“For patients with paroxysmal nocturnal hemoglobinuria (Epn), until recently the therapy was only supportive: transfusions, folic acid, iron supplementation, up to allogeneic bone marrow transplant which is the only curative approach, but with an important morbidity and mortality. Today, fortunately, we have an extra weapon at our disposal: ravulizumab, a new monoclonal antibody that can be given every 8 weeks compared to standard eculizumab therapy which requires an infusion in the hospital every 15 days. Therefore, having a drug like ravulizumab available, which has a lower treatment load, but the same efficacy and safety, is an important step forward for patients with Epn, but it is a therapy to be done for a lifetime “.
Like this Wilma Barcellini, 1st level medical director, head of the simple anemias physiopathology unit, Irccs Ca ‘Granda Foundation Ospedale Maggiore Policlinico di Milano, speaking this morning at the virtual press conference ‘Rare diseases: new life opportunities and perspectives for people with paroxysmal nocturnal hemoglobinuria‘, promoted by Alexion Pharma Italy, part of AstraZeneca, to take stock of new treatments and future standards of care that will allow a better quality of life for adult patients suffering from rare haematological disease. To moderate the work, Ilaria Ciancaleoni Bartoli, director of the Rare Diseases Observatory (Omar).
Paroxysmal nocturnal hemoglobinuria – recalls the expert – presents with non-specific symptoms, “fatigue, shortness of breath, abdominal and chest pain, impotence, all things that can be underestimated by the doctor”.
Symptoms that, Barcellini points out, may be underestimated by a doctor who is perhaps “not attentive and who does not imagine, instead, that he is facing the EPN which actually hides other pitfalls: thrombosis, bone marrow failure and possible clonal evolution. Diagnosis of the disease is extremely easy: just do a flow cytometric survey of negative Gpi cells on peripheral blood “.
In cases where it is necessary to treat the patient, continues the specialist, “the standard is eculizumab, a monoclonal antibody directed against a fraction of the complement system called C5, which inhibits its activation. The abnormal activation of C5, in fact, is at the origin of the disease: blocking it means blocking the hemolysis and significantly reducing anemia and the risk of thrombosis. Eculizumab has been available in Italy for more than 10 years and has changed the natural history of the disease, which in itself has high morbidity and mortality and for which there was no therapy before. Today, patients who respond well to the drug have a life expectancy comparable to that of the general population and have a much better quality of life than in the past “. But eculizumab should be administered intravenously every 2 weeks.” The therapy “therefore” represents a discreet commitment for the patient who every 14 days must go to his reference center for a new infusion “.
“Some patients, then – Barcellini points out – may not respond well to treatment: they are the so-called suboptimal responders and are those for whom the therapy fails to guarantee normal hemoglobin levels. A further problem that may occur is the breakthrough hemolysis (Bth), i.e. hemolysis that occurs despite the inhibition of C5. There are two types: kinetic Bth and dynamic Bth. The first can occur towards the end of the interval between two infusions and is due to the fact that eculizumab does not adequately cover the entire period, possibly because it is underdosed. The second, on the other hand, can occur at any time in the 14-day interval and is triggered by an intercurrent infection (from the banal cold to more serious infections, such as that from Sars-CoV-2 for which we have observed important Bths) , which leads to the supramaximal activation of the complement system “.
“Ravulizumab – continues the expert – has a half-life that is 4 times longer than eculizumab. This allows us to being able to administer the drug every 8 weeks instead of every 2, with considerable benefits for patients. Two clinical studies, one with patients switching from eculizumab to ravulizumab and one with naive patients, compared the safety and efficacy profile of ravulizumab with that of eculizumab and showed that the new monoclonal antibody is not inferior to that of to the standard of care. Ravulizumab is able to inhibit C5 more efficiently, stabilizing anemia and hemolysis. In other words, it does not leave C5 free, an index of suboptimal inhibition of the fundamental factor of pathogenesis. The data that will derive from the use in real life, finally, will be able to confirm the statistical significance demonstrated in the trials “.
But which patients are eligible for ravulizumab? “Patients with stable disease and long-term on eculizumab therapy are prime candidates to switch to ravulizumab – Clarifies Barcellini – Often it is the patients themselves who request it, precisely because they are now tried by repeated visits to the hospital. Even naïve patients can be candidates for treatment with ravulizumab, but with a little foresight on the part of the caregiver: the patient who has recently received the diagnosis must learn to know the disease well, what it entails and how to manage it. Therefore, even if he starts on ravulizumab, he will need to be monitored shorter than the expected 8 weeks. ”
A particular aspect concerns young patients who want children, “since at the moment – the specialist points out – we do not have sufficient safety data for the use of ravulizumab in pregnancy, where eculizumab is therefore recommended. controlled with eculizumab and for suboptimal responders a more in-depth assessment of the case is needed before proposing a switch to ravulizumab “.