Cancer and infectious disease therapeutics(PMV Pharmaceuticals/Chiromics)

The annual meeting of the American Society of Clinical Oncology brought an estimated 50,000 people to Chicago’s McCormick Place aiming for insights into the latest developments in cancer treatments. The big pharmaceutical companies always make big news at ASCO, and this year was no exception as Gilead Sciences and AstraZeneca each posted data updates that could have strong implications for their respective breast cancer drugs. But some clinical-stage biotech companies also made headlines, unveiling new data suggesting their experimental therapies could offer patients new treatment options. The growth of cell therapy research was reflected in the presentations this year. In addition to the approved CAR T treatments, several companies presented data for their off-the-shelf alternatives. Here’s a recap of some news highlights from the conference. Breaking breast cancer news Two years ago, Gilead Sciences plunked down $21 billion to acquire Immunomedics betting that its then recently approved breast cancer drug, Trodelvy, could become a blockbuster. The initial approval for the antibody drug conjugate covers the rare but aggressive triple negative breast cancer. At ASCO, Gilead reported data from a Phase 3 test in HR positive and HER2 negative breast cancer, a more common type of the disease. While the primary analysis shows the study met the main goal measuring progression-free survival, the improvement over chemotherapy was a median six weeks. Overall survival data are not yet mature. Véronique Dieras, an oncologist at Centre Eugene Marquis in Rennes, France, acknowledged that the Gilead drug met the main study goal. But she added that it’s not yet clear whether that is enough to translate to a better quality of life for patients. “Perhaps my potential concern, when we look to the result of a Phase 3 study, we have to ask about magnitude of benefit and if it’s clinically meaningful,” she said. Meanwhile, partners AstraZeneca and Daiichi Sankyo posted data that could significantly expand the use of their antibody drug conjugate, Enhertu. The product’s approval currently covers HER2 positive breast cancers. Patients with low HER2 levels have been classified as HER2 negative, based on the thinking that a drug that targets this HER2 genetic signature would not work on patients with low levels of the protein. Data reported for the drug at ASCO suggest otherwise. The Phase 3 study enrolling “HER2-low” patients; the main goal was to assess progression-free survival. On this measure, the Enhertu group lived a median 10.1 months compared to a median 5.4 months for those who received chemotherapy. Jane Meisel, a professor of hematology and oncology at Emory University and an ASCO breast cancer expert, described the results as “practice changing.” Enhertu does come with some lung toxicity risks. Memorial Sloan Kettering Cancer Center’s Shanu Modi, the lead investigator for the study, acknowledged these risks but said clinicians can monitor for these adverse effects and manage them when they arise. Progress for BCMA-targeting drugs Partners Johnson & Johnson and Legend Biotech won FDA approval last year for Carvykti, a CAR T cell therapy that treats multiple myeloma by targeting a protein called B-cell maturation antigen (BCMA). That decision was based on Phase 1b/2 data. Legend now has longer term data showing the durability of the therapy after more than two years and those results were presented at ASCO. In heavily pretreated multiple myeloma patients whose disease relapsed or had not responded to earlier treatment, Legend reported a 98% overall response rate at a median 28-months of follow up. At the time of the follow up, data were not available for median progression-free survival or median overall survival, which the company said suggests the long-term durability of responses and survival of patients treated with the drug. In addition, a separate study is underway evaluating Carvykti as an earlier line of treatment in 20 multiple myeloma patients who had previously received one to two lines of prior therapy and whose disease cannot be treated with Revlimid, a standard of care drug for myeloma. At a median follow-up of 17.1 months, Legend reported a 95% overall response rate; 90% of patients achieved a complete response or better. Arcellx is a relative latecomer to targeting BCMA for treating multiple myeloma, trailing Carvykti and Bristol Myers Squibb drug Abecma, which was approved last year. But Arcellx brings different technology to the BCMA hunt—synthetic binding domains it calls D-Domains—and it presented early Phase 1 data at ASCO suggesting its approach could offer even better efficacy. A total of 31 patients from the Phase 1 expansion study were evaluable for efficacy and safety at least one month following treatment. As of a May 3 cutoff date, Arcellx reported its therapy, CART-ddBCMA, achieved a 100% overall response rate. The complete response rate was 71% (22 of 31 patients). Toxicities have been manageable and all of them resolved with standard treatment at both of the dose levels tests. Arcellx said that there were no cases of neurotoxicity or parkinsonian symptoms. In a research note, William Blair analysts Raju Prasad and Sami Corwin wrote that the strong clinical activity and durability of Arcellx’s therapy has de-risked the company’s technology. If the pivotal study recruits patients with prognoses better representative of population of relapsed and refractory multiple myeloma patients—similar to those enrolled in Legend’s study—William Blair believes a successful clinical trial could make the Arcellx therapy best in the class of BCMA CAR T therapies. Adicet nails down key data for off-the-shelf CAR T Off-the-shelf cell therapies are seen as key for making these treatments more widely available in part because the process of making personalized cell therapies from a patient’s own T cells is lengthy and expensive. Adicet Bio continued to post data supporting its approach, which uses a rarer type of T cell, called gamma delta T cells, which are sourced from healthy donors. Last year, the biotech reported preliminary Phase 1 data from four patients indicating that its approach is working. At ASCO, Adicet provided an update on the study, enrolling patients with advanced B-cell non-Hodgkin’s lymphoma. As of a May 31 data cutoff, Adicet now has data from eight total patients. In this group of heavily pre-treated patients who had received a median of four prior treatments, the Adicet therapy ADI-001, led to a 75% overall response rate and a complete response at all dose levels. In three patients that relapsed after previously receiving an autologous CAR T-therapy, Adicet reported that all of them responded to ADI-001. In addition to the manufacturing edge of an off-the-shelf therapy, Adicet aims to offer safety advantages as well. The company reported no dose-limiting toxicities, nor were there any immune responses or neurological problems that are associated with CAR T treatments. Adicet said it expects to identify a recommended Phase 2 dose in the second half of this year; at least one study that could support a registrational filing could start in the first half of 2023. Bringing mRNA to cancer vaccines Before BioNTech became known for its Covid-19 vaccine, it was applying its messenger RNA technology to the development of cancer vaccines. At ASCO, the German company reported preliminary data from a Phase 1 study evaluating autogene cevumeran, a personalized mRNA-based vaccine based on neoantigens from the patient. This vaccine is being developed as an adjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) that has been surgically removed. The program is progressing under a partnership with Roche; BioNTech’s cancer vaccine candidate is being tested in combination with Roche immunotherapy atezolizumab and chemotherapy. BioNTech reported preliminary results showing that of 16 patients who received the combination, the treatment was well tolerated. A neoantigen-specific T cell response was observed in 50% of patients (eight of 16). At a median follow-up of 18 months, eight patients with de-novo immune responses had a significantly longer recurrence-free survival compared with those that did not have vaccine-induced immune responses. Based on these early results, the partners are now planning a randomized study to further evaluate the treatment combination patients with resected PDAC. Mirati moves in on Amgen’s KRAS drug KRAS mutations were long thought to be undruggable. That changed last year with FDA approval for Lumakras, an Amgen drug that treats non-small cell lung cancer by targeting the rare KRAS G12C mutation . Mirati Therapeutics aims to offer an alternative with its drug, adagrasib, and the company revealed at ASCO more data from the therapeutic candidate’s pivotal study. On efficacy, the Mirati drug appears comparable to the Amgen product. But Mirati aims to differentiate its drug on its ability to treat NSCLC that has metastasized to the central nervous system. Of 19 evaluable patients, the objective response rate was 32%. Three patients achieved a complete response and three others achieved a partial response. In a research note, William Blair analyst Matt Phipps acknowledged adagrasib’s CNS activity but he added that it’s unclear whether that’s enough to differentiate the drug given its similar efficacy data in the general population. Adagrasib is currently under FDA review; a decision is expected by mid-December. Speaking of undruggable targets… The p53 protein has been regarded as something of a holy grail for drug hunters. It has several anti-cancer properties but has been an elusive drug target. PMV Pharmaceuticals reported at ASCO its first clinical data indicating that its small molecule can drug p53, with results spanning a range of tumor types, including ovarian, prostate, and pancreatic cancers. In the dose-escalation part of the Phase 1/2 study, PMV reported a 32% overall response rate (eight of 25 patients). Dose-limiting toxicity was reported in two patients at the highest dose, but the company said it is working to identify a lower dose that balances safety and efficacy. The clinical trial is continuing to determine the dose to advance to Phase 2 testing that the company expects could begin early next year. Meanwhile, PMV also plans to move forward with a Phase 1 study testing its drug in combination with a checkpoint inhibitor.

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. 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. “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 regaining 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.