Ravulizumab-CWVZ

Novartis has shared positive results from a phase 3b study of Fabhalta (iptacopan) in a new population of patients with the rare blood disorder paroxysmal nocturnal haemoglobinuria (PNH). The APPULSE-PNH trial has been evaluating twice-daily Fabhalta in adults with PNH and higher haemoglobin levels of at least 10g/dl, expanding the clinical evidence base for the drug. Patients enrolled to the trial had also switched from the anti-C5 therapies eculizumab or ravulizumab. In PNH, an acquired mutation causes patients to produce red blood cells susceptible to premature destruction by the complement system, potentially leading to anaemia, thrombosis, fatigue and other symptoms that can impact quality of life. The disorder affects approximately ten to 20 people per million worldwide. Results presented at this year’s European Hematology Association (EHA) Congress showed that, after 24 weeks of treatment with Fabhalta monotherapy, haemoglobin levels improved on average by 2.01 g/dl and most patients achieved normal or near-normal levels. No patients required transfusion during the study and Fabhalta was associated with clinically meaningful improvements in fatigue. Patients receiving Novartis’ drug also maintained intravascular haemolysis control and resolved extravascular haemolysis control. “The positive results from APPULSE-PNH reinforce that Fabhalta can provide clinically meaningful improvements in haemoglobin among patients with higher baseline haemoglobin levels than those enrolled in previous trials, while offering an oral monotherapy for patients,” said Austin Kulasekararaj, consultant haematologist at King’s College Hospital and King’s College London. Fabhalta, an oral Factor B inhibitor of the alternative complement pathway, already holds approvals to treat adults with PNH. The drug is also authorised to treat immunoglobulin A nephropathy and complement 3 glomerulopathy, two rare kidney diseases. Shreeram Aradhye, president, development and chief medical officer, Novartis, said outlined that Fabhalta is the “first and only oral monotherapy currently available for the treatment of adults with PNH, regardless of previous treatment experience”. Alongside results from APPULSE-PNH, longer-term data from patients initially included in the phase 3 APPLY-PNH and APPOINT-PNH trials of the drug were presented at EHA. “New data from APPULSE-PNH, combined with findings from the phase 3 roll-over extension of the APPLY-PNH and APPOINT-PNH studies, reinforces the efficacy and safety profile of Fabhalta in delivering real benefits to patients,” Aradhye said.

TMAs are a group of severe blood disorders that cause clotting and damage to blood vessels, which can damage organs and eventually lead to organ failure and death. Now that Ultomiris has matched the indications of its predecessor Soliris, AstraZeneca is eyeing new avenues for the C5 drug to make its mark.Next up, the complement inhibitor—which AZ inherited in its $39 billion Alexion purchase—could help address a potentially life-threatening transplant complication without any targeted treatments, according to early phase 3 data from a single-arm trial released over the weekend.In initial results from the late-stage ALXN1210-TMA-314 study, Ultomiris (ravulizumab) helped pediatric patients with thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) achieve an overall survival rate of 87.2% at the trial's 26-week mark, AZ said in a June 14 press release.AZ presented the data at the 2025 meeting of the European Hematology Association (EHA) in Milan, Italy. HSCT-TMA is a rare and potentially deadly complication that can occur after a stem cell transplant procedures for cancer and other diseases. TMAs are a group of severe blood disorders that cause clotting and damage to blood vessels, which can damage organs and eventually lead to organ failure and death, AstraZeneca explained.HSCT-TMA can be tough to identify given that its symptoms frequently overlap with other conditions. The post-transplant complication is often fatal, too, with six-month overall survival rates estimated to be as low as 18% in kids and 26% in adults, AstraZeneca added.AstraZeneca’s latest study results covered 41 pediatric HSCT-TMA patients aged 28 days to less than 18 years. The British drugmaker is also studying Ultomiris in adults and adolescents with HSCT-TMA in the phase 3, placebo-controlled ALXN1210-TMA-313 trial.Digging deeper into the pediatric data, just 17.1% of patients hit the trial’s primary endpoint of complete TMA response at 26 weeks, which AstraZeneca defined as a composite measure of hematologic and kidney parameters.Meanwhile, 29 patients—or around 71% of the trial’s enrolled cohort—met “at least one TMA response criterion,” while 22 patients (53.7%) met one or two response criteria, AstraZeneca said. Among those patients, AZ said it observed “clinically meaningful improvements” across various components of TMA response.Specifically, 58.5% and 53.7% of patients met predefined response criteria for platelet and urine protein-to-creatine ratio at the study’s 26-week mark, respectively, AZ explained. Additionally, 36.6% of patients normalized levels of the enzyme lactate dehydrogenase (LDH) from baseline over that same stretch of treatment.The body releases excess LDH into the bloodstream and other bodily fluids in response to damage or injury to tissues. Elevated levels of LDH—which are most concentrated in the muscles, liver and kidneys—are also associated with multiple conditions beyond HSCT-TMA, including kidney disease, anemia and muscular dystrophy, according to the Cleveland Clinic.As it stands, there are no targeted therapies approved to specifically tackle HSCT-TMA, Franco Locatelli, M.D., Ph.D., who served as an investigator in AstraZeneca’s Ultomiris trial, said in a statement.“The response rates and the overall survival observed with ravulizumab may be a practice-changing advancement in this field, providing a potentially effective option for these young patients and their families,” he added.Reflecting on the results and study design, AstraZeneca noted that the trial’s primary endpoint of complete TMA response required certain criteria to be met at the same time across blood and kidney parameters at two separate points at least 24 hours apart and at any measurement taken between those assessments.Though survival formed a secondary endpoint in the trial, it remains a “critical measure of clinical benefit” in HSCT-TMA patients as understanding of the post-transplant complication continues to evolve, AZ stressed.Ultomiris was well-tolerated in the study and its safety was on par with the profile recorded in previous trials, the company added.Ultomiris—which Alexion developed as a successor to its autoimmune drug Soliris—was a key motivating factor in AstraZeneca’s decision to shell out $39 billion for the rare disease drugmaker in 2021.Since the acquisition, AstraZeneca has continued to expand Ultomiris’ reach to match that of Soliris, most recently scoring an FDA approval in neuromyelitis optica spectrum disorder (NMOSD) last March. With that nod, Ultomiris has successfully scooped up all the indications held by its predecessor.AstraZeneca has previously communicated blockbuster sales expectations for the antibody drug in both HSCT-TMA and cardiac surgery-associated acute kidney injury, should Ultomiris ultimately win approval in those indications. Aside from those studies, AZ is also running trials on Ultomiris in lupus nephritis and immunoglobulin A nephropathy. In the meantime, Ultomiris is continuing to do gangbusters in its approved indications. For all of 2024, the drug grew sales (PDF) roughly 32% to $3.9 billion.