Karyopharm Therapeutics’ latest Phase III trial for its rare blood cancer drug produced a hit and a miss, achieving one key endpoint while falling short on another.
In the SENTRY study (NCT04562389), patients with myelofibrosis who received the study drug, Xpovio (selinexor) plus Jafaki (ruxolitinib), met one co-primary endpoint of spleen reduction; however, the second co-primary endpoint of change in absolute total symptom score (Abs-TSS) after 24 weeks was not statistically significant.
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Myelofibrosis is a rare, chronic blood cancer where abnormal stem cells cause bone marrow scarring, which disrupts blood cell production. Symptoms include severe fatigue, anaemia, and an enlarged spleen.
Of the patients that received the combination, 50% achieved a statistically significant improvement in spleen volume reduction of 35% or more (SVR35) at week 24 compared to 28% of patients who received Jafaki alone. This reduction was sustained, with 47% of patients on the combination achieving SVR35 at week 36 compared to 23% who received Jafaki alone.
Symptom improvement in Abs-TSS from baseline was 9.89 points in the combination cohort compared to a 10.86-point improvement in the comparator arm.
There were positive signals towards overall survival (OS) with the combination, with a hazard ratio of 0.43. Karyopharm will continue to follow OS to maturity.
There was also early evidence of disease modification from a pre-specified exploratory endpoint, with 32% of patients in the combination arm achieving a ≥20% reduction in variant allele frequency (VAF) for JAK2, MPL, and CALR compared to 24% of patients who received Jafaki alone.
There was no meaningful difference observed between arms in secondary and exploratory endpoints, including progression-free survival (PFS), haemoglobin stabilisation, and bone marrow fibrosis improvement, as of the 20 February cut off.
The combination demonstrated a manageable safety and tolerability profile consistent with the known profile of each drug individually, with no new safety signals observed.
Dr John Mascarenhas, Professor of Medicine at the Icahn School of Medicine at Mount Sinai, said: “Reducing spleen volume remains one of the most important treatment goals in myelofibrosis since achieving SVR35 is associated with improvement in OS. While the symptom endpoint did not reach statistical significance, patients treated in both arms achieved similar symptom improvement relative to baseline. Importantly, while JAK inhibitors have been the backbone of therapy, continued progress requires new therapies that target additional biological pathways. Inhibition of XPO1 represents a differentiated mechanism that has the potential to address these pathways and evolve treatment beyond JAK inhibition alone.”
The missed endpoint rattled investors, with Karyopharm Therapeutics’ stock opening 9% lower on 24 March, at $6.05, compared to a 23 March close of $6.66. The companies stock value has continued to decrease throughout the day, reaching a low of $5.17 (correct at 12.10pm ET).
Despite missing one of its co-primary endpoints, Karyopharm still plans to meet with the US Food and Drug Administration (FDA) about its supplemental new drug application (sNDA) filing. Further data from SENTRY will be presented at an upcoming, undisclosed medical meeting.
While JAK inhibitors, such as Jafaki, Inrebic (fedratinib) and Vonjo (pacritinib) are the standard of care (SOC) for myelofibrosis, they are not always effective with some patients requiring blood transfusions and splenectomy.
“The myelofibrosis community is waiting for new treatment options that can build upon the benefit of JAK inhibitors. Improving OS is the ultimate goal for people living with myelofibrosis and I am incredibly encouraged by these results,” said Kapila Viges, CEO of the MPN Research Foundation.
