safety, pharmacokinetic (PK) and efficacy study of rIX-FP in previously treated patients with severe hemophilia B (FIX ≤ 2%).

This study was designed to compare the change in frequency of spontaneous bleeding events between on-demand treatment and a weekly prophylaxis regimen in patients previously receiving only on-demand treatment; and the number of patients developing inhibitors against factor IX as primary outcome measures. The study evaluated multiple prophylaxis regimens, including 7-day and 14-day intervals. A sub-study evaluated the prevention and control of bleeding in patients with hemophilia B undergoing a surgical procedure.

Study design details for rIX-FP (CSL654) are available at www.clinicaltrials.gov.

About rIX-FP

CSL Behring engineered rIX-FP to extend the half-life of recombinant factor IX through genetic fusion with recombinant albumin. CSL Behring selected recombinant albumin as its recombinant genetic fusion partner for its coagulation factor proteins due to its long physiological half-life. In addition, recombinant albumin has been shown to have a good tolerability profile, low potential for immunogenic reactions and a well-known mechanism of clearance. The cleavable linker connecting recombinant factor IX and recombinant albumin has been specifically designed to preserve the native function of the coagulation factor in the fusion protein, while benefiting from recombinant albumin’s long physiological half-life.

In 2012, the FDA granted Orphan Drug Designation for rIX-FP for the treatment and prophylaxis of bleeding episodes in patients with hemophilia B. The designation includes routine prophylaxis treatment, control and prevention of bleeding episodes, and prevention and control of bleeding in perioperative settings. 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.

About Hemophilia B

Hemophilia B (congenital factor IX deficiency) is characterized by deficient or defective factor IX and affects approximately 1 in 25,000 to 50,000 people. Hemophilia B is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. Nearly all hemophilia B patients are male.

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 used around the world to treat coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease, and neurological disorders in certain markets. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic disease of the newborn.

CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a global biopharmaceutical company and a member of the CSL Group of companies. The parent company, CSL Limited (ASX:CSL), is headquartered in Melbourne, Australia. For more information, visit http://www.cslbehring.com.

Baxter Provides Progress Update on Gene Therapy Program, Including Phase I/II Clinical Trial of BAX 335, Investigational Gene Therapy for Hemophilia B

Leave a comment

DEERFIELD, Ill., FEBRUARY 12, 2015 – Baxter International Inc. (NYSE:BAX) today provided an update on its gene therapy program, including progress on the Phase I/II open-label clinical trial assessing the safety and optimal dosing level of BAX 335, an investigational factor IX (FIX) gene therapy treatment for hemophilia B, during a sponsored symposium at the 8th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) in Helsinki, Finland.

The trial is assessing the safety of ascending doses of BAX 335 to determine the optimal single dose in up to 16 adult patients with hemophilia B at treatment centers in the United States. The primary endpoint is the safety of a single dose of BAX 335 administered intravenously. Secondary endpoints include evaluation of the optimal dose to achieve stable therapeutic plasma FIX activity, as well as pharmacokinetics and immune response to treatment.

As of the end of 2014, a total of six patients in three dosing cohorts have been treated in the trial with evidence of a dose-related response. No patients have developed FIX inhibitors to date. In the two highest dose cohorts, FIX activity levels around 10 percent or above have been observed in two patients, who also experienced no bleeding events. One of these patients showed elevated levels of liver enzymes indicative of an immune response, which is being treated with oral corticosteroids, per protocol. Immune responses have been reported in previous studies with gene therapy technology. Additional patients are being screened and more information on the trial is available at www.clinicaltrials.gov , by using Identifier #01687608.

“We continue to make steady progress in advancing our hemophilia B program with this technology and look forward to better understanding the applicability of this technology platform in hemophilia A patients as well,” said John Orloff, MD, vice president and global head of research and development at Baxter BioScience. “With the potential to redefine the treatment of hemophilia, this gene therapy technology is a central part of our R&D focus as we prepare to become an independent company this year,”

Patients with hemophilia B lack the ability to produce clotting factor IX and are treated with plasma-derived or recombinant factor IX today. BAX 335 is designed to provide a mechanism for the patient’s own liver to begin producing factor IX over an extended period following a single dose of the genetically engineered treatment.

In April 2014, Baxter announced the acquisition of Chatham Therapeutics, LLC, an affiliate of Asklepios BioPharmaceutical, Inc. (AskBio), and its developmental gene therapy programs. Chatham’s Biological Nano Particles (BNP), an advanced recombinant adeno-associated virus- (rAAV-) based gene therapy technology, has shown potential therapeutic benefit in early studies. In addition to the research in hemophilia B, Baxter is also advancing plans to evaluate the gene therapy technology in the treatment of hemophilia A.

About Hemophilia B
Hemophilia B is the second most common type of hemophilia (also known as Christmas disease) and is the result of insufficient amounts of clotting factor IX, a naturally occurring protein in blood that controls bleeding. Approximately 26,000 people worldwide, including more than 4,000 in the U.S., have been diagnosed with hemophilia B. Hemophilia B is often a debilitating, chronic disease with complications that include bleeding episodes, hemophilic arthropathy (bleeding into a joint) and hospitalization.

About Baxter in Hemophilia
Baxter has more than 60 years of scientific experience in supporting the treatment needs of patients with hemophilia and has introduced a number of therapeutic firsts. Baxter has the broadest portfolio of hemophilia treatments and is able to meet individualized patient therapeutic needs by providing a range of options at each treatment stage. The company’s work focuses on optimizing hemophilia care and improving the lives of people worldwide living with bleeding disorders.

About Baxter International Inc.
Baxter International Inc., through its subsidiaries, develops, manufactures and markets products that save and sustain the lives of people with hemophilia, immune disorders, cancer, infectious diseases, kidney disease, trauma and other chronic and acute medical conditions. As a global, diversified healthcare company, Baxter applies a unique combination of expertise in medical devices, pharmaceuticals and biotechnology to create products that advance patient care worldwide.

This release includes forward-looking statements concerning a Phase I/II open-label clinical trial of BAX 335, as well as plans to separate Baxter’s biopharmaceutical and medical products businesses and related research and development strategies. These statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: clinical trial results; satisfaction of regulatory and other requirements; actions of regulatory bodies and other governmental authorities; changes in laws and regulations; product quality or patient safety issues; and other risks identified in Baxter’s most recent filing on Form 10-K and other SEC filings, all of which are available on Baxter’s website.Baxter does not undertake to update its forward-looking statements.

For original press release, click here.

Weekly prophylaxis with nonacog beta pegol safe, effective for hemophilia B

Leave a comment

Collins PW. Blood. 2014;doi:10.1182/blood-2014-05-573055.

Nonacog beta pegol effectively treated bleeding episodes and was associated with low annualized bleeding rates in patients with hemophilia B, according to study results.

From www.healio.com October 31, 2014

Peter W. Collins, MD, of the Arthur Bloom Hemophilia Center at Cardiff University in the United Kingdom, and colleagues sought to evaluate the safety and efficacy of nonacog beta pegol (N9-GP, Novo Nordisk) — a recombinant glycoPEGylated Factor IX with an extended half-life — in 74 previously treated patients with hemophilia B.

Thirty patients received with 10 IU/kg weekly for 52 weeks, and 29 patients received 40 IU/kg weekly for 52 weeks. The other 15 patients received on-demand treatment for 28 weeks.

The mean number of exposure days was 54 days in the weekly prophylaxis arms and 14 days in the on-demand arm.

Fifty-five patients (74%) experienced a combined 345 bleeding episodes; of these, 202 occurred in the weekly prophylaxis arms and 143 occurred in the on-demand treatment arm. Most bleeding episodes (78.5%) occurred in joints. Researchers classified 65.8% episodes as spontaneous and 33.6% as traumatic.

Researchers calculated a 92.2% (95% CI, 86.9-95.4) success rate for treating bleeding episodes. A greater proportion of bleeding episodes resolved after one injection of nonacog beta pegol in the 40 IU/kg arm (98.6%) than in the 10 IU/kg arm (84.1%) and the on-demand treatment arm (83.9%).

Fifty-two percent of patients in the 40 IU/kg arm did not require treatment for any bleeding episodes, compared with 17% of patients in the 10 IU/kg arm and 7% of patients in the on-demand arm. The median annualized bleeding rate also was lower in the 40 IU/kg arm (1.04; interquartile range [IQR], 0-4) than in the 10 IU/kg arm (2.93; IQR, 0.99-6.02) and the on-demand arm (15.58; IQR, 9.56-26.47).

Researchers used the EuroQOL-5 Dimensions visual analogue scale to assess health-related quality of life in each study arm. Patients in the 40 IU/kg arm experienced the greatest improvements in quality of life, from a median score of 75 (range, 35-100) at baseline to 90 (range, 60-100) at the end of the trial.

Sixty patients (81%) experienced a combined 215 adverse events. The most commonly reported adverse events were nasopharyngitis (13.5%), influenza (10.8%) and upper respiratory tract infection (10.8%).

No patients developed an inhibitor, and researchers reported no deaths, thromboembolic events or allergic reactions related to treatment.

“Nonacog beta pegol was effective for the treatment of bleeding episodes in both prophylaxis and on-demand patients,” Collins and colleagues wrote. “Low bleeding rates were observed in patients on prophylaxis and are likely related to high trough levels due to the extended half-life of nonacog beta pegol. These data suggest that once-weekly prophylaxis with nonacog beta pegol may provide a new and safe alternative for the prevention and treatment of bleeding episodes in patients with Hemophilia B.”

Disclosure: The study was funded in part by Novo Nordisk A/S. The researchers report honoraria and research funding from, advisory/consultant roles with and employment with Baxter, Bayer, Biogen Idec, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Sanquin and Swedish Orphan Biovitrum.

Gene therapy found effective in hemophilia B

Leave a comment

(Reuters Health) – Ten patients with severe hemophilia B have remained cured of the inherited bleeding disorder for as long as three years thanks to gene therapy, according to a new report on the technique in the New England Journal of Medicine.

The study updates an earlier one from 2011, in which six volunteers were successfully treated with various doses of the treatment that uses a virus to insert genetic material into the liver. The four additional patients received the highest dose.

“I believe that, scientifically, this is ready for prime time,” the chief author, Dr. Andrew Davidoff of St. Jude Children’s Research Hospital in Memphis, Tennessee, told Reuters Health in a telephone interview.

The problem, he said, is that the genetically engineered virus that delivers the cure “is really a bear to make” and better methods to produce the treatment are desperately needed. To engineer enough virus to treat the 10 patients required six months of work.

Davidoff and his colleagues found that the higher the dose of the engineered virus, the more factor IX the body produced. Factor IX is a protein crucial to blood clotting and is defective in hemophilia B patients.

The researchers used an adeno-associated virus or AAV, which infects the liver without causing apparent illness.

The therapy seemed to have no serious side effects and is designed to eliminate the need to give patients injections of factor IX every two or three days at a cost of about $250,000 per year.

The treatment produced factor IX levels in a range of 1 percent to 6 percent of normal. But even a few percentage points can be enough to prevent dangerous bleeding. A single infusion was sufficient.

For the six high-dose recipients, the factor IX level averaged 5.1 percent, “which resulted in a reduction of more than 90 percent in both bleeding episodes and the use of prophylactic factor IX concentrate,” the research team wrote.

“I think it’s going to have a big impact. The study showed both safety and efficacy and the side effects were minimal,” said Dr. Timothy Nichols, who heads the Francis Owen Blood Research Laboratory at the University of North Carolina and was not involved in the study.

“This is a single shot of medicine given to patients who are treating themselves two or three times a week,” he told Reuters Health by phone. “Suddenly, they don’t have to take the medicine anymore.”

Worldwide, about 1 in 25,000 men are born with hemophilia B each year. It is less common than hemophilia A, which is caused by a problem with a different protein and affects about 1 in 5,000 men.

Because the genetic code for the clotting factors is carried on the X chromosome, and males don’t have a backup copy of that chromosome as women do, the condition is almost exclusively a disease of men.

Nichols said most people with hemophilia would be “very eager to consider the treatment and move forward if production issues can be resolved.”

“Hopefully (the new results) will be a catalyst for us and others to find a more effective way to produce AAV,” Davidoff said. “In fact, we’re in discussions with other companies in terms of investing in our research for improving production.”

SOURCE: bit.ly/1t6duWb New England Journal of Medicine, online November 19, 2014.

For original post, click here.

Click links for other articles about this study – medicalxpress.com
ScienceDaily.com
Foxnews.com

Recombinant long-acting glycoPEGylated factor IX in hemophilia B

Leave a comment

a multinational randomized phase 3 trial

Peter W. Collins1,*, Guy Young2, Karin Knobe3, Faraizah Abdul Karim4, Pantep Angchaisuksiri5, Claus Banner6, Türkiz Gürsel7, Johnny Mahlangu8, Tadashi Matsushita9, Eveline P. Mauser-Bunschoten10, Johannes Oldenburg11 Christopher E. Walsh12, and Claude Negrier13

Key points

  • Nonacog beta pegol, a recombinant glycoPEGylated FIX with extended half-life, was developed to improve care for hemophilia B patients.

  • Weekly prophylaxis with nonacog beta pegol was well tolerated and associated with low bleeding rates and an improved quality of life.

Abstract

This multinational, randomized, single-blind trial (NCT01333111 [www.clinicaltrials.gov]) investigated safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in 74 previously treated hemophilia B patients (FIX activity ≤2 IU/dL). Patients received prophylaxis for 52 weeks, randomized to 10 IU/kg or 40 IU/kg once weekly, or on-demand treatment for 28 weeks. No patients developed inhibitors and no safety concerns were identified. Three-hundred and forty-five bleeding episodes were treated with an estimated success rate of 92.2%. The median annualized bleeding rates (ABRs) were 1.04 in the 40 IU/kg prophylaxis arm, 2.93 in the 10 IU/kg prophylaxis arm, and 15.58 in the on-demand treatment arm. In the 40 IU/kg arm, 10 of 15 patients (66.7%) experienced no bleeding episodes into target joints, compared with 1 of 13 patients (7.7%) in the 10 IU/kg arm. Health-related quality of life (HR-QoL) assessed with the EQ-5D VAS score improved from median 75 to 90 in the 40 IU/kg prophylaxis arm. Nonacog beta pegol was well tolerated and efficacious for treatment of bleeding episodes, and associated with low ABRs in patients on prophylaxis. Once-weekly prophylaxis with 40 IU/kg resolved target joint bleeds in 66.7% of the affected patients and improved HR-QoL.

Another article can be found below….

Bleeding episodes were effectively treated by nonacog beta pegol and was associated with low annualized bleeding rates in hemophilia B patients, according to a study published in Blood, shown above.
Researchers from the Arthur Bloom Hemophilia Center at Cardiff University in the United Kingdom examined 74 hemophilia patients which had been previously treated in order to evaluate the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX with an extended half-life. The patients were divided into 3 groups: 30 patients received weekly prophylaxis 10 IU/kg for 52 weeks; 29 patients received weekly prophylaxis 40 IU/kg for 52 weeks; and 15 patients received on-demand treatment for 28 weeks. Patients receiving weekly treatment averaged 54 exposure days, while the on-demand treatment group averaged 14 days.

The investigators identified 345 bleeding episodes which came from 55 patients (74 percent). A third of the episodes were classified by researchers as traumatic (33.6 percent) while the remaining 65.8 percent of episodes were considered spontaneous. More than half (202 episodes) came from the weekly prophylaxis group and 143 came from the on-demand treatment group. A majority (78.5 percent) of the bleeding episodes occurred in joints.

Successful treatment of bleeding episodes was calculated to be 92.2 percent. More episodes were resolved after 1 injection of nonacog beta pegol in the weekly 40 IU/kg group (98.6 percent) than in the weekly 10 IU/kg group (84.1 percent). The on-demand treatment group was 83.9 percent successful in controlling bleeding episodes.

Half of the patients (52 percent) in the weekly 40 IU/kg treatment group did not require any treatment from the bleeding episodes, while 17 percent and 7 percent in the weekly 10 IU/kg and on-demand treatment groups, respectively, did not require treatment. Researchers pointed out the annualized bleeding rate was lower in the weekly 40 IU/kg treatment group, than in the weekly 10 IU/kg and on-demand treatment groups.

Researchers determined the weekly 40 IU/kg treatment group experienced the greatest improvements in quality of life, based on baseline scores of about 75 to 90 by the end of the trial on the EuroQOL-5 Dimensions scale.

Adverse events were experienced by 60 patients (81 percent) for a combined 215 events. Most commonly, these adverse events were nasopharyngitis (13.5 percent), influenza (10.8 percent), and upper respiratory tract infection (10.8 percent). The researchers noted no patients developed an inhibitor. They also noted there were no deaths, thromboembolic events, or allergic reactions to the treatment.

“Nonacog beta pegol was effective for the treatment of bleeding episodes in both prophylaxis and on-demand patients,” Peter W. Collins, MD, and colleagues concluded. “Low bleeding rates were observed in patients on prophylaxis and are likely related to high trough levels due to the extended half-life of nonacog beta pegol. These data suggest that once-weekly prophylaxis with nonacog beta pegol may provide a new and safe alternative for the prevention and treatment of bleeding episodes in patients with hemophilia B.” – See more at: http://www.hcplive.com/publications/hemophilia-reports/2014/october2014/Treatment-for-Hemophilia-B-Patients-Is-Effective-Well-Tolerated#sthash.qGMJCrha.dpuf

FDA Approves Baxter’s RIXUBIS [Coagulation Factor IX (Recombinant)] for Treatment of Children with Hemophilia B

Leave a comment

Approval Based on Clinical Data Finding 39% of Pediatric Patients Less Than 12 Years of Age Experienced No Bleeds on Prophylactic Treatment

DEERFIELD, Ill., September 15, 2014 – Baxter International Inc. (NYSE:BAX) today announced that the United States Food and Drug Administration (FDA) has approved RIXUBIS [Coagulation Factor IX (Recombinant)] for routine prophylactic treatment, control and prevention of bleeding episodes, and perioperative management in children with hemophilia B. RIXUBIS was the first recombinant factor IX (rFIX) approved for routine prophylaxis and control of bleeding episodes in the U.S. for adults living with this chronic condition.

“In addition to the positive reception we’ve received from adult RIXUBIS patients, the approval for pediatric patients offers a valuable new option, particularly as our clinical data demonstrated a significant reduction in bleeding episodes for patients who were treated prophylactically, an important factor for this young patient population,” said John Orloff, M.D., vice president of global research and development at Baxter BioScience.

The approval is based on the results of a clinical trial investigating the efficacy and safety of RIXUBIS among 23 previously-treated male patients less than
12 years of age with severe or moderately severe hemophilia B. The patients were treated with a twice-weekly RIXUBIS prophylaxis regimen (mean dose
56 IU/kg) for a mean treatment duration of six months and a mean of 54 exposure days (EDs). The median annualized bleeding rate (ABR) was 2.0 (0.0 for spontaneous bleeds and joint bleeds). Nine patients in the study (39.1%) experienced no bleeds and 23 bleeding episodes (88.5%) were treated with 1-2 infusions. There were no reports of inhibitor development, no severe allergic reactions, and no thrombotic or treatment-related adverse events among the study participants. Common adverse reactions observed in >1% of subjects in clinical studies were dysgeusia, pain in extremity, and positive test for furin antibody. These data were presented during the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans, LA.

Baxter’s application for marketing approval for RIXUBIS for adults and pediatric patients is currently under review in the European Union, with a regulatory decision expected later this year. The treatment also recently gained regulatory approval in Australia.

About RIXUBIS
RIXUBIS [Coagulation Factor IX (Recombinant)] is an antihemophilic factor indicated in adults and children with hemophilia B for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis. RIXUBIS is not indicated for induction of immune tolerance in patients with hemophilia B.

RIXUBIS was the first rFIX approved by the FDA for both routine prophylaxis and control of bleeding episodes in adults with this chronic condition.

Important Risk Information for RIXUBIS

CONTRAINDICATIONS
RIXUBIS is contraindicated in patients who have:

  • Known hypersensitivity to RIXUBIS or its excipients including hamster protein
  • Disseminated Intravascular Coagulation (DIC)
  • Signs of fibrinolysis


WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions
Hypersensitivity reactions (including symptoms such as dyspnea and pruritus) have been reported with RIXUBIS. Anaphylaxis and other hypersensitivity reactions are possible. Early signs of allergic reactions, which can progress to anaphylaxis, include angioedema, chest tightness, hypotension, lethargy, nausea, vomiting, paresthesia, urticaria, rash, restlessness, wheezing, and dyspnea. Immediately discontinue administration and initiate appropriate treatment if allergic- or anaphylactic-type reactions occur.

Inhibitors
Development of neutralizing antibodies (inhibitors) to factor IX may occur. Regularly evaluate patients for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. If expected factor IX plasma activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor IX inhibitor concentration. Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis if re-exposed to RIXUBIS.

Nephrotic Syndrome
Nephrotic syndrome has been reported following attempted immune tolerance induction with factor IX products in hemophilia B patients that have factor IX inhibitors. The safety and efficacy of using RIXUBIS for immune tolerance induction have not been established.

Thromboembolic Complications
The use of factor IX containing products has been associated with the development of thromboembolic complications. Monitor patients for early signs of thromboembolic and consumptive coagulopathy, when administering RIXUBIS to patients with liver disease, with signs of fibrinolysis, peri- and post-operatively, or at risk for thromboembolic events or DIC.

ADVERSE REACTIONS
Common adverse reactions observed in >1% of subjects in clinical studies were: dysgeusia, pain in extremity, and positive test for furin antibody.

Post-marketing Experience
The following class adverse reactions have been seen with another recombinant factor IX: inadequate factor IX recovery, inhibitor development, anaphylaxis, angioedema, hypotension, and thrombosis.

About Hemophilia B
Hemophilia B is the second most common type of hemophilia (also known as Christmas disease) and is the result of insufficient amounts of clotting factor IX, a naturally occurring protein in blood that controls bleeding.1 Approximately 26,000 people worldwide, including more than 4,000 in the U.S., have been diagnosed with hemophilia B.2 Hemophilia B is often a debilitating, chronic disease with complications that include bleeding episodes, hemophilic arthropathy (bleeding into a joint) and hospitalization.3

About Baxter in Hemophilia
Baxter has more than 60 years experience in hemophilia and has introduced a number of therapeutic firsts for hemophilia patients. The company has the broadest portfolio of hemophilia treatments in the industry and is able to meet individual therapy choices, providing a range of options at each treatment stage. The company’s work is focused on optimizing hemophilia care and improving the lives of people living with hemophilia A and B worldwide. Its diverse pipeline includes longer-acting therapies for hemophilia A, potential new treatments for hemophilia B (including gene therapy), von Willebrand disease and a recombinant treatment for patients with inhibitors.

About Baxter International Inc.
Baxter International Inc., through its subsidiaries, develops, manufactures and markets products that save and sustain the lives of people with hemophilia, immune disorders, cancer, infectious diseases, kidney disease, trauma and other chronic and acute medical conditions. As a global, diversified healthcare company, Baxter applies a unique combination of expertise in medical devices, pharmaceuticals and biotechnology to create products that advance patient care worldwide.

This release includes forward-looking statements concerning RIXUBIS, including expectations with regard to regulatory filings. The statements are based on assumptions about many important factors, including the following, which could cause actual results to differ materially from those in the forward-looking statements: satisfaction of regulatory and other requirements; actions of regulatory bodies and other governmental authorities; additional clinical results; changes in laws and regulations; product quality or supply or patient safety issues; and other risks identified in Baxter’s most recent filing on Form 10-K and other SEC filings, all of which are available on Baxter’s website. Baxter does not undertake to update its forward-looking statements.

 

1Types of Bleeding Disorders: Hemophilia B. National Hemophilia Foundation. Accessed on May 10, 2013. Available at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=181&contentid=46&rptname=bleeding
22011 Annual Global Survey. World Federation of Hemophilia. Accessed on May 10, 2013. Available at: http://www1.wfh.org/publications/files/pdf-1488.pdf
3Lee-Rodríguez-Merchán, E.-C. and Valentino, L. A. (2011) New Developments in Hemophilic Arthropathy, in Current and Future Issues in Hemophilia Care (eds E.-C. Rodríguez-Merchán and L. A. Valentino), Wiley-Blackwell, Oxford, UK. doi: 10.1002/9781119979401.ch29

Find original Press Release here.

Older Entries

Follow

Get every new post delivered to your Inbox.

Join 65 other followers