2023-05-15 08:03:39 ET
Summary
- PMV Pharmaceuticals has very interesting science.
- PMVP's drug seems to be active in activating p53.
- However, the toxicity profile may be unacceptable.
PMV Pharmaceuticals ( PMVP ) develops small molecule, tumor-agnostic therapies for p53 mutations in cancer. The company's co-founder Dr. Arnold Levine was one of the four discoverers of the p53 protein in 1979. The p53 protein is formed by the TP53 gene. p53 is a very important protein. It is a tumor suppressor protein and is called the "guardian of the genome" because it protects the genome from mutations. However, a mutation in the TP53 gene itself may cause misfolded p53 protein to form in humans. Such misfolded proteins and the associated mutation is seen in 50% of all human cancers. Thus, p53 is a very important target of cancer therapy.
PMVP focuses on developing tumor-agnostic small molecules that structurally correct p53 mutant proteins and restore their tumor suppressing abilities. Lead and only clinical candidate is called PC14586, which targets the Y220C mutation while sparing wild-type p53, and is tumor agnostic. From their 10-K :
The Y220C mutation results from tyrosine being substituted by a cysteine at amino acid position 220 and is associated with 1.0-1.5% of all cancers, including breast, NSCLC, colorectal, pancreatic and ovarian cancers.
It is in two phase 1 clinical trials, one as a monotherapy and one in combination with pembrolizumab, both in a tumor-agnostic setting. The company has discovery stage assets targeting other p53 mutations. Here's the pipeline:
They have a Fast Track designation of PC14586 for the treatment of patients with locally advanced or metastatic solid tumors that have a p53 Y220C mutation. Last year, in June, the company presented preliminary Phase 1 clinical data, and they continue enrolling patients in this trial. In December, they opened a separate arm within this phase 1/2 trial, which combines PC14586 with Keytruda. The company thinks this trial could become a pivotal trial. Tumor agnostic trials are rare, and the FDA's granting them Fast Track indicates their acceptance of the idea of tumor agnostic trials.
Here's some interesting preclinical data from the 10K:
In preclinical studies, PC14586 has shown selective on-target activity (i.e., primarily functions in cells with the p53 Y220C mutation) and exhibited robust anti-tumor activity evidenced by potent tumor growth inhibition, or TGI, and strong tumor regression as a single agent. Further, preclinical studies have demonstrated significant synergistic effects in combination with anti-PD-1 therapy.
The phase 1 data was presented at ASCO in June, here . The trial was designed to establish a maximum tolerated dose, or MTD, which was found to be 1500mg BID. The drug was well-tolerated. Of the 41 patients tested, 25 had measurable disease and were given therapeutic doses of PC14586, i.e., doses between 1150mg QD and 1500mg BID. Partial responses were observed by investigator review (RECIST v1.1) in 32% (six confirmed partial responses and two partial responses pending confirmation as of May 10, 2022) across six different tumor types.
The drug had 9 grade 3 treatment related adverse events and a single grade 4 AE. Dose-limiting toxicities were reported in 2 patients at 1500 mg BID, which were Grade 3 AST/ALT increase and Grade 3 acute kidney injury.
Here's the waterfall plot of the data:
If you look at this closely, you can see that those two unconfirmed PRs are barely making it into PR territory. Most critically, 5 of the 6 confirmed PRs were gained at the highest dose - and these doses were marred by severe liver and blood tox issues. Only the one patient, a 71 year old woman with ES-SCLC, had a nice solid PR at the lower range of the active dose. More details of this patient:
- Progressed after 2 prior lines of therapy with worsening dyspnea and complete occlusion of the left bronchus with atelectasis
- Etoposide, carboplatin and atezolizumab (10 months)
- Topotecan (4 months)
- Prior radiotherapy of brain metastasis
- TP53 Y220C detected by NGS
- PC14586 1150mg QD was started
- PR after 6 weeks with relief of respiratory symptoms
- Increased to 2000mg QD at week 30
- Well tolerated with transient treatment related Grade 3 neutropenia
- Treatment ongoing for 9+ months
But this was the only patient who had real benefit, although I would be curious to see how she was faring at the 2000mg QD dose. However, other than this single patient, the rest of the story is not good. p53 remains undruggable, or at least, unmanageable. There is no doubt there is drug activity here, but it comes at a great cost. The TEAE list is not good, the tox profile is poor.
Other companies that have tried the p53 activation approach have failed. Evaluate cites one such story :
Still, those interested in mutated p53-driven cancer will recall Aprea, a group that had styled itself as the p53 reactivation company. Its lead asset, eprenetapopt, flunked phase 3 in front-line p53-mutant myelodysplastic syndromes and then was hit with two clinical holds.
Aprea's problems stemmed from unacceptable toxicity, including one fatality. The trial also failed to reach statistical significance.
Financials and others
PMVP has a market cap of $258mn and a cash balance of $230mn. Research and development (R&D) expenses were $15.1 million for the quarter ended March 31, 2023, while General and administrative (G&A) expenses were $6.4 million. The company recently abandoned two other discovery programs to focus on the lead asset and conserve money. At this rate, they have a cash runway of 8-9 quarters.
Here's the company's IP estate:
As of January 31, 2023, we owned three issued US patents and five granted foreign patents relating to methods of use and composition of matter of PMV compounds, including PC14586, at least 20 pending US patent applications, and at least 40 pending foreign patent applications, each of which relates to methods of use and composition of matter of PMV compounds. The three issued US patents are expected to expire in 2037, without taking into account any possible patent term adjustment or extensions.
The company is heavily smart money owned, with low retail presence. Orbimed, at 23%, is the top holder. Insiders regularly sale stock, and have not bought in the last two years.
Bottomline
I would like a p53 program to succeed. Earlier programs failed on both efficacy and safety. This one seems to be okay, efficacy wise - the drug is active. The question is: at what cost? The tox profile is not good at all. I will look forward to further data, but my interest will be clinical, not for investing.
For further details see:
PMV Pharmaceuticals: Drug Is Active, But Tox Profile Is Poor