Lackluster midphase efficacy data have pushed Ionis Pharmaceuticals to trim its pipeline. The antisense specialist tossed out acromegaly prospect cimdelirsen and abandoned hopes of developing sapablursen in beta thalassemia.
Both safety profiles were “clean, pristine,” Ionis CEO Brett Monia, Ph.D., said on a conference call with investors, adding that the decisions were “all about efficacy.”
In acromegaly, Monia said Ionis saw “some reductions” in IGF-1—a growth factor found at elevated levels in patients with the rare hormonal disorder—in recipients of the antisense medicine cimdelirsen, but they fell short of the biotech’s minimum target product profile.
“It wasn't good enough and, considering the richness of our pipeline, it just didn't clear the bar,” Monia said.
The CEO went on to discuss sapablursen, a drug candidate he called “more interesting.” In 2019, Ionis moved the prospect into a phase 2 trial in non-transfusion-dependent beta thalassemia intermedia, a milder form of the blood disease, on the strength of data in healthy volunteers that dialed up expectations at the company.
In phase 1, Monia saw “quite remarkable” target engagement plus “very significant elevations in hepcidin levels.” However, “in beta-thalassemia intermedia, we didn't see those changes,” the CEO said.
Researchers have linked low levels of hepcidin to iron overload in beta thalassemia and have shown the hormone is negatively regulated by TMPRSS6. As such, Ionis bet that lowering TMPRSS6 would up-regulate hepcidin, alter iron metabolism and improve symptoms. But something went awry in the move into patients.
“TMPRSS6 is a pathway target; it's not a genetically validated target, keep that in mind. And we didn't see the biology translate from preclinical to clinical in that setting, so it didn't meet the product profile,” the CEO said.
Ionis is continuing to study sapablursen in polycythemia vera, a type of chronic leukemia characterized by dysregulated iron metabolism. A phase 2 study in that indication kicked off in 2021 and is scheduled to wrap up next year.