Five Deaths in Prostate Cancer Trial Send MacroGenics’ Stock Plummeting

Antibody Drug Conjugate with Cytotoxic Payload

Pictured: 3D illustration of antibody-drug conjugate molecules carrying toxic payloads/iStock, Love Employee

MacroGenics’ stock dropped by as much as 70% Friday morning after the biotech disclosed five deaths in the Phase II TAMARACK trial for its investigational antibody-drug conjugate vobramitamab duocarmazine in metastatic castration-resistant prostate cancer.

The five fatal adverse events included two grade 5 toxicities—one case of acute myocardial infarction and another of cardiac arrest—which were deemed unrelated to the study treatment.

Two of the deaths were caused by pneumonitis, or inflammation of lung tissues, while the fifth patient died of pleural effusion, or the build-up of fluids in the pleural cavity. MacroGenics is still investigating these three deaths. TAMARACK is ongoing and follow-up is still incomplete.

Despite these fatal toxicities and negative stock reaction, CEO Scott Koenig in an investor call on Thursday struck a positive note, calling the candidate’s side effects “extremely manageable.” Study investigators, he continued, are “very comfortable” with managing these toxicities “and are very encouraged by both the safety and obviously, the activity data they’ve seen.”

Vobramitamab duocarmazine, also called vobra duo, is an investigational antibody-drug conjugate (ADC) therapy designed to target the B7-H3 antigen, which is overexpressed in cancer cells. Vobra duo carries the toxic payload seco-duocarmycin hydroxybenzamide azaindole, an alkylating agent that damages DNA in cancer cells and triggers their cell death, according to MacroGenics’ website.

The Maryland-based biotech is developing vobra duo as a treatment for various solid tumors, including non-small cell lung cancer, melanoma and squamous cell carcinoma of the head and neck. Its most mature program, however, is in metastatic castration-resistant prostate cancer (mCRPC), for which it is running the mid-stage, open-label TAMARACK study.

Data from TAMARACK, which MacroGenics also released on Friday, show that the lower, 2.0-mg/kg dose of vobra duo elicited an overall response rate (ORR) of 24.4%, when counting even unconfirmed instances of treatment response. At the higher, 2.7-mg/kg dose, vobra duo treatment resulted in a 43.8% ORR. Disease control rates were 91.1% and 87.5% for the low and high rates, respectively.

With these data in hand, MacroGenics is preparing for a potential Phase III study in mCRPC, slated for 2025. The decision to push through with this late-stage trial will depend on the final analysis of TAMARACK, including progression-free survival data, when available, according to the press release.

MacroGenics has had a history of patient deaths in its trials. In September 2021, the biotech posted Phase I data for vobra duo, revealing two fatal grade 5 toxicities—one with an unknown cause and the other attributable to COVID-19.

Nearly a year later, in June 2022, MacroGenics reported seven patient deaths, this time in connection with its investigational antibody enoblituzumab, which also targets the B7-H3 antigen, forcing the company to discontinue its Phase II study in head and neck cancer.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

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