ADC Therapeutics terminates Zynlonta study after FDA puts a hold

ADC Therapeutics has decided to terminate its Zynlonta trial after the FDA imposed a partial clinical hold, following a week of suspension due to concerns over patient deaths and respiratory events. The trial aimed to assess the combination of Zynlonta with Roche’s Rituxan in frail and untreated diffuse large B-cell lymphoma (DLBCL) patients. However, defining the appropriate target population proved to be challenging, leading ADC to believe that the study’s benefit-risk profile does not justify its continuation.

When Zynlonta, an antibody-drug conjugate, binds to the transmembrane CD19 protein, the drug is then internalised by the cell. When Zynlonta enters the cell, it releases its cytotoxic payload, SG3199, which tangles the DNA and finally causes cell death.

The decision to halt the trial came after ADC Therapeutics engaged in discussions with the FDA, during which the agency restricted the enrolment of new patients but allowed those already receiving treatment and experiencing clinical benefits to remain in the study, provided they reconsent. Once these patients have completed their treatment, ADC will proceed with concluding the trial.

The trial encountered a total of 12 treatment-emergent adverse events related to respiratory issues, which impeded its progress. However, upon investigation, 11 of these events were deemed unrelated or unlikely to be associated with Zynlonta treatment. The seven patients who unfortunately passed away during the study were all at least 80 years old and had at least one significant comorbidity at the time the trial was initially paused. The safety and well-being of all patients in clinical trials were emphasized as the top priority by ADC Therapeutics’ CEO, Ameet Mallik.

Zynlonta had previously gained FDA approval in 2021 through an accelerated pathway as a standalone treatment for relapsed or refractory DLBCL in adults who had undergone two prior lines of therapy. It was considered the first CD19-targeted antibody-drug conjugate to achieve approval as a single agent, boasting an overall response rate of 48.3% in its phase 2 trial. As of now, Zynlonta remains the sole approved product for ADC Therapeutics.

In May, ADC Therapeutics revealed its intention to implement a “new corporate and capital allocation strategy,” which entailed laying off 17% of its workforce, including contractors. The company decided to abandon investments in two preclinical cancer programs in favor of prioritizing the development of more advanced and lower-risk value-generating projects. This strategic shift coincided with the replacement of CEO and co-founder Chris Martin with former Novartis executive Ameet Mallik. Shortly after, another former Novartis executive, David Gilman, was brought on board to oversee business and strategy matters.

In conclusion, ADC Therapeutics has chosen to discontinue its Zynlonta trial due to challenges in defining the appropriate target population and the unfavorable benefit-risk profile. The company will now focus on advancing other promising projects while maintaining its commitment to patient safety in all clinical trials.

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