Gene Therapy SB-525 Controls Bleedings in Men for at Least 2 Years

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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A single dose of the investigational gene therapy SB-525 (giroctocogene fitelparvovec) continues to prevent bleeds and the need for prophylaxis, or preventive treatment, for at least two years in men with severe hemophilia A.

These are the latest results from the five men given the highest dose of the therapy — 3×10e13 (30 trillion) vector genomes (vg)/kg — in the ongoing Alta Phase 1/2 clinical trial (NCT03061201).

All of them also showed a fast and sustained increase in the activity of clotting factor VIII (FVIII) — the missing clotting protein in hemophilia A — which remained in the therapeutic range through two years post-dosing.

“We continue to be encouraged by findings from the Phase 1/2 Alta study in patients with severe hemophilia A,” Rob Schott, MD, head of development at Sangamo Therapeutics, said in a press release. Sangamo is developing SB-525 in collaboration with Pfizer.

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“We believe these two-year results demonstrate the potential of this gene therapy candidate to minimize significant symptoms associated with hemophilia A and become an alternative to the current burden of disease management,” Schott added.

Seng H. Cheng, PhD, senior vice president and chief scientific officer of Pfizer’s rare disease research unit, said that these new results “further suggest the potential of this investigational therapy to bring transformational benefit to eligible patients living with severe hemophilia A, if confirmed in ongoing clinical trials.”

The findings were recently shared in an oral presentation at the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition, held Dec. 11–14 in Atlanta and virtually.

The presentation was titled “Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia A.”

Given through a single infusion directly into the bloodstream, SB-525 is designed to increase FVIII levels by providing patients with a modified, working version of F8, the gene that contains the instructions for making FVIII and that is mutated in hemophilia A patients. A modified and harmless version of an adeno-associated virus is used to carry and deliver the gene specifically to liver cells, the body’s main producers of clotting factors.

Maintenance of FVIII activity in the mild range (between 5% and 40%, up to 50%, or normal) has been shown to improve outcomes in people with severe hemophilia A.

The therapy is expected to promote a sustained production of FVIII that reaches levels at least within the mild range, thereby reducing or possibly eliminating bleeding events and the need for a lifetime of FVIII replacement therapies.

The ongoing Phase 1/2 Alta study is assessing the five-year safety and efficacy of four different doses of SB-525 — 9×10e11 (900 billion) vg/kg, 2×10e12 (two trillions) vg/kg, 1×10e13 (10 trillions) vg/kg, and 3×10e13 (30 trillions) vg/kg — in 11 adult men (mean age, 30.3) with severe hemophilia A.

Two men were dosed per group, except for the highest dose group, which was expanded to five patients.

Previous results showed that SB-525 was generally well-tolerated and resulted in dose-dependent raises in FVIII activity levels that were maintained within the therapeutic range through at least one year in the highest dose group. Such activity levels prevented bleeding events and the need for FVIII usage in all five men during the first year.

Newly presented results, at a cut-off date of Oct. 1, cover two to four years of follow-up after SB-525’s single dose (except for one participant in the 10 trillions vg/kg group who left the trial).

Two-year data showed that the five men given the highest dose had a mean FVIII activity of 25.4%, reflecting a drop from one-year (42.6%) and 1.5-year (48.9%) values, but still remaining within the mild, therapeutic range.

While no bleeding events occurred in this group in the first 16 months post-dosing, two men later experienced bleeds that required FVIII therapy. One patient had a single joint bleed, while the other had eight bleeding events: five traumatic, two spontaneous, and one of unknown cause.

As such, men in the highest dose group showed a mean annualized bleeding rate (ABR) of zero in the first year, and a mean of 1.4 bleeds per year over up to four years. None of these men resumed prophylaxis.

The therapy’s safety profile up to four years post-dosing was consistent with previous analyses, with no additional treatment-related adverse events reported since August.

The most common adverse events were infusion-related reactions and higher-than-normal levels of liver enzymes, which occurred in the first months and were fully resolved with appropriate treatment (specifically, with oral corticosteroids). Abnormally high levels of these enzymes, which are indicative of liver damage, are a common side effect of virus-based gene therapies.

At last assessment, no patient had developed FVIII inhibitors (neutralizing antibodies) or experienced blood clot-related events, and no liver masses were detected.

These findings highlight that a single dose of SB-525 in men with severe hemophilia A “was generally well tolerated with associated increases in FVIII levels in the mild to normal range, without sustained [adverse events], and with minimal bleeding in the highest-dose cohort,” the researchers wrote.

“Additional follow-up is required to assess durability of efficacy and other long-term effects of [SB-525], such as impact on overall liver health,” they added.

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In 2020, Pfizer launched a Phase 3 trial, called AFFINE (NCT04370054), to evaluate the safety and effectiveness of a single infusion of SB-525 in up to 63 men, ages 18–64, with moderate to severe hemophilia A.

The study, which has completed more than half of its target enrollment, was placed on a clinical hold in November by the U.S. Food and Drug Administration to give the agency time to review AFFINE’s most recent protocol changes.

These changes were implemented by Pfizer after abnormally high levels of FVIII were detected in some treated participants. Given that these levels, greater than 150% of normal (the top threshold for the normal range), raise the risk of blood clots, implemented protocol changes are meant to provide guidance for managing participants with such high FVIII levels.