Crovalimab effective, safe in PNH patients up to 4 years, study shows
Injections every 4 weeks found to control red blood cell loss in adults
Monthly injections of the experimental therapy crovalimab controlled red blood cell loss and the need for blood transfusions for up to four years in adults with paroxysmal nocturnal hemoglobinuria (PNH), according to data from a long-term extension study.
In fact, more than 80% — and up to 92% — of patients were able to avoid transfusions during the approximate six-month study intervals.
“This work supports the continued clinical development of crovalimab, a potential new treatment option for symptomatic patients with PNH, that can be delivered in a low volume, subcutaneous [under-the-skin] injection every 4 weeks,” the researchers wrote.
Findings from the extension study were reported in “Crovalimab treatment in patients with paroxysmal nocturnal haemoglobinuria: Long-term results from the phase I/II COMPOSER trial,” published in the European Journal of Haematology.
Crovalimab works to block complement protein C5
In PNH, red blood cells are missing certain proteins on their surface that are responsible for shielding them from immune responses. As a result, a part of the immune system called the complement cascade mistakenly identifies these cells as foreign and attacks them, leading to their destruction, which is known as hemolysis.
Hemolysis, the hallmark of PNH, leads in turn to symptoms such as fatigue, low blood cell counts, and blood clotting problems.
Crovalimab is an antibody-based therapy designed to block the activation of the complement cascade by binding to complement protein C5.
While Soliris is given via an intravenous or into-the-vein infusion every two weeks, Ultomiris can be similarly administered once every one or two months, or given subcutaneously once weekly.
In Japan, Chugai Pharmaceutical, a Roche group member developing crovalimab along with Genentech, now has applied to regulatory authorities seeking crovalimab’s approval in that nation.
The request included data from two Phase 3 clinical trials: COMMODORE 1 (NCT04432584), an open-label study evaluating the effects of crovalimab in PNH patients switching from other complement-blocking therapies, and COMMODORE 2 (NCT04434092), which tested crovalimab against Soliris in patients who had never been on complement blockers.
Data from COMMODORE 2 showed that crovalimab was similar to Soliris in its ability to control hemolysis and enable patients to remain transfusion-free. Early findings from the ongoing COMMODORE 1 study also suggested that disease activity remained stable after patients switched to crovalimab.
Now, researchers reported long-term data from the open-label extension (OLE) study associated with the Phase 1/2 COMPOSER trial (NCT03157635), sponsored by Chugai and Roche. Like the COMMODORE program, this study tested crovalimab in PNH patients who had never been on C5 blockers, as well as in those switching from Soliris.
Patients show stable hemoglobin levels on crovalimab
COMPOSER first established the safety and tolerability of ascending doses of crovalimab in healthy volunteers. Then, it demonstrated crovalimab’s ability to sustain complement suppression and effectively control hemolysis over 20 weeks (nearly five months) in previously untreated patients, as well as in those switching from Soliris. Additional patients were enrolled to optimize dosing regimens.
From the 44 patients who completed the initial 20 weeks, all but one — 43 participants in total — entered the OLE. Assessments were conducted in 24-week or roughly six-month intervals. These were done for up to 4.4 years (median 3.4 years) for the 18 previously untreated participants and for up to 3.9 years (median 2.9 years) for the 25 patients switching from Soliris.
Blood tests revealed that the once-monthly crovalimab dose suppressed complement activity, with levels close to or below the lower limit over the course of the study. C5 also was maintained at low levels in most patients.
Mean levels of lactate dehydrogenase or LDH, a marker of tissue damage, were maintained within 1.5 times of the upper limit of normal for 80% to 100% of patients at each visit during the study.
Between 83% and 92% of the patients did not need blood transfusions across the 24-week study intervals. At the time of this report, 11 patients had required transfusions. Similarly, 79% to 88% of participants had stable levels of hemoglobin, the protein in red blood cells that carries oxygen.
Patients with PNH treated with crovalimab maintained disease control over long-term follow-up as indicated by efficacy endpoints.
Overall, there were five occurrences of breakthrough hemolysis, each a single event in a different individual. All resolved with continued treatment, and none led to study withdrawal.
Treatment-related adverse events occurred in 14 patients (32%), with the majority (77%) being mild or moderately severe. Common treatment-related adverse events included headache (7%), breakthrough hemolysis (5%), rash (5%), and viral infections (5%).
“Over a 3-year median treatment duration, crovalimab was well tolerated and sustained C5 inhibition was achieved,” the researchers wrote. “Intravascular haemolysis control, haemoglobin stabilisation and transfusion avoidance were maintained, signifying long-term crovalimab efficacy.”
Overall, the team noted that “patients with PNH treated with crovalimab maintained disease control over long-term follow-up as indicated by efficacy endpoints.”