FDA Partial Hold On Cancer Drug Adds To Molecular Templates’ Growing List Of Woes

A Molecular Therapeutics cancer drug candidate, one of the surviving programs of a recent corporate shakeup that slashed the company’s workforce in half, is now on pause. The FDA is asking for more information about two patients whose cardiac problems reported last year led to a dose reduction in the Phase 1 clinical trial.

The partial clinical hold announced late Friday means patients already in the study can continue to receive the experimental cancer treatment, MT-0169. However, no new participants may enroll in the open-label study.

Austin, Texas-based Molecular Templates, which is sometimes shortened to MTEM like its stock symbol, develops targeted biologic drugs for cancer. The company’s therapies are engineered toxin biologics (ETBs), a type of drug that employs an engineered version of a bacterial protein subunit that can gain entry into a cell to kill it. MTEM’s drugs are made by fusing this protein subunit to antibody domains or fragments that are specific to a cancer target. The class of drugs called antibody drug conjugates (ADCs) takes a similar approach by linking a targeting antibody to a tumor-killing drug payload. But MTEM says its drugs have the ability to get into cells that are tough for ADCs to address, which means its ETB drugs have the potential to broaden the universe of cancer drug targets.

MT-0169 is designed to seek out CD38, a protein abundant on a variety of hematologic cells and the target of some drug candidates and approved therapies, including Johnson & Johnson’s multiple myeloma medicine Darzalex. ADCs have not yet been developed for CD38, which MTEM says is likely because this target does not efficiently internalize these drugs, thereby limiting the amount of drug that could be delivered.

The Phase 1 test of MT-0169 is enrolling patients with advanced cases of multiple myeloma or non-Hodgkin lymphoma. MTEM said it previously disclosed cardiac adverse events in two patients who received the 50 microgram per kilogram dose: One had asymptomatic grade 2 myocarditis while the other had asymptomatic grade 3 cardiomyopathy. Both patients recovered within two months and no toxicities classified as grade 4 or 5 were observed at the high dose.

The adverse events prompted MTEM to reduce dosing in the study to 5 mcg/kg. Since then, MTEM said four patients have received that dose while three more have received a 10 mcg/kg dose. No adverse events have been reported at either dose level. According to MTEM, the FDA asked for narratives on the two patients who experienced toxic effects at the high dose as well as justification for the revised doses. The agency also asked for data evaluating the benefits and risks at the lower doses of the cancer drug.

“One patient dosed at 5 mcg/kg is in a stringent complete response and is in his seventh month of therapy,” MTEM Chief Medical Officer Roger Waltzman said in a prepared statement. “We look forward to sharing these data with the FDA and are confident in the benefit-risk profile of MT-0169 at these lower doses.”

The partial clinical hold comes as MTEM has had to make hard choices about its drug pipeline. In its report of 2022 financial results two weeks ago, the biotech disclosed a reprioritization that cut plans for early clinical development of the HER2-targeting drug candidate MT-5111. In addition to MT-0169, MTEM will continue clinical development of MT-6402, which targets PD-L1, and the CTLA-4-targeting drug candidate MT-8421.

In the financial report, MTEM said its cash position at the end of 2022 was $61 million, including $35 million from a loan and security agreement that has a June 1, 2024 maturity date for repayment. As long as MTEM remains in compliance with that agreement, the company expects its cash will be enough to last into the second quarter of next year.

The restructuring left intact a preclinical collaboration with Bristol Myers Squibb. In 2021, MTEM began the alliance focused on using the ETB platform to develop drugs addressing multiple targets. BMS paid MTEM $70 million up front, with up to $874.5 million tied to the achievement of milestones.

However, MTEM faces nearer-term financial hurdles. The Nasdaq notified the company on April 4 that it no longer satisfied the $2.5 million minimum stockholders’ equity requirement needed to continue its listing on the stock exchange. It’s the second listing notice from the Nasdaq in the past year. Last August, the stock exchange sent MTEM a deficiency letter noting that the biotech’s stock price had traded below $1 for 30 consecutive days. In that notice, the Nasdaq said MTEM does not qualify for the 180-day grace period because it was also non-compliant with the $5 million stockholders’ equity initial listing requirement.

Photo by Flickr user Dominick Guzzo via a Creative Commons license


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