The tumor-suppressing protein p53 has long been considered a valuable target—as long as drug hunters can figure out how to hit it. Many research efforts aimed at harnessing the protein’s abilities have failed. Early clinical data from PMV Pharmaceuticals showing its approach is working were presented Tuesday at the annual meeting of the American Society of Clinical Oncology.
The way p53 works is by binding to DNA, providing multiple mechanisms to prevent cancer. In addition to stopping the cell cycle, it can repair DNA or trigger cell death. Mutations in the gene encoding p53 render the inactive version of the protein unable to perform these anticancer functions. These mutations are common in all human cancers, so successfully targeting it could lead to a treatment for many different cancer types, said Ecaterina Dumbrava of the MD Anderson Cancer Center, principal investigator of the PMV study and presenter of early clinical trial results. drug.
PMV in Cranbury, NJ does not attempt to resolve all p53 mutations. It is looking for a rare product called Y220C. This mutation creates a cleft that prevents the protein from interacting with the DNA. The mutation is present in about 1 percent of solid tumors and is involved in multiple tumor types, including breast, pancreatic, ovarian and lung cancers, Dumbrava said. The PMV drug PC14586 is a small molecule designed to bind to the gap and stabilize the protein, restoring its function.
The ongoing Phase 1/2 trial is a dose-escalation study enrolling patients with solid tumors with the p53 Y220C mutation. As of the May 10 cutoff date, 41 patients were enrolled and assigned to receive PMV at one of eight dose levels. According to preliminary results, the overall response rate to PMV drugs was 32% (8 of 25 patients) in patients taking 1150 mg per day or higher. Of the eight responders, six confirmed partial responses and two did not.
Across all dosing groups, the overall response rate was 24% (8 of 33 patients). These responses were observed in all tumor types, including breast, endometrial, prostate, pancreatic and small cell lung cancers. Dumbrava added that while it may seem small that 1 percent of solid tumors could be addressed by targeting the Y220C mutation, the approach appears to be applicable to many solid tumor types, including pancreatic cancer, which has few treatment options. These results are interim data from a small study. But on a PMV investor conference call on Tuesday night, Dumbrava said the results suggest p53 can be drugged.
“This proves that this is an active drug that may help many patients in the future,” she said.
PMV drugs do come up with a warning sign. Although the drug was well tolerated and the most common side effects were nausea and vomiting, Dumbrava said in her ASCO report that two patients reported two dose-limiting toxicities at 1,500 mg, which was determined to be maximally tolerated dose. These toxicities were high levels of liver enzymes in one patient and acute kidney injury in another.
Irene Brana, an oncologist at the Vall d’Hebron Institute of Oncology in Barcelona, commented on the PMV drug after the abstract.she said she confirmed Abstract The authors believe that PMV drug toxicity is dose-dependent. While the drug produced an impressive response in one patient with small cell lung cancer, not all tumor types responded the same way. A lingering question for her is whether these patients have any genomic background that might affect their response to treatment.
The toxicity report clearly spooked investors, as PMV’s stock fell more than 30% after the ASCO report, before recovering some lost ground by Tuesday’s close.Investors may have recalled The p53 drug candidate from Aprea Therapeutics stalled last year after two clinical trials. Last month, Aprea Acquired Atrin Pharmaceuticals and shifted its focus to the biotech’s cancer drugs.
During the investor conference call, Dumbrava said the two patients who experienced toxicities discontinued treatment because of disease progression, not because of the PMV drug’s toxic effects. The study is ongoing with the goal of finding lower doses that can be tested in Phase 2. She also said that PC14586’s safety data was superior to chemotherapy and many other drugs presented at this year’s ASCO meeting.
PMV chief medical officer Leila Alland said the company expects to provide more data later this year as the Phase 1 study continues. If all goes well, Phase 2 testing 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 checkpoint inhibitors. PMV hopes to begin a Phase 1 study testing the combination in the second half of this year.
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