Coverage from the 64th Annual American Society of Hematology Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana.
An experimental oral therapy, iptacopan, raised hemoglobin levels and eliminated the need for transfusions for most patients with a rare blood disorder, causing the lead investigator of the phase 3 trial to declare that results involving paroxysmal nocturnal hemoglobinuria (PNH), “could essentially allow patients to live a normal life with just 1 pill each morning and night.”1
Régis Peffault de Latour, MD, PhD, professor of hematology and bone marrow transplant, Hôpital Saint-Louis in Paris, France, presented the groundbreaking findings from APPLY-PNH (NCT04558918) at a late-breaking session of the 64th American Society of Hematology Annual Meeting and Exposition in December 2022.2
Iptacopan is being developed by Novartis, which sponsored
For many patients with PNH, he said, a simple pill could spell the end of treatment with intravenous monoclonal antibodies such as eculizumab (Soliris) or ravulizumab (Ultomiris), which are the current standard of care for this devastating disease. PNH, which gets its name from the dark red urine that signals its onset, is caused by a genetic flaw that causes the immune system to break down red blood cells, leading to serious illnesses such as anemia, chronic kidney disease, or thrombosis. According to Cleveland Clinic, PNH can occur if patients have bone marrow disorders such as myelodysplastic syndrome or aplastic anemia.3
According to the authors of the late-breaking abstract, current standard of care (SOC) is both inconvenient and inadequate. Up to 60% patients still have anemia even with treatment and may require blood transfusions to keep up hemoglobin levels. Iptacopan, a first-in-class oral selective complement factor B inhibitor, works to block the proteins that trigger immune system attacks on red blood cells. However, it works by a different pathway than current therapies—it appears to reduce infection risk and forestall the need for dialysis or transfusion.4
Peffault de Latour explained that iptacopan works by targeting biological mechanisms further “upstream” than other available treatments before they have time to wreak havoc. This allows the drug to achieve its results without additional complications, while offering patients a more convenient mode of delivery.
In the late-breaking session, he reported primary efficacy and safety data from the 24-week randomized treatment period of the pivotal, multicenter trial, with data cutoff September 26, 2022. A total of 97 patients were randomly assigned 2:1 to receive iptacopan monotherapy 200 mg twice daily or continue their SOC regimen. Randomization was stratified by prior SOC therapy and red blood cell transfusions in the 6 months preceding the trial.
Two primary end points were reported: the proportion of patients with at least a 2 g/dL hemoglobin (Hb) increase from baseline and the proportion of patients with Hb of at least 12 g/dL, each in the absence of transfusions. Among the secondary end points were transfusion avoidance, changes from baseline in Hb level, assessment of fatigue, major adverse vascular events (MAVE), and safety.
Results. The iptacopan arm had 62 patients and the SOC arm had 35 patients. Baseline characteristics were balanced; mean age was 51 years and 69.1% of patients were women, who have higher incidence of the disease. In the 6 months prior to the trial, 57.7% of patients had transfusions; of these, 64.9% had been treated with eculizumab and 35.1% had been treated with ravulizumab for a mean of 4 years. Both primary end points were met in the iptacopan arm, showing superiority with SOC:
“This treatment represents a new class of agent that is not only more convenient,” Peffault de Latour said in a statement, “but offers a much better clinical response. It’s a huge step forward for treating this devastating disease.”1
1. Study in ASH late-breaking abstracts: iptacopan resolves anemia in phase 3 trial for paroxysmal nocturnal hemoglobinuria. News release. American Society of Hematology. December 13, 2022. Accessed December 19, 2022. https://bit.ly/3G49GVr
2. Peffault de Latour R, Roeth A, Kulasekararaj A, et al. Oral monotherapy with iptacopan, a proximal complement inhibitor of factor B, has superior efficacy to intravenous terminal complement inhibition with standard of care eculizumab or ravulizumab and favorable safety patients with paroxysmal nocturnal hemoglobinuria and residual anemia: results from the randomized, active-comparator-controlled, open-label, multi-center phase 3 APPLY-PNH study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract LBA-2. Accessed December 18, 2022. https://ash.confex.com/ash/2022/webprogram/Paper171469.html
3. Paroxysmal nocturnal hemoglobinuria. Cleveland Clinic. April 25, 2022. Accessed December 19, 2022. https://my.clevelandclinic.org/health/diseases/22871-paroxysmal-nocturnal-hemoglobinuria
4. Iptacopan (LNP023) update. Novartis. June 22, 2021. Accessed December 19, 2022. https://www.novartis.com/sites/novartis_com/files/2021_iptacopan-lnp023-update-presentation.pdf
Adding isatuximab (Sarclisa) to the combination of carfilzomib (Kyprolis) and dexamethasone (Kd) creates deeper responses and improves progression-free survival (PFS) among patients with relapsed or refractory multiple myeloma (MM), regardless of how many prior treatments a patient has received. Although the number of months of PFS was numerically larger among patients with 1 prior line of therapy, the relative benefit of isatuximab with Kd compared with Kd only was statistically significant among patients with more than 1 prior line of therapy.1
This finding was presented in 1 of 2 abstracts that analyzed subgroups of patients enrolled in the phase 3 IKEMA trial (NCT03275285)1,2 during the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans, Louisiana. The results show that benefits from isatuximab support its use in combination with Kd “as a standard-of-care treatment for patients with relapsed MM, irrespective of prior lines of therapy, including those with first relapse,” according to the investigators.
Isatuximab is an IgG1 monoclonal antibody that targets a CD38 protein on the surface of MM cells. It attaches to cells that express CD38 and sets in motion a multipronged response of the body’s immune system to destroy those cells.
Interim results for IKEMA were presented in a late-breaking session during the virtual meeting of the European Hematology Association in June 2020.3 IKEMA compared the use of isatuximab with Kd and Kd alone in patients who had received between 1 and 3 prior lines of therapy; a 46% PFS benefit was seen in the isatuximab group.
In March 2020, isatuximab received FDA approval based on findings from the ICARIA-MM trial (NCT02990338), which evaluated the targeted immunotherapy in combination with pomalidomide and low-dose dexamethasone. Patients receiving this combination had 40% improved PFS compared with those receiving pomalidomide and low-dose dexamethasone alone.4
Effective Across Prior Lines of Therapy
The updated results are from a specified final PFS analysis. Key secondary end points included rate of minimal residual disease (MRD) and complete response (CR) rate, which were updated from the initial analysis.1
Among 302 randomized patients, 134 (44.4%) had 1 prior line of therapy and 168 had more than 1 prior line of therapy. After a median follow-up of 44 months in each group, investigators found the following:
Almost all patients reported at least 1 treatment-emergent adverse event (TEAE), regardless of subgroup.
Early vs Late Relapse
A second abstract at ASH evaluated patients from the IKEMA study based on whether they had early or late relapse, based on experience that shows patients who relapse quickly have worse outcomes.2 For patients with 2 or more prior lines of therapy, early relapse was defined as relapse within 12 months of treatment; for those with 1 prior treatment, early relapse was defined as 18 months from treatment. Patients who relapsed within 12 months of autologous stem cell transplant were also considered to have early relapse.
In IKEMA, there were 107 patients with early relapse and 176 of patients with late relapse; the treatment arms were well balanced between patients with early relapse and late relapse. Among patients with early relapse, the isatuximab arm had a higher share of patients with renal failure and fewer with stage I MM. Data showed:
1. Capra M, Martin T, Moreau P, et al. Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma: Ikema subgroup analysis by number of prior lines of treatment. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 3176. https://ash.confex.com/ash/2022/webprogram/Paper162731.html
2. Facon T, Moreau P, Baker R, et al. Isatuximab plus carfilzomib and dexamethasone in patients with early versus late relapsed multiple myeloma: Ikema subgroup analysis. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 753. https://ash.confex.com/ash/2022/webprogram/Paper159105.html
3. Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open-label study. Presented at: 25th European Hematology Association Annual Congress; June 11-21, 2020; virtual. Abstract LB2603. https://bit.ly/3GgDvlX
4. FDA approves new therapy for patients with previously treated multiple myeloma. News release. FDA. March 2, 2022. Accessed December 21, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-patients-previously-treated-multiple-myeloma