PMV Pharma gets $74M boost for personalized chemistry

In 1979, a team of researchers working across multiple institutions in the United States and the United Kingdom discovered a transcription factor that has since been implicated in more than 50 percent of human cancers.

It’s called p53 or “the guardian of the genome.”

It wields a variety of anticancer mechanisms, including DNA repair and programmed cell death. That makes it a very attractive field of research — but it hasn’t yet delivered in the clinic.

PMV Pharma plans to change that with a chemistry-centric approach to binding and correcting the function of p53. On Wednesday, the Cranbury, New Jersey-based company announced a $74 million Series B to push forward into human proof-of-concept studies, scheduled for the second half of 2018.

Topspin Biotech Fund led the round, with support from investors involved in an earlier $30 million Series A.

P53 clearly has potential — it has even been referred to as a “holy grail” cancer target — so why have few people heard of it and why has no one successfully drugged this protein before?

According to PMV President and CEO David Mack, the obvious tactics haven’t worked in this unique therapeutic setting. The aim is not to attack, silence or replace the protein. Instead, the transcription factor needs to be corrected, he said.

“A lot of things had to come together to allow us to definitively say, ‘are we structurally correcting it, is it acting like wild-type p53 and is it killing cells with a p53-mediated mechanism?'” Mack explained. “We’re in our fourth decade. It was discovered in 1979, so it’s 38 years in the making,”

P53 is a transcription factor that works almost like a kill switch. When a cell shows signs of runaway division (consistent with cancer), it instigates apoptosis or programmed cell death. It does this by binding the DNA and activating other genes — a secondary effect.

When mutations in p53 occur, the transcription factor loses its ability to bind, deactivating the kill switch. Incredibly, the mutations are often as simple as a single nucleotide substitution.

Recent research, including by those on PMV’s scientific board, has shown that mutant p53 proteins also exhibit a gain of function that makes cancers more aggressive and likely to metastasize.

With such a clear and critical need, PMV is developing drug candidates that directly match common p53 mutations. It’s a type of personalized medicine. However, unlike modern biologic or immunotherapy approaches, the team is resurrecting the power of chemistry and small molecules.

“What our small molecules do is bind the mutant p53 conformation and restore the wild-type structure,” Mack said.

A patient’s tumor would be sequenced to determine which p53 amino acids were mutated. The corresponding therapy would then be prescribed to bind and restore function to P53 proteins with that exact sequence. This idea is to restore the wild-type function in cancer cells, without interfering with healthy tissue.

“The tipping point has been the emergence of chemistries that are amenable to physically binding a target protein and altering their shape,” he explained. “That has emerged over the last 5-10 years.”

Subsequent clinical trials are likely to follow a basket trial approach. Patients with all types of cancer would be sequenced and then matched with a targeted small molecule based on their specific p53 mutations. The tissue the tumor arises in would be a secondary factor.

That’s a long way out. In the meantime, the company is maximizing the expertise of its formidable scientific advisory board and progressing towards the clinic.

And if it p53 doesn’t make it as a drug, the guardian of the genome sounds like a pretty good candidate for an HBO T.V. series. Stay tuned.

Photo: theasis, Getty Images