AACR: C4's multiple myeloma data prompt dosing switch, giving patients a longer treatment reprieve

C4 Therapeutics has learned a lot from just five multiple myeloma patients reporting out from the first cohort in a phase 1 trial of its lead candidate, a IKZF1/3 degrader called CFT7455.

For starters, the company now knows that the candidate needs a different dosing schedule than the medicines in the same class that came before it. They’ve also shown the potency of CFT7455, which is designed as a next-generation degrader of IKZF1/3, a protein known to spur on multiple myeloma.

And finally, C4 has evidence to back up its hypothesis that the med can be delivered alone, without a challenging steroid called dexamethasone that has long been delivered with this type of degrader therapy to treat multiple myeloma. Bristol Myers Squibb's Revlimid is in the IKZF1 and IKZF3 degrader class. 

Treatment with dexamethasone is associated with weight gain, insomnia, buffalo hump, sexual dysfunction and other troubling side effects, Adam Crystal, M.D., Ph.D., C4's chief medical officer, said in an interview. In preclinical evidence, CFT7455 was extremely active, raising hopes that it could serve as a dexamethasone-sparing agent. Now, the early evidence is starting to add confidence to that hypothesis.  

In data to be presented at the American Association for Cancer Research meeting in New Orleans on April 12, C4 will showcase early efficacy signals for CFT7455 in the five patients. This is the first time the Watertown, Massachusetts-based biotech is presenting human data.

While C4 leadership took an upbeat tone to the results, investors clearly did not see what they were hoping for. The company's shares plummeted the minute the results were posted at 1 p.m. ET Friday, dropping 55% to $10.21, compared to a prior close of $22.90.

Confident, manageable

C4 began testing the drug dosed over three weeks followed by a one-week break, which is how this class is typically administered. But the results showed dose-limiting toxicities early on, which told them a few things: the drug was degrading what it was supposed to be but patients also could have a longer break between dosing. The therapy will now be tested with two weeks on and two weeks off. 

While this seems like a small change, CEO Andrew Hirsch and Crystal said an extra week off treatment can be revitalizing for patients. The study features patients who have been through several courses of treatment already. Any bit of relief helps, the executives said.

Two patients experienced neutropenia, a known adverse event with this type of medicine that occurs when the body does not have enough of the infection-fighting white blood cells. Hirsch said the appearance of this signal was not unexpected, especially as it occurred at the same time that efficacy was showing.

“We're confident that we're going to be able to deliver the drug in a manner that makes those neutropenias manageable,” Crystal said. “The conclusion that we reached based on the data is that with our understanding of what causes this neutropenia and our understanding of the pharmacokinetic profile of this molecule, we can actually give patients a longer time off of drug than that one week.”

That should resolve cases of neutropenia with the therapy going forward, Crystal said.

C4 has also seen evidence in three patients that CFT7455 lowers a multiple myeloma biomarker called serum-free light chain at a dose lower than expected. This biomarker is normal but when seen in higher levels, indicates multiple myeloma. Crystal said this kind of lowering of the biomarker with such a low dose is, to his knowledge, a first for the class. One patient, however, saw the biomarker rise 56%.

Three patients in the trial achieved stable disease, while two had a best response of progressive disease.

This initial readout for the five patients in cohort A was meant to be a quick study until signs of clinical activity appeared. C4 then plans to split the trial into several other cohorts, adding patients and a group for non-Hodgkin's lymphoma.

C4 has not yet provided guidance on when the study will advance, but enrollment is underway as per the new two-week on, two-week off schedule. The company will update when the recommended phase 2 dose is secured, Hirsch said.

“What I'd like to see—and truly the only way to know where we land will be the clinical data which emerges—is that with alteration of the schedule, we can actually get more drug in upfront,” Crystal said.