Troubling Safety Data Overshadows Efficacy in MacroGenics' Phase 2 Study

MacroGenics, a biotechnology company, has reported concerning safety outcomes in its phase 2 trial of vobramitamab duocarmazine, a B7-H3-directed antibody-drug conjugate (ADC) aimed at treating metastatic castration-resistant prostate cancer. This news follows a reassessment and reduction of dosage levels after adverse events characterized early-phase trials.

The ongoing study tests two dosages, 2 mg/kg and 2.7 mg/kg, administered every four weeks. Initial higher and more frequent doses in phase 1 had led to significant adverse events and participant withdrawal, necessitating these adjustments.

Even with these these changes, recent safety data reveals a troubling uptick in treatment-emergent adverse events (TEAEs), with over half of the participants experiencing grade 3 or worse effects, a considerable increase from earlier reports. These issues have had a profound impact on the company's stock (NASDAQ:MGNX), which plummeted more than 70% following the update.

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Adding to the concerns, the trial reported five deaths, with three potentially linked to the study drug. Two deaths were attributed to cardiovascular causes deemed unrelated to the drug, while the other three, all at the higher dose, included two cases of pneumonitis and are currently under investigation. The increased incidence of serious side effects led to significant disruptions in treatment, with drug-related interruptions and discontinuations sharply rising in both trial arms.

Despite the serious safety concerns, the efficacy data presents a mixed picture. The study reported initial response rates of 17.8% and 25.0% in the low and high dose groups, respectively, with the rates increasing when including patients with unconfirmed responses. This suggests some potential for the drug, although the lasting impact of these responses and the primary endpoint of radiographic progression-free survival remain to be determined.

MacroGenics CEO Scott Koenig, commenting to Fierce Biotech News, emphasized the manageability of the side effects and the encouraging aspects of both safety and efficacy observed by investigators:

What we had indicated was an rPFS baseline of 6 [months] or greater and obviously looking for 7, 8, 9, 10 or higher. I think that the data that we show today and the fact that these patients are still on therapy … there is no reason we can't meet some of the longer-lived rPFS values.

However, the significant safety concerns and the drop in investor confidence reflect the challenges facing the company as it continues to assess the therapeutic potential and safety profile of vobramitamab duocarmazine.

Topics: Clinical Trials