Gene therapy on brink of golden age: Here’s why

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: From – GeneticLiteracyProject.org

Bruce is 18 years old and for most of his life he has had to be extremely careful. During childhood, and all through high school, sports were out of the question because he has hemophilia B, a bleeding disorder, also called “Christmas disease” since it results from a deficiency of coagulation factor IX. Coagulation factor IX is also known as the “Christmas factor” and, because of a faulty gene on the X-chromosome that he received from his mother, it was useless in Bruce. Bruce’s mother is perfectly normal. In fact, all the females in Bruce’s family are normal; a classic feature of an X-linked recessive disease.

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Until recently, Bruce had to receive recombinant factor IX –the protein his body doesn’t make can be synthesized by genetically modified microorganisms– through intravenous infusion several times per week. That kept Bruce from bleeding to death but he still suffered from frequent “breakthrough bleeds” because the infused factor did not render him completely normal. Had he skinned a knee, as so many school children routinely do during recess, he could have bled into the joint. Had he bumped his head, even modestly, blood could have accumulated in the connective tissue layers between his skull and brain, causing a life-threatening situation. That’s why he avoided sports, all sports, and had to be cautious in everything he did, even shaving.

But last year, Bruce got the best Christmas present ever: a permanent cure of his Christmas disease. Now, he can play soccer and basketball with the kids at the after school program where he volunteers as a big brother. He no longer needs intravenous infusions of factor IX and if he nicks himself shaving, there will be no concern; he’ll heal as quickly as anyone else, since his liver now makes working factor IX. This all happened because of gene therapy and Bruce is quite satisfied, even though he will have to be monitored for the rest of his life (just in case the gene therapy produces any long-term effects). Unlike hemophilia A, the most common type of hemophilia, where gene therapy faces slightly more difficult technical challenges, clinical trials to replace the needed gene, leading to permanent cure for hemophilia B, are well underway.

Hemophilia A will follow soon, and in the meantime gene therapy is also being tested in human patients to treat a class of conditions known as hemoglobinopathies (where red blood cells make either defective globin proteins, or not enough of them) and for certain eye diseases that lead to blindness due to inherited gene defects involving the retina.

There are reasons why these are the first areas of gene therapy success, reasons that are connected with a rather bumpy history of gene therapy that has been characterized over the last quarter century by some hefty promises interspersed with some serious disappointments. But it’s through navigating that bumpy history that researchers learned what the challenges actually were and developed a realistic idea of which conditions gene therapy could potentially cure sooner and, conversely, in which areas clinical success would likely take a lot more time.

Cystic fibrosis: Promise, failure, and finally needed insight

Though ideas for gene therapy can be traced back to the early 1970s, the field really started moving from the realm of science fiction to science reality when the transmembrane regulator (CFTR) gene responsible for cystic fibrosis (CF) was cloned in 1989. Like hemophilia, CF is a recessive disease. Unlike hemophilia, CF is autosomal, not X-linked, so the disease occurs equally in males and females.But like hemophilia, CF is monogenetic, meaning the problem involves just one gene, rather than a whole bunch.

With the CFTR gene cloned, it seemed obvious that if you could give CF patients a normal copy of the defective gene, the disease would go away. Without at least one working CFTR gene, a person makes abnormally thick mucous along membranes, such as in the digestive tract. This leads to terrible symptoms but usually what kills CF patients are the effects of the thick mucous in the lungs. By the mid 1990s there were clinical studies set on using inhalation to deliver an engineered virus carrying the needed gene to the cells that needed it.

A virus is the easiest type of vector (delivery device) to be adapted for use in gene therapy because the one thing that viruses do very well is infect tissues and cells, thereby delivering genetic material. The CF gene therapy researchers used an attenuated form of adenovirus to deliver the needed CFTR gene to the cells lining the lungs of CF patients by inhalation. This virus had been modified to eliminate viral pathogenicity genes and was incapable of spreading throughout the body without the help of a different virus. Despite the sound scientific rational and promising results in laboratory animals, clinical trials in the 1990s and early 2000s failed, mostly because patients generated an immune response against the proteins on the viral “coat” enclosing the genetic material. Subsequent attempts to deliver the gene using vectors other than viruses also failed because they had trouble penetrating the mucous in the diseased lungs and because they stimulated inflammation.

In the midst of all of this, in 1999, during a University of Pennsylvania gene therapy trial targeting a different genetic condition (more rare than CF), an 18-year old subject, Jesse Gelsinger, died after having adenovirus particles injected into his liver, probably because of an immune response. Jesse’s death generated enormous ethical controversy because his condition, ornithine transcarbamylase (OTC) deficiency, had previously been controlled by a low-protein diet and medications since his birth and because it was only a phase I trial. The injected viral particles were not intended to cure him. Instead, they were injected only to test the safety of the procedure, which would allow testing to proceed to phase II, where the goal would be actual treatment that ultimately might have helped Jesse and others with OTC deficiency.

But it did not work out that way. As stated at the time by Georgetown University bioethicist, LeRoy Walters, “I think it’s a perilous time for gene therapy, ‘Until now, we have been able to say, ‘Well, it hasn’t helped many people, but at least it hasn’t hurt people.’ That has changed.” Thus, reporting on the case for the New York Times, Sheryl Gay Stolberg wrote:

Every realm of medicine has its defining moment, often with a human face attached. Polio had Jonas Salk. In vitro fertilization had Louise Brown, the world’s first test-tube baby. Transplant surgery had Barney Clark, the Seattle dentist with the artificial heart. AIDS had Magic Johnson. Now gene therapy has Jesse Gelsinger.

This, plus the failure of the CF gene therapy trials in the same era, put a damper on things; however, the research continued. By studying the immune reactions to the adenovirus, researchers came up with new ways to tinker with the delivery system. Ultimately, this led them to develop a fat-like molecule that could form spheres around the genetic material that they wanted to deliver, similar to the various kinds of  spherical carriers that transport cholesterol in the blood that have given rise to the popular terms “good cholesterol” (uses one type of carrier) and “bad cholesterol” (uses a slightly different carrier). This, and other non-viral vectors, has made gene therapy for CF a candidate for clinical trials once more, but the knowledge base today is orders of magnitude greater than it was 20 years ago.

Importantly, experience over the past 20 years has also taught investigators developing gene therapy for other diseases that each type of vector (viral and non-viral) has benefits and drawbacks, leading to an overriding pearl of wisdom: the formula is different for each disease. While this means that the pathway to successfully using gene therapy for specific diseases many be long and complicated, it also means that there are many diseases that could ultimately be permanently cured using this approach.

Blood diseases, eyes, and brain

Just as vaccination began first for smallpox, expanded to a handful of other diseases, and has since grown to prevent many more, the same is happening with gene therapy.

For some diseases, vaccine development was easier. With smallpox vaccination, for instance, Dr. Edward Jenner successfully used a cowpox virus back in the year 1796, even though he had no idea why it worked nor what he was administering. The 20th century saw rapid development of vaccines for measles, polio, and various other common infectious diseases, thus saving millions of people. However, for certain other infections, like Ebola and flu virus, success has only been partial and full protection against these diseases has not been realized. Yet.

An entire generation since AIDS first presented itself to medical researchers, a promising vaccine against human immunodeficiency virus (HIV) finally beckons. It has been a complex task because the way HIV causes disease, and importantly the way it incorporates into human cells, makes it a much tricker prospect, than for example, the measles virus.

A similar complex scenario applies to gene therapy. One of the great hopes is that it will be used some day to cure cancer, but that’s going to be a complex task, and rest assured it will not cure all cancers all at once. Instead, there will be different gene therapies for different types of cancer, which really constitutes a wide range of different diseases. Currently the promise and success are with diseases that lend themselves to having genes knocked out or introduced in limited anatomic sites, or in a limited number of tissues, since this allows both for targeting and concentrating the genetic modification as well as avoiding, or limiting the risk of an immune response.

Thus, people who have gone blind because of certain inherited enzyme deficiencies affecting the retina today are getting their site back in clinical trials, because the eyes lend themselves well to gene therapy delivered locally. It may sound scary, but specialized ophthalmologists who focus on treating retinal conditions are very good at injecting treatments directly to the retina at the back of the eyeball. They do it with drugs all the time, so they can just as easily do it with genetic treatments. The old adenovirus vectors used in early gene therapy have evolved into what are called adeno-associated virus (AAV) vectors, and these have proven to be the right kind of delivery system for getting genes into retinal cells, or for delivering agents knock out genes. AAV gene therapy is showing promise in the retina, because the treatment is concentrated where it’s needed and also does not evoke an immune response.

AAV vector also has been the vector employed in cases like that of Bruce, and others who have received gene therapy for hemophilia B. This is because AAV has been modified successfully to carry the factor IX gene and needed gene editing equipment, and also because the virus hones in on the liver. Unlike the experimental treatment that led to Jesse Gelsinger’s tragic death, the AAV system as employed for hemophilia B is not injected directly to the liver. Rather, it’s injected into the blood and simply has a tendency to make its way into liver cells. That’s a good thing, because the liver is where the coagulation factors, including factor IX, are made normally, and that’s why gene therapy for hemophilia B is working. As for hemophilia A, the problem is a lack of a different factor, factor XIII, which is much bigger than factor IX and thus is more likely to evoke an immune response. That’s the reason why investigators chose to work on hemophilia B first. It’s always good to gain experience doing the easier thing. But the difference in complexity between hemophilia A and B is not insurmountable, and given the success with treating the latter, the research is poised to expand to hemophilia A. There is also a hemophilia C, caused by a defect in yet another coagulation factor (XI), which affects mostly Jews, and this too could become a target for gene therapy.

As for hemoglobinopathies, these include thalassemia and sickle cell anemia. In clinical trials, gene therapy has already cured a handful of patients with one of the worse types of thalassemia, beta-thalassemia major. Since the problem gene of beta-thalassemia is the same gene that malfunctions in sickle cell anemia, patients with the latter have also begun getting the same gene therapy as of a year ago. Gene therapy is working with these conditions for a few reasons. One reason is that the genetic modification is done ex vivo, meaning outside of the patient. Bone marrow stem cells are harvested, genetically modified, then put back, so a virus or other vector is not delivered systemically. Also, for technical reasons, it’s actually easier to knock out a gene than to add a gene. With both beta-thalassemia and sickle cell anemia, rather than adding the needed gene, the patient’s hemoglobin can be improved by knocking out certain genes. But this approach does not work for another type of thalassemia called alpha-thalassemia, for which genes MUST be added, thereby adding to the technical challenge. But as with gene therapy for hemophilia A, the added layer of complexity only pushes back the treatment by a few years.

Finally, the brain is another area where gene therapy is starting to look promising. This may be surprising, since usually the brain is a the most challenging part of the body to treat, but various neurological conditions result from deficiencies localized to very limited anatomic regions. One example is Parkinson disease, where there’s a deficiency of the neurotransmitter dopamine in an area called the substantia nigra. Synthesis of dopamine requires certain enzymes and by adding the gene for a needed enzyme researchers are now getting the substantia nigra, or areas near it, to produce the needed dopamine, and thus curing Parkinson in some patients. They’re making similar strides curing children of rare diseases resulting from absence of the same enzymes in what same area of the brain, and they’re doing it using catheters to deliver the gene in a viral vector in a surgical procedure. Because the delivery of the treatment is local, there’s no stimulation of immune reactions, so the risk is reduced.

While this is all fairly technical, the take home message here is not the specifics of each disease and treatment, but rather the idea that they are all very different. As with many treatments in medicine, as with genetic technology applied to agriculture and other areas, there is no one size fits all solution. Gene therapy, like many other areas of technology, is advancing and succeeding in increments. And like the first 18 years of Bruce’s life, it must follow a very cautious pathway.

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VeinViewer Flex

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MEMPHIS, Tenn., Nov. 4, 2015 /PRNewswire/ — Christie Medical Holdings Inc., a global leader in portable vein imaging systems to aid in venipuncture procedures, has donated a VeinViewer® Flex to the Hemophilia Federation of America (HFA) as part of the Christie CARES philanthropy program.

The Christie VeinViewer Flex system uses harmless near-infrared light to detect patient veins and then projects a real-time, high definition image of the vein pattern directly on the skin surface. Nurses can quickly find more options for accessing a patient’s veins. A more thorough assessment with VeinViewer Flex means patients may avoid multiple needle sticks and possible future complications sometimes associated with IV access.

VeinViewer Flex

VeinViewer® Flex is a highly portable vascular access imaging device that can help you find the optimal venipuncture site and avoid potential complications.

Overview

​With HD imaging and Df² technology, this small VeinViewer model is the brightest and only handheld vein illuminator that provides benefits for all patients during the entire Pre-, During- and Post- vascular access procedure. It is ideal for alternate care facilities, such as surgery and blood/plasma centers, as well as home healthcare and Emergency Medical Services (EMS), VeinViewer Flex is designed for durability and maximum portability. Flex is also suited for hospital departments such as the Emergency Department and NICU where space requirements and speed of assessment demand an ultra-portable and reliable vein finder.

How Does It Work?

With HD imaging and exclusive Df2 (digital full field) technology, VeinViewer is the only vein illuminator that provides benefits for all patients during the entire Pre, During and Post vascular access procedure.

Projected near-infrared light is absorbed by blood and reflected by surrounding tissue. The information is captured, processed and projected digitally in real time directly onto the surface of the skin. It provides a real time accurate image of the patient’s blood pattern.

VeinViewer patented technology, using AVIN™ (Active Vascular Imaging Navigation), allows you to see blood patterns up to 15mm deep and clinically relevant veins up to 10mm. With VeinViewer clinicians can see peripheral veins, bifurcations and valves and assess in real time the refill/flushing of veins. With visualization Pre-, During- and Post-procedure, clinicians can potentially avoid complications from accidental puncture. Improving the total vascular access procedure, not just the stick.

Find Videos on how the VeinViewer works, here.

FDA approves modified antihemophilic factor for hemophilia A

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November 13, 2015

The U.S. Food and Drug Administration today approved Adynovate, Antihemophilic Factor (Recombinant), PEGylated for use in adults and adolescents, aged 12 years and older, who have Hemophilia A. Adynovate is modified to last longer in the blood and potentially require less frequent injections than unmodified Antihemophilic Factor when used to reduce the frequency of bleeding.

Adynovate is approved for on-demand (as needed) treatment and control of bleeding episodes and to reduce the frequency of bleeding episodes (prophylaxis) in patients with Hemophilia A. Adynovate consists of the full-length Coagulation Factor VIII molecule (historically known as Antihemophilic Factor) linked to other molecules, known as polyethylene glycol (PEGylated). This link makes the product last longer in the patient’s blood.

“The approval of Adynovate provides an important therapeutic option for use in the care of patients with Hemophilia A and reduces the frequency of Factor VIII infusions needed to avoid bleeding,” said Karen Midthun, M.D., director of the FDA’s Center for Biologics Evaluation and Research.

Hemophilia A is an inherited, sex-linked, blood-clotting disorder that primarily affects males, which is caused by defects found in the Factor VIII gene. According to the Centers for Disease Control and Prevention, Hemophilia A affects one in every 5,000 male births in the United States. Patients with hemophilia A may experience repeated episodes of serious bleeding, primarily into the joints, which can be severely damaged as a result.

The safety and efficacy of Adynovate were evaluated in a clinical trial of 137 adults and adolescents aged 12 years and older, which compared the recommended routine prophylactic (preventative) treatment regimen to on-demand therapy. The trial demonstrated that Adynovate was effective in reducing the number of bleeding episodes during routine care. Additionally, Adynovate was effective in treating and controlling bleeding episodes. No safety concerns were identified during the trial.

Adynovate is manufactured by Baxalta US Inc., based in Westlake Village, California.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

For FDA article, click here.

FDA Approves Octapharma’s NUWIQ® for the Treatment of Adults and Children with Hemophilia A

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14.09.2015

HOBOKEN, N.J. September 15th, 2015: Octapharma USA today announced the U.S. Food and Drug Administration (FDA) has approved NUWIQ®, Antihemophilic Factor (Recombinant), an intravenous therapy for adults and children living with Hemophilia A. The NUWIQ® approval includes on-demand treatment and control of bleeding episodes; routine prophylaxis to reduce the frequency of bleeding episodes; and perioperative management of bleeding.

NUWIQ® is the first B-domain deleted recombinant Factor VIII (FVIII) derived from a human cell-line, not chemically modified or fused with another protein, designed for the treatment of patients with Hemophilia A, congenital FVIII deficiency. Hemophilia A impacts the lives of up to 16,000 individuals in the U.S. and their caregivers. Although present therapies for Hemophilia A treatment exist in the U.S., significant challenges still remain, including development of inhibitors and the need for multiple infusions on a prophylactic basis. Octapharma USA is a subsidiary of global human protein products manufacturer Octapharma AG, which develops and manufactures high-purity recombinant and plasma-derived coagulation factor concentrates for patients with bleeding disorders.

“Octapharma has been committed to the bleeding disorders community for many years and its decade-long drive to find solutions for Hemophilia A challenges has never wavered,” said Octapharma USA President Flemming Nielsen. “Early development strategies were integral in the development of NUWIQ® and these initial goals have been realized with the FDA approval. NUWIQ® has demonstrated safety and efficacy in global clinical trials and has the potential to positively impact patients’ quality of life in the years ahead. Octapharma is dedicated to providing life enhancing and saving therapies for Hemophilia A and looks forward to bringing NUWIQ® to the U.S. marketplace.”

The European Commission first approved the therapy in August 2014. NUWIQ® is currently approved in many countries, including the United Kingdom, Australia, Canada, Germany, Italy and Sweden.

“We are pleased that the treatment options for adults and children with Hemophilia A continue to advance with ever more innovative therapies being approved for the U.S.,” said Val Bias, chief executive officer of the National Hemophilia Foundation (NHF). “The continued commitment to develop life-enhancing products for the bleeding disorders community is absolutely vital. Empowering patients and providers with treatment options, as well as education and support programs, is extremely important to people living with Hemophilia A.”

The initial global clinical study program for NUWIQ® commenced with a pharmacokinetic (PK) evaluation in an open-label, multi-center clinical trial of 22 (20 adults, 2 adolescents) previously treated patients (PTPs). In this study, NUWIQ® demonstrated a mean half-life of 17.1 hours using a one-stage clotting assay in adults.  NUWIQ® was also evaluated in children using a one-stage clotting assay with a mean half-life of 11.9 hours for ages 2 to 5; and a mean half-life of 13.1 hours for ages 6 to 12. These PK results for mean half-life were longer than earlier generations of recombinant FVIII products currently available in the U.S.

The second set of global clinical studies for NUWIQ® also evaluated overall efficacy and tolerability in three prospective, open-label clinical studies in PTPs with severe Hemophilia A. Across all clinical studies, a total of 135 patients with Hemophilia A were treated with NUWIQ®, including 74 adults, 3 adolescents between ages 12 and 17, and 58 pediatric patients between ages 2 and 11. These 135 patients were treated with a total of 16,134 infusions over 15,950 exposure days using NUWIQ®.

In a study of 32 adults, overall prophylactic efficacy of NUWIQ® for spontaneous bleeds was rated as excellent or good in 92% of patients. In a study of 59 children, prophylactic efficacy for spontaneous bleeds was rated as excellent or good in 97% of patients. The mean annualized bleeding rates (ABR) for spontaneous bleeds during prophylaxis were approximately 1.5 in children and 1.2 in adults. For Hemophilia A patients receiving NUWIQ® prophylaxis compared to on-demand treatment, the ABR was reduced 96% for adults and 93% for children. Treatment of breakthrough bleeds during NUWIQ® prophylaxis was rated as excellent or good in 30 of 30 (100%) bleeds in adults and for 89 of 108 (82%) bleeds in children. For on-demand treatment with NUWIQ® in 20 adults and 2 adolescents, efficacy for the treatment of bleeds was excellent or good in 931 of 986 (94%) bleeds. Overall efficacy in surgical prophylaxis was rated excellent or good in 32 of 33 (97%) procedures using NUWIQ®.1

In all clinical studies, NUWIQ® had a total of 7 reported adverse events. Each of these adverse events occurred one time with a rate of 0.7% across all 135 patients. These events were parathesia, headache, injection site inflammation, injection site pain, back pain, vertigo, and dry mouth.

As part of its continuing commitment to the bleeding disorders community, Octapharma USA will offer Hemophilia A patients educational and support services in connection with the introduction of NUWIQ®. Octapharma USA aims to have NUWIQ® available in the U.S. marketplace by early 2016.

About NUWIQ®

NUWIQ®, Antihemophilic Factor (Recombinant) Lyophilized Powder for Solution for Intravenous Injection is a recombinant antihemophilic factor [blood coagulation factor VIII (Factor VIII)] indicated in adults and children with Hemophilia A for on-demand treatment and control of bleeding episodes; perioperative management of bleeding; and routine prophylaxis to reduce the frequency of bleeding episodes. NUWIQ® is not indicated for the treatment of von Willebrand Disease.

Important Safety Information

NUWIQ® is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components. Hypersensitivity reactions, including anaphylaxis, are possible. Should symptoms occur, discontinue NUWIQ® and administer appropriate treatment. Development of Factor VIII neutralizing antibodies (inhibitors) may occur. If expected plasma Factor VIII activity levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures Factor VIII inhibitor concentration. Monitor all patients for Factor VIII activity and development of Factor VIII inhibitor antibodies.

The most frequently occurring adverse reactions (0.7%) in clinical trials were paresthesia, headache, injection site inflammation, injection site pain, non-neutralizing anti-Factor VIII antibody formation, back pain, vertigo, and dry mouth. For full prescribing information on NUWIQ® please visit www.octapharmausa.com.

About the Octapharma Group

Headquartered in Lachen, Switzerland, Octapharma is one of the largest human protein product manufacturers in the world and has been committed to patient care and medical innovation since 1983. Its core business is the development and production of human proteins from human plasma and human cell-lines. Octapharma employs approximately 6,000 people worldwide to support the treatment of patients in over 100 countries with products across the following therapeutic areas:  Hematology (coagulation disorders), Immunotherapy (immune disorders) and Critical Care. The company’s American subsidiary, Octapharma USA, is located in Hoboken, N.J. Octapharma operates two state-of-the-art production sites licensed by the U.S. Food and Drug Administration (FDA), providing a high level of production flexibility. For more information, please visit www.octapharmausa.com.

REFERENCES

1 – Octapharma, Data on file. 2015.

Forward-looking Statements

This news release contains forward-looking statements, which include known and unknown risks, uncertainties, and other factors not under the company’s control. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. These factors include results of current or pending research and development activities and action by the FDA or other regulatory authorities.

For Original Press release, click here

U.S. FDA Grants Breakthrough Therapy Designation

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U.S. FDA Grants Breakthrough Therapy Designation for Genentech’s Investigational Medicine ACE910 for People With Hemophilia A With Factor VIII Inhibitors

First factor VIIIa-mimetic bispecific antibody to be investigated for the prophylactic treatment of hemophilia A

Ninth breakthrough therapy designation for Genentech’s portfolio of medicines

South San Francisco, CA — September 3, 2015 —

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to ACE910 (RG6013, RO5534262) for the prophylactic treatment of people who are 12 years or older with hemophilia A with factor VIII inhibitors. Hemophilia A, a rare genetic disorder, occurs when an essential blood clotting protein called factor VIII is either not present in sufficient amounts or is defective. People with severe hemophilia A can be susceptible to uncontrolled or difficult to control bleeding including internal bleeding, especially into the joints, which can lead to the need for joint replacements.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

In a Phase I study, ACE910 showed promising results as a prophylactic treatment administered as a weekly subcutaneous injection in people with severe hemophilia A with and without inhibitors to factor VIII. The development of inhibitors is a serious complication of hemophilia A treatment regardless of disease severity, making it difficult, if not impossible, to achieve a level of factor VIII sufficient to control bleeding with traditional replacement therapies. Management of bleeding in people with hemophilia A who have inhibitors to factor VIII is a major challenge, and there remains a need for additional treatment options for these patients.

“People with hemophilia A may require regular and frequent infusions of replacement clotting factor to reduce the risk of dangerous bleeding, and they can develop inhibitors that make replacement ineffective,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “We are pleased that the FDA has granted breakthrough therapy designation for ACE910, recognizing an unmet need for patients with inhibitors and the promise of these early data. Genentech has been developing antibody treatments for people with blood disorders for over 20 years, and we are excited to expedite the development of a potential new treatment for hemophilia A.”

Genentech is preparing to initiate a Phase III trial of ACE910 in patients with hemophilia A with factor VIII inhibitors by the end of 2015 and a Phase III trial in patients without inhibitors in 2016. Additionally, a trial in pediatric patients with hemophilia A is planned to commence in 2016.

The breakthrough therapy designation for ACE910 was granted based on results of a Phase I study of ACE910 in people with severe hemophilia A presented at the annual meeting of the American Society of Hematology (ASH) in 2014, and the Phase I/II extension study of the same patients presented at the annual meeting of the International Society of Thrombosis and Haemostasis (ISTH) in 2015.

About ACE910

ACE910 is an investigational humanized bispecific monoclonal antibody engineered to simultaneously bind factors IXa and X. ACE910 thereby mimics the cofactor function of factor VIII and is designed to promote blood coagulation in hemophilia A patients, regardless of whether they have developed inhibitors to factor VIII. ACE910 is administered subcutaneously once weekly, and as it is distinct in structure from factor VIII, it is not expected to lead to the formation of inhibitors against factor VIII. The development program of ACE910 is assessing its potential to help overcome some of the clinical challenges faced in hemophilia care, such as the development of factor VIII inhibitors and the need for frequent venous access. ACE910 was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Genentech.

About Genentech In Hematology

For more than 20 years, Genentech has been developing medicines with the goal of redefining treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines Rituxan and Gazyva, Genentech’s pipeline of investigational hematology medicines includes the antibody-drug conjugate polatuzumab vedotin, a small molecule antagonist of MDM2 and, in collaboration with AbbVie, the small molecule BCL-2 inhibitor venetoclax. Genentech’s dedication to developing novel molecules in hematology expands beyond oncology, with the development of the investigational hemophilia A treatment ACE910.

About Genentech

Founded more than 35 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

For Press release, Click here.

First factor VIIIa-mimetic bispecific antibody to be investigated for the prophylactic treatment of hemophilia A

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U.S. FDA Grants Breakthrough Therapy Designation for Genentech’s Investigational Medicine ACE910 for People With Hemophilia A With Factor VIII Inhibitors

Ninth breakthrough therapy designation for Genentech’s portfolio of medicines

South San Francisco, CA — September 3, 2015 —

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to ACE910 (RG6013, RO5534262) for the prophylactic treatment of people who are 12 years or older with hemophilia A with factor VIII inhibitors. Hemophilia A, a rare genetic disorder, occurs when an essential blood clotting protein called factor VIII is either not present in sufficient amounts or is defective. People with severe hemophilia A can be susceptible to uncontrolled or difficult to control bleeding including internal bleeding, especially into the joints, which can lead to the need for joint replacements.

Breakthrough therapy designation is designed to accelerate the development and review of medicines that demonstrate early clinical evidence of a substantial improvement over current treatment options for serious diseases.

In a Phase I study, ACE910 showed promising results as a prophylactic treatment administered as a weekly subcutaneous injection in people with severe hemophilia A with and without inhibitors to factor VIII. The development of inhibitors is a serious complication of hemophilia A treatment regardless of disease severity, making it difficult, if not impossible, to achieve a level of factor VIII sufficient to control bleeding with traditional replacement therapies. Management of bleeding in people with hemophilia A who have inhibitors to factor VIII is a major challenge, and there remains a need for additional treatment options for these patients.

“People with hemophilia A may require regular and frequent infusions of replacement clotting factor to reduce the risk of dangerous bleeding, and they can develop inhibitors that make replacement ineffective,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “We are pleased that the FDA has granted breakthrough therapy designation for ACE910, recognizing an unmet need for patients with inhibitors and the promise of these early data. Genentech has been developing antibody treatments for people with blood disorders for over 20 years, and we are excited to expedite the development of a potential new treatment for hemophilia A.”

Genentech is preparing to initiate a Phase III trial of ACE910 in patients with hemophilia A with factor VIII inhibitors by the end of 2015 and a Phase III trial in patients without inhibitors in 2016. Additionally, a trial in pediatric patients with hemophilia A is planned to commence in 2016.

The breakthrough therapy designation for ACE910 was granted based on results of a Phase I study of ACE910 in people with severe hemophilia A presented at the annual meeting of the American Society of Hematology (ASH) in 2014, and the Phase I/II extension study of the same patients presented at the annual meeting of the International Society of Thrombosis and Haemostasis (ISTH) in 2015.

About ACE910

ACE910 is an investigational humanized bispecific monoclonal antibody engineered to simultaneously bind factors IXa and X. ACE910 thereby mimics the cofactor function of factor VIII and is designed to promote blood coagulation in hemophilia A patients, regardless of whether they have developed inhibitors to factor VIII. ACE910 is administered subcutaneously once weekly, and as it is distinct in structure from factor VIII, it is not expected to lead to the formation of inhibitors against factor VIII. The development program of ACE910 is assessing its potential to help overcome some of the clinical challenges faced in hemophilia care, such as the development of factor VIII inhibitors and the need for frequent venous access. ACE910 was created by Chugai Pharmaceutical Co., Ltd. and is being co-developed by Genentech.

About Genentech In Hematology

For more than 20 years, Genentech has been developing medicines with the goal of redefining treatment in hematology. Today, we’re investing more than ever in our effort to bring innovative treatment options to people with diseases of the blood. In addition to approved medicines Rituxan and Gazyva, Genentech’s pipeline of investigational hematology medicines includes the antibody-drug conjugate polatuzumab vedotin, a small molecule antagonist of MDM2 and, in collaboration with AbbVie, the small molecule BCL-2 inhibitor venetoclax. Genentech’s dedication to developing novel molecules in hematology expands beyond oncology, with the development of the investigational hemophilia A treatment ACE910.

About Genentech

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Engineered protein safely, effectively controls bleeding in severe von Willebrand’s disease

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Recombinant von Willebrand’s factor appeared safe and effective for the treatment of bleeding episodes in patients with severe von Willebrand’s disease, according to the results of a phase 3 study.

Gill JC, et al. Blood. 2015;doi:10.1182/blood-2015-02-629873.

August 6, 2015

Recombinant von Willebrand’s factor stabilized endogenous factor VIII (FVIII) levels, which may eliminate the need for engineered FVIII (rFVIII) after the initial infusion.

Patients with von Willebrand’s disease lack a sufficient quality of fully functioning von Willebrand’s factor — a protein that stops bleeding when a blood vessel becomes damaged — and often experience excessive, hard-to-treat bleeding.

Standard treatment for severe von Willebrand’s disease consists of an infusion of purified von Willebrand’s factor, which circulates in combination with FVIII. Although this approach is usually effective, the purification of von Willebrand’s factor from plasma can potentially introduce patients to blood-borne contaminants, according to the researchers.

Bruce Ewenstein, MD, PhD, vice president of clinical affairs at Baxalta in Cambridge, Massachusetts, and colleagues, thus, sought to evaluate whether a highly active, recombinant von Willebrand’s factor (BAX 111, Baxalta) would safety and effectively treat the disease without the disadvantages of blood-derived products.

The analysis included 37 patients (median age, 37 years; 54.1% female) with type 3 (n = 29) or severe type 1 (n = 2), 2A (n = 5) or 2N (n =1) disease.

Researchers assigned patients to one of four arms composed of recombinant von Willebrand’s factor (50 IU/kg or 80 IU/kg) with or without rFVIII (Advate, Baxalta). Most patients also received as-needed treatment with recombinant von Willebrand’s factor of 40 IU/kg to 60 IU/kg for regular bleeding episodes and up to 80 IU/kg for major bleeds.

In total, 22 patients experienced 192 bleeding episodes (minor bleeds, n = 122; moderate bleeds, n = 61; major bleeds, n = 7).

A single infusion proved effective for 81.8% of bleeding episodes.

Using a 4-point scale (1 = excellent; 4 = no response), the researchers rated 96.9% of bleed control as excellent (minor bleeds, 119/122; moderate, 59/61; major, 6/7). Further, 100% of patients achieved treatment success, defined as a mean efficacy rating of less than 2.5.

Plasma concentrations of recombinant von Willebrand’s factor increased rapidly after a single infusion of 50 IU/kg, when administered with or without rFVIII.

Recombinant von Willebrand’s factor administered alone induced substantial stabilization of endogenous FVIII. Median FVIII levels increased more than 40% 6 hours post-infusion to a peak of 86 U/dL 24 hours post-infusion. These levels were sustained through 72 hours post-infusion, which suggests these patients are unlikely to require additional rFVIII infusions.

Eight adverse events occurred, including two serious adverse events — chest discomfort and increased heart rate without cardiac symptomatology — that occurred concurrently in one patient. However, no thrombotic events or severe allergic reactions occurred.

The researchers did not detect the development of any von Willebrand’s factor or FVIII inhibitors, anti-von Willebrand’s factor–binding antibodies or antibodies against host-cell proteins.

“These efficacy and safety data of [recombinant von Willebrand’s factor] represent a major advance in our quest to develop an optimal treatment for people living with [von Willebrand’s disease],” Ewenstein said in a press release. “As this product is specifically designed to be administered without FVIII, it will allow physicians to dose [von Willebrand’s disease] and FVIII separately and precisely based on the needs of each individual patient. This treatment strategy has the potential to become the standard of care for patients with severe [von Willebrand’s disease].” – by Cameron Kelsall

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Disclosure: Baxalta provided funding for this study. Ewenstein reports an employment role with Baxalta. Please see the full study for a list of all other researchers’ relevant financial disclosures.

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