RARE Daily

Sangamo Provides Positive Updates on Hemophilia A and Beta Thalassemia Gene Therapy Trials

April 2, 2019

MSangamo Therapeutics provided updates on two of its on-going early stage trials, one for hemophilia A and one for beta thalassemia.

Hemophilia A is a rare bleeding disorder caused by a deficiency of clotting factor VIII protein, in which blood does not clot or stop bleeding when blood vessels are injured. SB-525 is a gene therapy that uses an AAV vector to deliver a new therapeutic copy of the factor VIII gene to the patient’s liver cells, designed to enable the liver to produce and secrete functionally active factor VIII protein into the bloodstream.

Sangamo and its partner Pfizer said interim data from a phase 1/2 study evaluating the investigational gene therapy SB-525 for severe hemophilia A indicate that it was generally well-tolerated and demonstrated a dose-dependent increase in factor VIII levels across the four dosage cohorts, an important benchmark for moving forward. Based on the results, the safety monitoring committee recommended cohort expansion at the highest dose in the study to an additional five patients.

“These interim results suggest that SB-525 may be well-tolerated and may prove to have the predictability and sustained treatment effect that can bring clinical benefit in patients with hemophilia A,” said Edward Conner, chief medical officer of Sangamo. “We need to continue observing how the data mature and how additional patients in the expansion cohort respond to SB-525.”

The phase 1/2 interim data from the open-label Alta study include eight patients treated across four ascending dosage cohorts, with two patients per cohort. Patients demonstrated a dose-dependent increase in factor VIII levels, achieving clinically relevant increases in factor VIII activity in the higher dosage cohorts and normal factor VIII levels in the highest dose cohort (normal range: 50-150 percent).

At six weeks post infusion, the second dose cohort patients reached 140 percent and 94 percent of normal, or 93 percent and 65 percent of normal, depending on the assay used. A dose-dependent reduction in the use of factor VIII replacement therapy was also observed, with patients in the highest dose cohort not requiring factor replacement therapy after initial use of prophylactic factor and experiencing no bleeding events to date. SB-525 was generally well-tolerated, with one patient in the highest dose cohort reporting a treatment-related serious adverse event of hypotension and fever following vector infusion that resolved with treatment within 24 hours of completion of the vector infusion.

Patients in the open-label Alta study were not treated with prophylactic steroids. No treatment-related serious adverse events and no ALT elevations (a sign of liver injury) requiring more than seven days of corticosteroid treatment were observed in the first three cohorts. One patient in the fourth cohort experienced an ALT elevation at week four that required a tapering course of oral steroids. The patient did not have any associated loss of factor VIII activity or ALT elevations seven weeks following initiation of the steroid therapy (five weeks post vector infusion). The same patient in the fourth cohort experienced the aforementioned serious adverse event.

Seng Cheng, senior vice president and chief scientific officer of Pfizer’s Rare Diseases Research Unit, said he was encouraged by the early data and looks forward to expanding the higher dose cohort and planning for a pivotal trial. “As the development and commercial partner for SB-525, we are encouraged by the possibility that SB-525 may one day transform the treatment landscape for patients with hemophilia A,” he said.

Sangamo also revealed positive early data on one patient for ST-400, an ex vivo gene-edited beta thalassemia cell therapy developed in partnership with Sanofi. Beta thalassemia is a blood disorder caused by a mutation in the HBB gene that reduces the production of hemoglobin, which leads to a lack of oxygen in many parts of the body.

ST-400 is an autologous cell therapy that involves gene editing of a patient’s own hematopoietic stem cells using non-viral delivery of zinc finger nuclease technology. The first patient treated with ST-400 in the phase 1/2 study has the most severe form of transfusion-dependent beta thalassemia, and for the two years prior to treatment in the study, received packed red blood cell (PRBC) transfusions every other week.

During the ST-400 infusion, the patient experienced a serious adverse event, a transient allergic reaction considered related to the cryoprotectant present in the product. Thereafter, the post-transplant clinical course was routine. The patient demonstrated neutrophil and platelet recovery, within two and four weeks of infusion, respectively, indicating that ST-400 successfully reconstituted hematopoiesis following conditioning.

Indels (small insertions or deletions generated at the targeted DNA sequence) were detected in circulating white blood cells, indicating successful editing of the BCL11A gene and disruption of the BCL11A erythroid specific enhancer, which is intended to upregulate endogenous fetal hemoglobin production in red blood cells.

At seven weeks post ST-400 infusion, total hemoglobin levels remained stable, and levels of fetal hemoglobin have continued to rise from approximately 1 percent of total hemoglobin at the time of infusion to 31 percent as of the most recent measurement.

The patient received several PRBC transfusions for approximately two weeks after the ST-400 infusion. During the subsequent five weeks, the most recent data available, no further PRBC transfusions have been required.

“While these data are very early and will require confirmation in additional patients as well as longer follow-up to draw any clinical conclusion, they are promising,” said Angela Smith, associate professor in the division of Pediatric Blood and Marrow Transplantation at the University of Minnesota. “The detection of indels in peripheral blood with increasing fetal hemoglobin at seven weeks is suggestive of successful gene editing in this transfusion-dependent beta thalassemia patient.”

Enrollment in this trial is ongoing and Sangamo expects to present longer-term ST-400 data in the fourth quarter of 2019, including results from additional patients.

Photo: Edward Conner, chief medical officer of Sangamo

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