Image courtesy of Emma Frances Logan at Unsplash
In early 2021, a young boy in Barcelona was the first to receive Pfizer’s investigational gene therapy for Duchenne muscular dystrophy (DMD). This was part of a global Phase 3 human trial to test Pfizer’s lead candidate, PF-06939926, in a cohort of 99 patients with DMD—a debilitating genetic condition that causes progressive muscle wasting mostly in males—for which there are currently no approved treatment options.
This is the last lap for Pfizer in the onerous race towards an approved gene therapy for DMD, but the pharma giant isn’t the only competitor. Others with similar gene therapy offerings have sprinted forward with bursts of apparent success, only to end up stumbling and losing their lead.
Take Sarepta Therapeutics, for instance, whose experimental gene therapy SRP-9001 was reported to dramatically improve DMD patients’ conditions in early trials, cutting in half the time it took for one patient in the trial to rise up from the ground and climb a set of stairs. However, these triumphs were short-lived, with no significant differences observed between the placebo and treated groups in mid-stage trials, causing the company’s stock prices to plummet.
Sarepta blamed the disappointing results on an issue with patient recruitment: the placebo group had higher baseline values, which meant seeing statistically significant improvements in the boys who received SRP-9001 was “virtually impossible”. This is a very real challenge in conducting trials for rare diseases like DMD. First, it’s not easy to recruit enough patients to achieve statistical confidence. Even with these numbers, patients present with a spectrum of symptom baselines, making it difficult to judge improvements as a result of the treatment.
In spite of these hurdles, Pfizer has reached the milestone of a late-stage trial and, in doing so, has overtaken Sarepta. But does PF-06939926 have what it takes to go all the way?
Both Pfizer’s and Sarepta’s lead candidates are “one-and-done” gene therapies, which deliver a shortened version of the human DMD gene to replace the faulty one in patients. The gene encodes a mini version of the dystrophin protein (as the largest human gene, full-length DMD is too complicated to deliver as a therapeutic). The gene is shuttled directly to the muscles via a viral vector, where patients’ cellular machinery manufactures a functional form of dystrophin.
During this Phase 3 trial, Pfizer will assess the safety of the gene therapy across different doses and measure its influence on boosting the expression of mini-dystrophin in the muscles of DMD patients. Over a period of five years, functional aspects of the boys’ motor function will also be monitored.
For now, PF-06939926 seems to be moving in the right direction. Positive data from an ongoing Phase 1b trial were enough for the FDA to award Pfizer with a fast track status for PF-06939926, an expedited process for reviewing new drugs to treat serious conditions without alternative clinical options. Pfizer was able to demonstrate the robust and sustained production of mini-dystrophin in the DMD patients participating in the trial, and that these levels translated to improvements in their mobility.
Additionally, Pfizer has an advantage over its competitors in that the PF-06939926 being evaluated was produced using commercial-scale gene therapy manufacturing processes, which is one of the FDA’s checkboxes prior to awarding approvals.
Whether or not this will be enough to help the thousands of anxious DMD patients and their families anytime soon remains to be seen. In the meantime, hope comes in the form of exciting research towards novel treatment approaches for DMD.
For instance, Dr. Michael Rudnicki’s team at The Ottawa Hospital Research Institute has identified a means of regenerating muscle cells by activating the epidermal growth factor receptor (EGFR) pathway. This could be achieved using a small-molecule drug, which could be a lower barrier to the clinic than a gene therapy and bypasses the need for replacing dystrophin in muscles to restore function.
A tissue engineering expert from the University of Toronto, Dr. Penney Gilbert, is also pushing the envelope in DMD research. Gilbert and colleagues have found a way of growing functional human muscle tissue—complete with nerves—in a lab setting. These models provide scientists with an unprecedented glimpse into how muscle fibres and neurons communicate with each other, how this crosstalk is disrupted in DMD patients, and whether commercially available therapies may be able to restore functionality across the neuromuscular junction.
In addition, the way clinical trials are conducted is evolving, with computer modelling methodologies opening up a whole new dimension to analyzing the effectiveness of new therapies coming through commercialization pipelines. In the future, these technologies could empower drug developers, such as Pfizer, to select the best lead candidates, design optimal treatment administration strategies, and assess patient outcomes to lower risks and accelerate therapies’ paths from bench to bedside.
Tara Fernandez
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