Spotlight On High Doses Again After Pfizer Duchenne Gene Therapy Death
US Regulator May Call For Limits
Executive Summary
The death in Pfizer’s Phase I study could reflect wider safety issues for AAV-based gene therapy and could spur intervention from regulators in 2022.
A trial of Pfizer’s investigational gene therapy for Duchenne muscular dystrophy (DMD) has been halted after the death of a young male.
The company announced on 20 December that it had paused screening and dosing in the Phase I study and it will now work with the trial site investigator to understand the cause of death, and if it was linked to the administration of the AAV9-based gene therapy named fordadistrogene movaparvovec (PF-06939926).
Pfizer disclosed the death and trial halt in a letter to patient advocacy group Parent Project Muscular Dystrophy (PPMD) and revealed that the individual who died was part of the non-ambulatory group in the Phase Ib portion of the study.
The US Food and Drug Administration has also placed a clinical hold on the study, adding to concerns about high dose gene therapy trials, which have been linked to severe adverse events and several deaths in recent years.
Pfizer’s Phase I study aims to recruit up to 35 patients and includes non-ambulatory and ambulatory patients given a one-time dose of up to 2E14 vg/kg. This is among the highest doses given in any gene therapy trial, although differences in dosage measurements vary between developers.
The latest news adds to wider concerns about AAV gene therapies, which were the subject of an FDA enquiry in July.
The FDA’s Cellular, Tissue and Gene Therapies Advisory Committee held a two-day meeting to discuss toxicities risks associated with the vector-based gene therapies. These include liver toxicity, vector integration and cancer risks, thrombotic microangiopathy issues and clinical as well as non-clinical neurotoxicity signals.
While the committee has not moved to impose any new restrictions on gene therapy trials, its leaders have not ruled out putting an upper limit on doses in order to limit toxicities.
Other trials experiencing similar problems include those being undertaken by Astellas in X-linked myotubular myopathy (XLMTM) and BioMarin in phenylketonuria (PKU). (Also see "Astellas Pauses XLMTM Gene Therapy Trial After Another Safety Scare" - Scrip, 1 Sep, 2021.)
However the higher dose is not the only potential cause of the safety issues, as an immune response to the inserted transgene could also play a role.
Pfizer was forced to modify the design of its pivotal Phase III CIFFREO trial for fordadistrogene movaparvovec in September after three adverse effects involving muscle weakness and heart inflammation were recorded.
Pfizer’s chief scientific officer Mikael Dolsten told analysts last month that the trial’s data monitoring committee backed the hypothesis that an immune response against the mini-dystrophin protein caused the problems.
It is believed that subsets of DMD patients born without any dystrophin gene mount an immune response against it when it is introduced via the gene therapy. Consequently, the study protocol was updated to exclude patients with gene mutations affecting exons 9 to 13 inclusive, or a deletion that affects both exon 29 and 30.
Pfizer believes careful patient selection can help avoid these safety issues, though it will inevitably limit the number of patients who could benefit.
Mikael Dolstein
Dolsten said the risk was “potentially inherent to any gene replacement therapy” and said similar severe adverse events reported in other programs supported the idea that it could be a class effect.
However, these changes meant Pfizer had to push back the expected trial readout from 2022 to the first quarter of 2023, citing the extra time needed to complete the targeted enrolment of 99 participants.
The company’s main rival in the field is Sarepta Therapeutics. Like Pfizer, it is hoping its gene therapy can successfully replace the missing protein dystrophin in DMD patients, where its absence causes progressive muscle degeneration.
However Sarepta is using a slightly different vector - AAVrh74 – and a much lower 1.33 x 1014 vg/kg dose in its ongoing EMBARK Phase III study.
Sarepta has not suffered from any similar safety concerns with its candidate delandistrogene moxeparvovec so far and could have an initial readout in 2022.
Meanwhile a third player in the field, Solid Biosciences, had seen its candidate SGT-001 hit by a string of safety issues, but its IGNITE DMD Phase I/II clinical trial is now ongoing, with the first six patients treated.
Nevertheless, analysts still believe the chances of failure are much higher than likely success for any of the current DMD gene therapy candidates.
Another company, Regenxbio, is developing a candidate based on improved AAV vectors for DMD, while others are exploring other modalities, such as Vertex and Editas, who have a CRSPR Cas9 gene editing program in pre-clinical development.