ATC 2012 Report – New highly specific antibody shows good safety results

by Thomas R. Collins –  TOL101, a new murine monoclonal antibody that targets the alpha-beta T-cell receptor, showed a good safety profile despite a problem with hives that seem to go away on their own, according to new results from a Phase IIa trial presented here at the 2012 American Transplant Congress.

The key feature of the study was that increasing doses were used.

The drug is being investigated for prevention of kidney transplant rejection. And the transplant community is interested in TOL101, developed by Tolera Therapeutics, because it functionally inactivates CD3-positive T cells without actually depleting them and has been shown to lead to low cytokine production. That offers hope that the drug will produce a low number of adverse events, said Stuart Flechner, MD, Professor of Surgery at the Lerner College of Medicine at Cleveland Clinic.

In the trial, two patients each were given 7mg and 14mg doses a day, 6 were given 28mg, 4 were given 32mg, 4 were given 42mg a day, and another 6 had their doses boosted over three days from 14mg to 42mg.

The average donor age was 40, with 24 being live donors and 4 cadaveric donors. The average age of the recipient was 44, with 23 men and 5 women.

With an average follow-up period of 169 days, all patients and all grafts had survived. Fifteen patients have gone through the study’s 6-month follow-up period.

Three patients had episodes of biopsy-proven acute rejection. Those episodes all occurred in women, even though there were just 5 women enrolled in the study. Those episodes happened early in treatment — one on Day 10, one on Day 11 and one on Day 14 — and were Banff grade 2a. There were no cases of acute rejection in the dose getting the escalating doses, researchers found.

The trial’s pharmacodynamic target was greater than 90 percent inactivation of CD3, and it was reached at the 28mg dose level.

“The interesting finding, I think… is that the reconstitution or re-identification of CD3-positive cells occurs pretty briskly and by the 14-day point they recover to the point of the pre-treatment levels,” Dr Flechner said.

There was no delayed graft function reported, with glomerular filtration rates remaining steady through the study period.

Hives occurred in 10 patients after 14 of 165 infusions of the drug, but all of those cases resolved after about 24 hours. They were treated with steroids and an antihistamine.

Researchers were encouraged that the cytokine levels —including IL-6, tumour necrosis factor and interferon gamma — all remained low during the study period. One questioner asked Dr Flechner after the presentation why IL10 wasn’t measured — since it is a commonly produced cytokine — and he said he didn’t know, but added that there are “hundreds” that could have been tested for.

Phase III testing is scheduled to begin in 2013 after expected U.S. Food and Drug Administration approval for the trial.

“From this initial Phase II, first-in-man use of TOL101 as an induction agent for the prophylaxis of rejection, successful TOL101 dose escalation was demonstrated with a promising safety profile,” Dr Flechner said. “TOL101 induced measurable dose-dependent T-cell modulation without inducing significant cytokine release.”