Pfizer halted two ongoing phase 2 trials of its Duchenne muscular dystrophy drug domagrozumab after the main efficacy study failed to meet its primary endpoint after one year of treatment.
The treatment aimed to increase skeletal muscle mass and function by blocking the naturally occurring protein responsible for regulating and containing growth. Domagrozumab was granted Fast Track and orphan drug designations by the FDA in 2012 and received a European orphan designation the year after. Pfizer enrolled its first phase 2 patient in late 2014.
The first, blinded study of 121 participants was unable to demonstrate time improvements in the four-stair climb test compared to placebo with its primary analysis scheduled halfway through the two-year trial, the company said in a statement. The second trial was an open-label extension study.
In its statement, Pfizer said the totality of evidence, including secondary endpoints, did not support a significant treatment effect with the myostatin-inhibiting antibody. Pfizer said it wasn't however worried about safety.
DMD is caused by mutations in the dystrophin gene that stop the production of the stabilizing protein dystrophin. Without it, muscle fibers weaken and eventually die. There have been a number of failures in this area over the years, including just last month when Summit Therapeutics' DMD drug missed its primary and secondary endpoints in a phase 2 trial, leading the biotech to ax the program.
But there are also glimmers of hope: Also last month, Sarepta presented very early data from a phase 1/2 clinical trial of a potentially curative gene therapy. Biopsies taken from the first three patients dosed with the treatment showed they had "robust levels" of microdystrophin, producing 38% of the protein compared to normal. All three patients also showed "significant decreases" in their level of serum creatine kinase, a biomarker linked to muscle damage caused by DMD. Sarepta's stock leapt 50% on the news.
And this comes off the back of Sarepta's first Duchenne drug, Exondys 51, which scored FDA approval back in 2016, but is only effective in a small subset of patients whose disease is amenable to exon skipping and was also controversial in its approval, given its fairly limited efficacy.
Sarepta is working on a number of prospects that could be more widely usable, as well as those that could become one-time, curative therapies. These include a next-generation peptide-conjugated version of the technology Exondys 51 is based on as well as gene therapies, which is an area Pfizer will now turn to.
The Big Pharma will set its DMD sights on a viral vector gene therapy—which it hopes can become an effective one-shot treatment—that it acquired through its $700 million purchase of Bamboo Therapeutics in 2016.
PF-06939926 carries both the shortened version of the human dystrophin gene and a promoter sequence, and the company launched a phase 1b trial at Duke University Medical Center earlier this year. The full dystrophin gene is too large to fit into an adeno-associated virus vector, so developers are using truncated versions in hopes of correcting the defective gene.
“We are disappointed by these results and while we are not progressing with the studies, the data will contribute to a greater understanding of this disease and we will evaluate the total data set to see if there is a place for this medicine in muscular diseases,” said Seng Cheng, Ph.D., senior VP and chief scientific officer of Pfizer’s rare disease research unit.