AstraZeneca’s HPP Readout Puts Trial Design in Focus for Rare Bone Disease Stocks

AstraZeneca attributes its Phase 3 HICKORY miss in hypophosphatasia to trial design, as Mereo seeks a path forward with the FDA and Mirum wins approval after a Phase 2 primary endpoint miss.

AstraZeneca (NYSE: AZN) presented new data from its Phase 3 HICKORY trial of efzimfotase alfa at the American Society for Bone and Mineral Research annual meeting in Boston. The company attributes the study’s miss in part to how it was designed. The enzyme replacement therapy for hypophosphatasia (HPP) remains under FDA priority review, with a decision due in the first half of 2027.

A 17-Meter Gain That Fell Short of Significance

HICKORY enrolled 124 adolescents and adults who had never received Strensiq, AstraZeneca’s approved HPP therapy. Patients were randomized 2:1 to efzimfotase alfa or placebo, given every two weeks by subcutaneous injection for 24 weeks, with the six-minute walk test as the primary endpoint at Day 169. According to data reported by Endpoints News, patients on efzimfotase alfa walked an average of 17.05 meters more than at baseline, compared with placebo patients. The result did not reach statistical significance.

Marc Dunoyer, CEO of AstraZeneca’s Alexion unit, told Endpoints News that among adult-onset patients, the share who had lost mobility at baseline was imbalanced between the treatment and placebo arms. “Mobility is not the best endpoint” for those patients, he said, adding that the company should have run two studies stratified by baseline mobility, each with its own primary endpoint.

Both pediatric trials were positive. In MULBERRY, children aged 2 to under 12 showed a median difference of 1.67 versus placebo on the RGI-C bone health score at week 25 (p=0.0003). In CHESTNUT, children who switched from Strensiq had a similar incidence of adverse events to those who stayed on it.

Strensiq sold $1.7 billion last year and is typically given three or six times a week. Efzimfotase alfa is dosed every two weeks. On AstraZeneca’s fourth-quarter earnings call, before the HICKORY readout, Dunoyer said the drug could be worth several times Strensiq’s value if it demonstrates efficacy and safety across the total population. After the March topline results, Jefferies analysts wrote that they viewed the opportunity as intact, citing unmet need, adherence issues with Strensiq, and more efficient manufacturing.

Mereo and Ultragenyx Seek an FDA Path After a Phase 3 Fracture Miss

Mereo BioPharma (NASDAQ: MREO) and partner Ultragenyx (NASDAQ: RARE) ran two Phase 3 studies of setrusumab in osteogenesis imperfecta, Orbit and Cosmic. Both missed the primary endpoint of annualized clinical fracture rate but achieved high statistical significance on bone mineral density, a key secondary endpoint. Mereo reports that the FDA has indicated openness to alternative approaches to fracture analysis, and the company expects to update investors on the path forward by year-end. Ultragenyx funds and leads global development, and Mereo retains EU and UK commercial rights.

Mirum Wins FOP Approval After a Phase 2 Primary Endpoint Miss

On September 25, the FDA approved Mirum Pharmaceuticals’ (NASDAQ: MIRM) Atebrioz for fibrodysplasia ossificans progressiva in patients 12 and older, the third FOP therapy approved in the U.S. after Ipsen’s Sohonos and Regeneron’s Pasatru. The approval was based on Cohort 1 of the Phase 2 PROGRESS study, which did not meet its primary endpoint but met a key secondary endpoint on total new heterotopic ossification lesion volume. At Week 24, that volume decreased by 3.2 cm³ in patients on zilurgisertib, compared with an increase of 24.6 cm³ in placebo patients. The approved indication uses the same measure. “If the data is clear in a rare disease, there are pathways to get medicine to patients in a reasonable amount of time, and to not put more draconian, larger indication standards on it,” CEO Chris Peetz told BioSpace.

Tyra Targets Dosing Burden in Achondroplasia

Tyra Biosciences (NASDAQ: TYRA) is developing dabogratinib, an oral FGFR3-selective inhibitor, for achondroplasia. BioMarin’s (NASDAQ: BMRN) Voxzogo, the approved therapy, is a daily injection. Tyra expects initial BEACH301 results across five dose levels at the end of the first quarter of 2027. It reported $353.9 million in cash, cash equivalents and marketable securities at June 30, with runway into the second half of 2028. Tyra also hired Jonathan Day, who led BioMarin’s clinical development strategy for its skeletal dysplasia portfolio, including vosoritide.

If AstraZeneca’s explanation holds, HICKORY reflects a design problem rather than a drug problem. AstraZeneca can absorb a missed primary endpoint and argue its case with regulators. For a smaller company running its own pivotal trial, the same miss can mean a new study and a new financing round. Endpoint selection carries as much risk as the drug itself.