Immunogenicity dragged on the efficacy of AstraZeneca’s rare endocrine disorder prospect in a phase 3 trial, causing the $800 million molecule’s response rate to fall short of the bar set by Ascendis Pharma’s Yorvipath.
AstraZeneca reported that the Calypso trial hit its primary endpoint 14 months ago. However, the drug developer shared little information from the chronic hypoparathyroidism trial beyond the revelation that the primary endpoint response rate was significantly higher on eneboparatide than placebo. AstraZeneca acquired the PTH-1 receptor agonist in 2024 by paying $800 million upfront to buy Amolyt Pharma.
Having deferred publication of the data until after the long-term extension period, AstraZeneca used the European Congress of Endocrinology to unwrap the results that will shape its pursuit of a market served by Ascendis and targeted by companies including MBX Biosciences.
At Week 24, 31.1% of people on eneboparatide met the composite primary endpoint, compared to 5.9% of their counterparts on placebo, achieving the trial’s primary endpoint. Participants met the composite endpoint requirements if they had normal albumin-adjusted serum calcium, independence from active vitamin D and oral calcium levels below a certain threshold.
Related
Ascendis tracked the same variables for the composite primary endpoint of its pivotal trial, reporting a 79% response rate for Yorvipath at Week 26 compared to 5% for placebo. Counting patients who needed active vitamin D or calcium in the final four weeks as non-responders cut the result to 74%. Yorvipath’s FDA label uses (PDF) a slightly different responder definition, resulting in a 68.9% response rate.
AstraZeneca’s response rate reflected immunogenicity, which was seen in most patients and reduced the treatment effects in some participants. Anecdotal evidence that immunogenicity hurt the trial emerged last year, when Guggenheim Securities analysts relayed a conversation with a participant who said they responded well to eneboparatide for two months before losing efficacy because of antidrug antibodies.
Trial design differences may also have contributed to the gulf between the Yorvipath and eneboparatide response rates. Patients in AstraZeneca’s trial had chronic hypoparathyroidism for 12 months or more, whereas Ascendis enrolled people diagnosed at least 26 weeks previously. AstraZeneca’s trial was larger, included more sites in more countries, and it used different calcium-related inclusion and exclusion criteria.
Ahead of the topline readout, AstraZeneca executives identified normalizing serum calcium, decreasing urinary calcium excretion and preserving bone mineral density as clinical priorities and areas where their asset could be differentiated. Albumin-adjusted serum calcium on eneboparatide was at the bottom of the normal range at Weeks 24 and 52. Bone health was preserved over 52 weeks, AstraZeneca said.
