Transplant-Associated Thrombotic Microangiopathy - Episode 13
Samer Khaled, MD reviews the design, results, and practical implications of the pivotal phase 2 trial of narsoplimab, a MASP-2 targeted monoclonal antibody under investigation for the treatment of thrombotic microangiopathy associated with hematopoietic stem cell transplantation.
Samer Khaled, MD: With that, we can go on to summarize the new data from a TCT [Transcatheter Cardiovascular Therapeutics] meeting from just last week about the phase 2 trial of narsoplimab. This is a single-arm open label study that was conducted in 10 centers across 8 countries from 2014 to 2019. This trial was converted to a pivotal trial after discussion with the FDA [Food and Drug Administration] because of the need of treatment for this devastating condition.
The trial was designed in 3 stages. Stage 1 was a dose escalation, and stage 2 was a dose expansion. Patients received narsoplimab weekly for 4 weeks. Then stage 3 was for patients who exhibited a response to narsoplimab or a clinical benefit, and a patient and investigator felt that the patients will continue to have benefit that they continue with the stage 3 and some other 4 weeks…narsoplimab was supported by a follow-up period.
The patient’s population on this trial was an adult population; 18 years old or older, and they exhibited manifestations of TA-TMA TMA [transplant-associated thrombotic microangiopathy]. So those were defined as having TA-TMA, schistocyte microangiopathy and schistocytes, that lasted for 2 weeks following modification or discontinuation of the calcineurin inhibitor. That in combination with decreased platelet counts, less than 150,000, and renal dysfunction.
Some of the patients who had other co-existing conditions before enrollment that were being controlled, such as graft versus host disease or infections, were allowed on the trial. Patients who received eculizumab within 3 months prior to the screening were excluded, and patients who had a positive coombs test also were excluded.
The primary endpoint of this trial was response-based efficacy. They looked at improvement in TMA laboratory and TMA improvement in the clinical status. The laboratory included the platelets, LDH [lactate dehydrogenase], haptoglobin and hemoglobin, and then the clinical status; transfusion freedom, improvement of the renal insufficiency, lung dysfunction, or the neurological dysfunction.
The secondary endpoint was a 100-day overall survival and change from baseline in laboratory markers.I will stop here and open it if there are any comments from Christine, Hari, or Jeff.
Christine Duncan, MD: I know it was an adult setting, that's where many things often start, and I know there's lots of thought and conversation about pediatrics studies at the start, but I think one of the things that was appealing to me from this data was that efficacy data and thinking about safety profiling. Everything that Dr Laurence spoke about and that you spoke about, Dr Khaled, are really important; I think this is very promising.
One of the things that's really appealing to me and I think to probably all of us is to have some options and to have some choice for patients; that is critical. Over time hopefully we'll figure out what the right drug is for everyone or individual patients or trying to figure out how to profile.
Jeffrey Laurence, MD: Yeah, I agree.
Transcript edited for clarity.