AstraZeneca's Efzimfotase Alfa Meets Goal in Children but Misses in Adults in Phase 3 HPP Trials

AstraZeneca said on March 31 that efzimfotase alfa, an investigational enzyme replacement therapy for the rare bone disease hypophosphatasia (HPP), met its primary endpoint in a Phase 3 trial in children but missed statistical significance on the primary endpoint of a second Phase 3 trial in adolescents and adults, according to the company's announcement, filed with the SEC.

The three-trial program, run by AstraZeneca's Alexion rare disease unit, enrolled 196 patients with childhood-onset or adult-onset HPP in 22 countries. The results are company-reported topline data, and the company said they will be presented at a forthcoming medical meeting and shared with regulators.

HPP is an inherited metabolic disease caused by deficient activity of the enzyme alkaline phosphatase, which leads to poorly mineralized bones and teeth, muscle weakness, fatigue and pain. Alexion already sells an enzyme replacement therapy for the disease, Strensiq (asfotase alfa). The company said efzimfotase alfa is designed to need a smaller injection volume and less frequent dosing; in the trials it was given under the skin once every two weeks.

Results in children

MULBERRY, a randomized, double-blind, placebo-controlled trial, enrolled 29 children aged 2 to under 12 who had not been treated with Strensiq and had HPP-related rickets on X-rays. Efzimfotase alfa produced a statistically significant improvement over placebo in the Radiographic Global Impression of Change score at week 25, the primary endpoint, and in the key secondary endpoint, the Rickets Severity Score. AstraZeneca said walking and motor-function measures also supported the benefit. The company did not give the numerical results.

CHESTNUT, an open-label trial in 43 children who had been on Strensiq for at least six months, randomized patients to switch to efzimfotase alfa or stay on Strensiq. Its primary endpoint was the rate of treatment-emergent adverse events. AstraZeneca said the drug was well tolerated and maintained Strensiq's bone-health benefit at week 25.

The HICKORY miss

HICKORY, a randomized, double-blind, placebo-controlled trial in 124 adolescents and adults aged 12 and older who had not received Strensiq, showed a numerical improvement in six-minute walk distance at week 25 that did not reach statistical significance. AstraZeneca attributed this largely to better-than-expected results in the placebo group among patients with adult-onset HPP.

The company reported nominally significant improvements in fatigue in the overall population. In a combination of prespecified subgroups of adolescents and adults with childhood-onset HPP, it said the drug showed nominally significant benefits in walking distance, physical function and pain. Patients in an ongoing open-label extension continued to improve at week 48, the company said.

AstraZeneca said efzimfotase alfa was well tolerated with an acceptable safety profile across all three trials. "Collectively, these results support the potential for efzimfotase alfa to transform the treatment paradigm for people living with this rare disease," Alexion chief executive Marc Dunoyer said in the announcement, as also carried by Indian Pharma Post.