ASH19: Pfizer, Sangamo's haemophilia A gene therapy SB-525 continues to show sustained increased FVIII levels

Pfizer and Sangamo Therapeutics said that the investigational gene therapy SB-525 demonstrated sustained increased Factor VIII (FVIII) levels in patients with severe haemophilia A through to 44 weeks following treatment. The updated results from the Phase I/II Alta study were presented at the American Society of Hematology (ASH) annual meeting.

Data from the trial reported in April showed that two patients administered the highest dose of SB-525 had reached normal FVIII levels, while results released in July from 10 subjects demonstrated a dose-dependent increase in FVIII activity levels. The update at ASH included findings from 11 patients treated across four ascending dose cohorts, with five subjects receiving the highest dose of 3e13 vg/kg.

Results showed that patients in the 3e13 vg/kg dose cohort achieved normal range FVIII activity within five to seven weeks of treatment with SB-525, while the first two subjects treated with this dose have demonstrated durability in the normal range through 44 and 37 weeks, respectively. Pfizer and Sangamo added that the two patients most recently treated in this cohort, who have 22 and 12 weeks of follow-up, respectively, demonstrated a similar pattern of FVIII expression.

However, the companies indicated that the FVIII expression pattern in the fifth subject in the cohort "differed" from that of the other patients. Data showed that seven weeks following treatment, the fifth patient achieved normal range FVIII levels, although beginning at week 13, FVIII levels fluctuated in a range below normal, before starting to rise at week 18, which has continued as of the latest measurement at week 24. Despite this, Pfizer and Sangamo noted that no patient in the 3e13 vg/kg dose cohort has experienced bleeding events up to 44 weeks of follow-up, and none required factor replacement following initial use of prophylactic factor.

Principal investigator Barbara Konkle remarked "I am pleased that all five patients in the high-dose…cohort rapidly achieved normal levels of [FVIII]," adding "it is important to continue to follow these patients to determine whether these results are sustained in the longer term." Results presented at ASH showed that in these five patients, four experienced transient low grade alanine aminotransferase elevations that were managed with a tapering course of oral steroids (for further analysis, see ViewPoints: ASH19- Pfizer and Sangamo start their engines against BioMarin).

Pfizer and Sangamo are jointly developing SB-525, which consists of a recombinant adeno-associated virus serotype 6 vector encoding the complementary DNA for B domain-deleted human FVIII, under the terms of a 2017 partnership potentially worth up to $545 million. Pfizer is currently enrolling patients in a Phase III lead-in study for SB-525, the data from which is expected to provide a baseline for patients who are subsequently enrolled into the Phase III study.

"We expect to dose the first patient in the Phase III registrational study in 2020," said Seng Cheng, chief scientific officer of Pfizer's rare diseases research unit, adding "we continue to believe that if the observed safety and efficacy results are sustained, this gene therapy has the potential to transform the treatment paradigm of severe haemophilia A."



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