PNH, promising data for a new subcutaneous therapy
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An ultra-rare chronic disease, which mainly affects young people between 20 and 35 years of age and which often manifests itself, in addition to the typical symptoms of anemia (such as fatigue, pallor, breathlessness), with darkening of the urine due to the presence of hemoglobin. We are talking about Paroxysmal Nocturnal Hemoglobinuria (PNH), for which a new monoclonal antibody, crovalimab, is being studied. Like those already in use for the therapy of these patients (for example eculizumab), it works by blocking the so-called complement system, a component of our immune system which, in the case of this disease, causes the destruction of red blood cells and therefore anemia . According to the results of two phase 3 studies – COMMODORE 1 and 2 – crovalimab is also effective when administered subcutaneously, rather than intravenously. This could mean a better quality of life for patients, because it would reduce the administrations: once every four weeks instead of once every two, with the possibility also of self-administering the therapy.
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What are C5 inhibitors
PNH is a life-threatening hematologic disease in which red blood cells are destroyed by the complement system, an integral part of innate immunity. Complement inhibitors, and in particular subunit 5 inhibitors (also called C5 inhibitors) have proven effective in the treatment of this pathology. Crovalimab was designed to provide sustained complement inhibition through subcutaneous administration at low doses every four weeks. Crovalimab also binds to a different C5 binding site than current treatments, potentially providing a treatment option for people with specific C5 gene mutations who are not responding to current therapies. It is also being studied for atypical hemolytic uremic syndrome, sickle cell anemia, and other complement-mediated diseases.
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The clinical studies
COMMODORE 1 is a phase 3 study that included 89 people with PNH (18 years of age and older) currently treated with eculizumab: of these 89, half (randomly selected) continued treatment with eculizumab given for intravenously every two weeks, the other half switched to crovalimab given subcutaneously every four weeks instead. In a non-randomized arm, the study also included pediatric patients (under 18 years of age) currently treated with eculizumab, people currently treated with ravulizumab, people currently treated with off-label doses of eculizumab (i.e. above the approved dose for PNH) or people with known mutations in the C5 gene who are unresponsive to current therapies.
COMMODORE 2 is also a Phase 3, randomized, open-label study evaluating the efficacy and safety of crovalimab versus eculizumab in people with PNH, in this case not previously treated with C5 inhibitors. The 204 adults enrolled in the study were randomized in a 2:1 ratio to receive subcutaneous crovalimab every four weeks or intravenous eculizumab every two weeks. The 6 participants younger than 18 years of age were included in a non-randomized arm for treatment with crovalimab administered subcutaneously every four weeks.
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The results
In the COMMODORE 2 study, 79.3% of crovalimab-treated participants achieved control of hemolysis from week 5 to week 25, compared with 79% seen with eculizumab. With crovalimab, 65.7% also achieved transfusion avoidance through week 25, versus 68.1% with eculizumab. The need for blood transfusion is an important clinical parameter of hemolysis caused by dysregulation of the complement system in PNH, and naturally has a strong impact on the quality of life of patients.
Also in the COMMODORE 2 study, adverse events occurred in 78% of crovalimab-treated participants and 80% of eculizumab-treated participants. Specifically, serious infections occurred in 3% of crovalimab-treated participants and 7% of eculizumab-treated participants, without meningococcal infections. The most common adverse event, affecting 16% of people treated with crovalimab and 13% of people treated with eculizumab, was infusion-related reactions. One participant in each arm experienced an adverse event leading to treatment discontinuation. Results from the COMMODORE 1 study indicate that crovalimab was well tolerated and maintained disease control in people switching from currently approved complement inhibitors. Data from the studies will be submitted to regulatory authorities around the world.
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