Moleculin has announced plans to launch a global Phase 2 clinical trial evaluating its candidate liposomal Annamycin as a less toxic and second-line therapy for relapsed or refractory acute myeloid leukemia (AML).
If results from this anticipated trial support the treatment’s efficacy and safety, the company plans to request its approval in the U.S. and Europe.
Annamycin, a next-generation anthracycline (a type of chemotherapy), was designed in collaboration with the MD Anderson Cancer Center to overcome the limitations of current anthracyclines, particularly an increased risk of heart damage (cardiotoxicity) and disease relapse (due to development of resistance mechanisms by cancer cells).
The therapy has received fast track and orphan drug designation from the U.S. Food and Drug Administration (FDA) as a potential AML treatment. These designations help to speed Annamycin’s development and review, as well as to provide regulatory support, financial benefits, and marketing exclusivity for seven years in the U.S. upon approval.
Moleculin’s announcement follows continuing positive results from two open-label Phase 1 clinical trials (one in Europe, NCT03388749; one in the U.S., NCT03315039) supporting Annamycin’s safety and preliminary effectiveness in relapsed or refractory AML patients.
The Phase 1 portion of each trial aims to determine Annamycin’s maximum tolerated dose and recommended dose to be used in the study’s Phase 2 portion. Patients are being given Annamycin intravenously (directly into the bloodstream) for three consecutive days within a 21-day treatment cycle.
Escalating doses of Annamycin are given in Phase 1 to groups of three patients each, with each successive group receiving the next higher dose level until toxicities prevent further increases. Doses beyond those permitted for anthracyclines in the U.S. (120 mg/m2) are being tested in the European study, taking place in Poland.
Recently, the U.S. Phase 1 study met its primary goal of safety at doses below or at the maximum permitted in the U.S. No unexpected serious adverse events and no dose-limiting toxicities were reported at any of the doses.
No signs of heart damage have been observed in all 17 patients given Annamycin in both the U.S. (six patients) and European (11 patients) trials to date. Seven of these patients received the maximum dose allowed in the U.S., and seven others were given a higher dose.
One Annamycin-related adverse event has been reported in the European trial: moderate mucositis, which was resolved within two days. Mucositis, a common side effect of chemotherapy, is characterized by painful inflammation and ulceration of the mucous membranes lining the digestive tract.
The company also announced a positive independent report finding no signs of cardiotoxicity among the first 14 participants in the two Phase 1 trials.
To date, early measures of effectiveness show that five patients — two (33%) in the U.S. and three (27%) in Europe — responded to treatment.
One patient achieved a complete response with incomplete recovery of white blood cells and/or platelets, and two patients showed a partial response (number of cancer cells lower than 25%). A substantial remission of leukemia cutis (a rare leukemia symptom) was observed in one patient, and another achieved a sufficient reduction in the number of cancer cells to be eligible for a bone marrow transplant.
Moleculin plans to now focus on the European trial, expected to conclude in December 2021, to establish a recommended dose for the Phase 2 portion.
“We believe relying upon the European trial to establish [a recommended Phase 2 dose] is the fastest and most efficient way to reach a pivotal Phase 2 trial. Recruitment in Europe has been faster than in the U.S. and the trial is progressing well,” Walter Klemp, Moleculin’s chairman and CEO, said in a press release.
Rob Shepard, MD, Moleculin’s chief medical officer for Annamycin, added that “the European trial continues with its dose escalation, and although dosing had now taken patients well beyond the lifetime maximum anthracycline limit with no evidence of cardiotoxicity, we are still below what we believe to be a therapeutic dose.”
“We look forward to reaching a therapeutic dose and a recommended Phase 2 dose in the coming quarters,” Shepard added.
Once that is achieved, the company intends to discuss the launch of a global, open-label Phase 2 study with the FDA and European Medicines Agency (EMA) that might support Annamycin’s approval to treat relapsed or refractory AML.
Shepard also noted that the company is aiming for accelerated approval from the FDA.