The tumor-suppressing protein p53 has long been considered a valuable target—if only drug hunters could figure out how to hit it. Many research efforts aiming to leverage the capabilities of this protein have fallen short. PMV Pharmaceuticals has early clinical data suggesting its approach is working and those results were presented Tuesday during the annual meeting of the American Society of Clinical Oncology.
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The way p53 works is by binding to DNA, offering up a variety of mechanisms to stop cancer. In addition to stopping the cell cycle, it can repair DNA or trigger cell death. Mutations to the gene that codes for p53 lead to inactive versions of the protein that are unable to execute these anti-cancer functions. These mutations are common across all human cancers so successfully targeting it could lead to a drug that addresses many different cancer types, said the MD Anderson Cancer Center’s Ecaterina Dumbrava, lead investigator of the PMV study and presenter of the early clinical trial results.
Cranbury, New Jersey-based PMV isn’t trying to address all p53 mutations. It’s going after a rare one called Y220C. This mutation creates a crevice that prevents the protein from interacting with DNA. Dumbrava said this mutation is present in about 1% of solid tumors across a range of tumor types, including cancers of the breast, pancreas, ovaries, and lungs. The PMV drug, PC14586, is a small molecule designed to bind to the crevice and stabilize the protein, restoring its function.
The Phase 1/2 test underway is a dose-escalation study enrolling patients with solid tumors that have the p53 Y220C mutation. As of a May 10 cutoff date, 41 patients were enrolled and assigned to receive the PMV drug at one of eight dose levels. According to preliminary results, the PMV drug showed an overall response rate of 32% (eight of 25 patients) in those who were given a daily dose of 1150 mg or higher. Of the eight responders, six had confirmed partial responses while two had unconfirmed partial responses.
Across all dosing groups, the overall response rate was 24% (eight of 33 patients). Those responses were observed across all tumor types, including breast, endometrial, prostate, pancreatic, and small cell lung cancer. Dumbrava added that while the 1% of solid tumors that can be addressed by targeting the Y220C mutation may seem small, this approach appears to work across many solid tumor types, including pancreatic cancer, which has few treatment options. These results are interim data from a small study. But speaking during a PMV investor call Tuesday evening, Dumbrava said the results indicate that p53 can be drugged.
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“It’s something that proves this is an active drug that will probably help many patients in the future,” she said.
One cautionary flag did come up for the PMV drug. Though the drug was well tolerated with the most common side effects being nausea and vomiting, Dumbrava said in her ASCO presentation that two dose-limiting toxicities were reported in two patients at 1,500 mg, which was determined to be the maximum tolerated dose. Those toxicities were high levels of liver enzymes in one patient and acute kidney injury in the other.
Irene Brana, an oncologist at Vall d’Hebron Institute of Oncology in Barcelona, commented on the PMV drug following the abstract presentations. She said that she confirmed with the abstract authors that the PMV drug’s toxicity was dose dependent. While the drug led to an impressive response in a small cell lung cancer patient, not all tumor types responded the same way. One lingering question she had is whether there is any genomic background for these patients that might influence their responses to the treatment.
The toxicity report apparently spooked investors, as shares of PMV sank more than 30% after the ASCO presentation, then regained some ground by Tuesday’s market close. Investors may have recalled the fate of a p53 drug candidate from Aprea Therapeutics that stalled last year following two clinical holds. Last month, Aprea acquired Atrin Pharmaceuticals and shifted its focus to that biotech’s cancer drugs.
Elaborating during the investor call, Dumbrava said that the two patients who experienced toxicity discontinued treatment because of disease progression, not because of toxic effects from the PMV drug. The study is ongoing, with the goal of finding a lower dose that can be tested in Phase 2. She also said that the safety data for PC14586 are better than chemotherapy and better than many of the other drugs that were presented at this year’s ASCO conference.
PMV Chief Medical Officer Leila Alland said that as the Phase 1 study continues, the company expects it will have more data to present later this year. If all goes well, a Phase 2 test could begin in early 2023. Alland added that the company has encouraging preclinical data testing its drug in combination with a type of cancer immunotherapy called a checkpoint inhibitor. PMV hopes to begin a Phase 1 study testing this combination in the second half of this year.
Photo: theasis, Getty Images
