Sangamo Therapeutics and Pfizer Announce Collaboration for Hemophilia A Gene Therapy

Sangamo Therapeutics, Inc. and Pfizer Inc. announced this week, an exclusive, global collaboration and license agreement for the development and commercialization of gene therapy programs for Hemophilia A, including SB-525, one of Sangamo’s four lead product candidates, which Sangamo expects will enter the clinic this quarter.

“Sangamo brings deep scientific and technical expertise across multiple genomic platforms, and we look forward to working together to advance this potentially transformative treatment for patients living with Hemophilia A,” said Mikael Dolsten, MD, PhD, President of Worldwide Research and Development at Pfizer. “Pfizer has made significant investments in gene therapy over the last few years and we are building an industry-leading expertise in recombinant adeno-associated virus (rAAV) vector design and manufacturing. We believe SB-525 has the potential to be a best-in-class therapy that may provide patients with stable and durable levels of Factor VIII protein with a single administration treatment.”

“With a long-standing heritage in rare disease, including hemophilia, Pfizer is an ideal partner for our Hemophilia A program,” said Dr. Sandy Macrae, Sangamo’s Chief Executive Officer. “We believe Pfizer’s end-to-end gene therapy capabilities will enable comprehensive development and commercialization of SB-525, which could potentially benefit Hemophilia A patients around the world. This collaboration also marks an important milestone for Sangamo as we continue to make progress in the translation of our ground-breaking research into new genomic therapies to treat serious, genetically tractable diseases.”

Under the terms of the collaboration agreement, Sangamo will receive a $70 million upfront payment from Pfizer. Sangamo will be responsible for conducting the SB-525 Phase 1/2 clinical study and certain manufacturing activities. Pfizer will be operationally and financially responsible for subsequent research, development, manufacturing and commercialization activities for SB-525 and additional products, if any. Sangamo is eligible to receive potential milestone payments of up to $475 million, including up to $300 million for the development and commercialization of SB-525 and up to $175 million for additional Hemophilia A gene therapy product candidates that may be developed under the collaboration. Sangamo will also receive tiered double-digit royalties on net sales. Additionally, Sangamo will be collaborating with Pfizer on manufacturing and technical operations utilizing viral delivery vectors.

Gene therapy is a potentially transformational technology for patients, focused on highly specialized, one-time, treatments that address the root cause of diseases caused by genetic mutation. The technology involves introducing genetic material into the body to deliver a correct copy of a gene to a patient’s cells to compensate for a defective one. The genetic material can be delivered to the cells by a variety of means, most frequently using a viral vector such as rAAV. There have been no gene therapy products approved in the U.S. to date.

Hemophilia A is a rare blood disorder caused by a genetic mutation resulting in insufficient activity of Factor VIII, a blood clotting protein the body uses to stop bleeding. There are approximately 16,000 patients in the U.S. and more than 150,000 worldwide with Hemophilia A. SB-525 is comprised of a rAAV vector carrying a Factor VIII gene construct driven by a proprietary, synthetic, liver-specific promoter. The U.S. Food and Drug Administration has cleared initiation of human clinical trials for SB-525, which also has been granted orphan drug designation. Sangamo is on track this quarter to start a Phase 1/2 clinical trial to evaluate safety and to measure blood levels of Factor VIII protein and other efficacy endpoints.

 

Capsule for Severe Bleeding Disorder Moves Closer to Reality

Motivated by the tribulations of hemophilia patients and their families, researchers funded by the National Institute of Biomedical Imaging and Bioengineering are working to develop a pill to treat this serious inherited bleeding disorder. Oral delivery of the treatment–clotting factor IX–would allow individuals with type B hemophilia to swallow a pill rather than be subjected to several weekly injections of factor IX to control potentially fatal bleeding episodes.

Such a pill is what Nicholas Peppas, Professor of Biomedical Engineering, Chemical Engineering and Medicine and his team are working to perfect at the University of Texas at Austin’s Institute of Biomaterials, Drug Delivery, and Regenerative Medicine.

Explains David Rampulla, Ph.D., Director of the NIBIB Program in Delivery Systems and Devices for Drugs and Biologics, “The problem with oral delivery is the need to protect proteins such as factor IX in the acidic environment of the stomach but then release them when they reach the small intestine. This is an extraordinary challenge and the Peppas group has spent years developing innovative polymer shells capable of shuttling the protein to its final destination in the digestive tract.”

Hemophilia B is a genetic disorder, which occurs in boys who have a defective factor IX gene that resides on the X chromosome they receive from their mother. The result is a deficiency of the factor IX protein, which the body needs for blood to clot. Though mothers carry the defect, they do not have the disease because they have a normal factor IX gene on their other X chromosome. It is very rare, but one way a daughter might inherit hemophilia is if her father has it and her mother carries the gene for hemophilia as well.

“Multiple weekly injections of factor IX is very difficult for the boys who need the clotting factor to avoid potentially fatal bleeding episodes, as well as for their families” said Peppas. “However, in working with these families, we soon learned that there was also an emotionally draining aspect for mothers, who carry the burden that they passed this disorder on to their sons. This has added an urgency to our research because we know that oral administration of factor IX would be a great relief for these families.”

Peppas and his team are using their skills in advanced materials, and chemical and biomolecular engineering to develop a capsule — actually a sophisticated delivery system – that can carry the swallowed factor IX protein to the small intestine, where it is absorbed and then released into the bloodstream. The current work is described in the November 30 issue of the International Journal of Pharmaceutics.

Outsmarting a harsh and variable digestive system

If one were to swallow the factor IX protein alone it would be quickly digested by stomach acids and lose its biological activity as a clotting factor. Thus, the researchers engineered a protective polymer capsule that has multiple critical functions in the changing environment of the gastrointestinal tract.

First, the polymer is designed to be impervious to harsh stomach acids, such as pepsin in order to protect the factor IX protein from being digested. Second, the capsule moves through the stomach and into the small intestine, which contains the protease, trypsin. The polymer is engineered to be degraded by trypsin, allowing the intestinal fluids to enter and swell the capsule. This swelling promotes degradation of the capsule and release of the clotting factor for absorption into the bloodstream.

The most recent version of the polymer has been improved from previous designs because it is highly biodegradable in the neutral pH of the small intestine. The new biodegradable capsule promotes a several-fold increase in the absorption of factor IX through the intestinal wall. The result is that each capsule can deliver more of the factor IX protein into the bloodstream.

Building on years of improvement in the capsule polymer design, the most recent results in experimental cell culture systems indicate that taking two capsules of the current formulation orally can deliver as much factor IX as a single needle injection.

Having reached this benchmark, Peppas is collaborating with industry to accelerate the necessary testing required in animals with the aim of moving to human clinical trials and FDA approval as rapidly as possible.

After One Dose of Gene Therapy, Hemophilia B Patients Maintain Near-Normal Levels of Clotting Factor

At ASH Meeting, CHOP Hematologist Leads Clinical Trial in Which All Subjects Safely Maintain Factor IX Expression that Curtails Disabling Bleeding

Researchers are reporting the highest and most sustained levels to date of an essential blood-clotting factor IX in patients with the inherited bleeding disorder hemophilia B. After receiving a single dose of an experimental gene therapy in a clinical trial, patients with hemophilia produced near-normal levels of clotting factor IX, allowing them to stop clotting factor infusions and to pursue normal activities of daily life without disabling bleeding episodes.

Lindsey A. George, MD, a hematologist at Children’s Hospital of Philadelphia (CHOP)is the lead investigator of the phase 1/2 clinical trial sponsored by Spark Therapeutics, Inc. and Pfizer, Inc. The American Society of Hematology (ASH) today highlighted updated findings from that trial in a press conference during its annual meeting in San Diego. George will present those study results tomorrow at an ASH plenary scientific session.

Katherine High, MD, a senior author of the study and Spark Therapeutics’s president and chief scientific officer, described the updated interim trial data at today’s press conference. The clinical trial of nine adult hemophilia B patients, aged 18 to 52 years, used a single dose of a gene therapy product engineered to enter patients’ liver cells and direct the production of the blood clotting factor that they lack.

George notes, “Our goal in this trial was to evaluate the safety of the gene therapy product and secondarily, to determine if we could achieve levels of factor IX that could decrease bleeding events in patients.” She added, “These patients have a severe or moderate level of hemophilia, with baseline clotting factor level less than or equal to 2 percent of levels in healthy people. In current treatment, patients with hemophilia give themselves intravenous doses of factor IX up to a couple times a week. While generally effective, factor levels fluctuate, and patients may suffer painful, disabling joint bleeds when their clotting factor levels drop. Such a regimen requires significant planning of daily activities.”

In the current trial, said George, the patients maintained factor levels of approximately 30 percent, enough to lift them out of the severe category. “At these new levels, hemophilia patients do not typically need to self-treat with factor to avoid bleeding events,” she said, adding, “This represents a potential dramatic improvement in their quality of life and a shift in the way we think about treating hemophilia.” A factor level of 30 percent is near-normal, she added, and patients would be expected to experience bleeding only in the event of major trauma or surgery.

One subject self-infused two days after receiving the gene therapy vector. Beyond this, no patients had any bleeding events or required factor for any reason. With significant reduction in bleeding events and factor use, six of the first seven patients reported increased physical activity and all reported improved quality of life. Two additional patients received the gene therapy product too recently to determine quality-of-life measures.

Previous hemophilia gene therapy trials have been frustrated by an immune response to the gene therapy product that limited the success of the therapy. In the current trial, two patients experienced an immune response to the gene therapy that did not result in safety concerns, and were treated with steroids. The patients are still undergoing treatment but have maintained factor IX activity without bleeding.

George reported that she is cautiously optimistic, acknowledging that this trial is a small study, with a short follow-up period as yet. However, as the researchers continue to monitor patients in the current trial, next steps will be to discuss with the U.S. Food and Drug Administration the outlines of a larger, phase 3 clinical trial. No gene therapies for any genetic diseases have yet been approved for clinical use in the U.S.

Formerly a research leader at CHOP, High pursued groundbreaking preclinical investigations in hemophilia B gene therapy and provided scientific expertise to previous gene therapy trials in hemophilia and other genetic disorders at CHOP before moving to Spark Therapeutics, which was spun off from CHOP in 2013. CHOP maintains a financial interest in the company.