Patient death prompts FDA hold on Mersana’s lead cancer ADC

Another antibody-drug conjugate has been stalled by concerns over safety. The FDA has placed a partial hold on Mersana’s lead candidate XMT-1522 after a patient death in a phase 1 trial, causing its shares to plunge.

The regulator won’t allow any new subjects to be enrolled into the study in HER2-positive breast, lung and gastric tumors, but patients already on the drug can continue to receive it, according to the Cambridge, Massachusetts, biotech.

Mersana said it will work with the FDA and the site investigator, who reported the death as possibly drug-related, to try to resolve the clinical hold, and insisted there was no impact on its second phase 1 ADC candidate XMT-1536 for NaPi2b-expressing tumors. Nevertheless, the news knocked a third off Mersana’s stock price yesterday, and it continued to slide after hours.

The trial is a dose-escalation study in which XMT-1522 is administered as an intravenous infusion once every three weeks and is intended to identify the maximum tolerated dose as well as select the dose for phase 2 testing. Patients can continue to receive their dose until disease progression if the ADC is well-tolerated.

The safety scare is the latest in a series affecting ADC drugs, which are made up of an antibody component targeting a cancer cell and a toxic payload designed to kill it. In April, Swiss biotech ADC Therapeutics pulled its HER2-targeting ADC because of toxicity issues in phase 1 testing, and in recent months safety has also halted the development of cancer ADCs from AbbVie and Seattle Genetics.

Side effects can be caused by ADCs if the payload is released prematurely, and a meta-analysis of 870 clinical trials published last year suggested that the main cause of severe ADC toxicities was related to this off-target delivery.

That is likely a main reason so few ADCs have made it to market despite decades of R&D. There are currently just a handful of ADCs available to patients, including Pfizer’s recently reintroduced Mylotarg for acute myeloid leukemia, Seattle Genetics/Takeda’s Hodgkin lymphoma therapy Adcetris and Roche’s Kadcyla for breast cancer.

Mersana isn’t speculating about the reasons behind the patient death and it would be premature to do so. However, if it can resolve the clinical hold and get the program back on track, XMT-1522 could become a competitor to Kadcyla, which approached $1 billion in sales last year.

The biotech says XMT-1522 has been pitted against Kadcyla in animal models and shown durable tumor regressions where Roche's drug is inactive—a profile that encouraged Takeda to pledge up to $1 billion for ex-U.S. rights to the drug in 2016.

"Patient safety is our utmost concern," said Mersana CEO Anna Protopapas, who joined the company from Takeda unit Millennium in March 2015. 

"Based on the totality of the data we have for XMT-1522, we believe that it continues to be a promising drug candidate in the solid tumor setting and we will be initiating the proper steps with the objective of resuming enrollment."