AZ considers filings for long-acting Strensiq follow-up

AstraZeneca's Alexion unit is planning to file a new, long-acting follow-up to its Strensiq therapy for ultra-rare disease hypophosphatasia (HPP), although its phase 3 readouts have shown mixed results.

The results of two phase 3 trials of efzimfotase alfa (ALXN1850) in paediatric patients met their main objectives, although a third in adolescents and adults missed the mark, according to a statement from AZ, which said it would share the results with global regulatory authorities.

It is positioning the new drug as a successor to Strensiq (asfotase alfa), sales of which grew 18% last year to $1.68 billion and is expected to start losing patent protection around the end of this decade or in the early 2030s.

Strensiq is an enzyme replacement therapy (ERT) that has been approved for more than a decade to treat children with HPP, a progressive, metabolic disease caused by changes in the ALPL gene that leads to devastating effects on multiple systems of the body, including defective bone formation, muscle weakness, severe pain, seizures, and respiratory failure.

It was the first and remains the only drug to be specifically approved for HPP, although some other therapies, like bisphosphonates, are used off-label to treat bone complications of the disease. For now, there is no approved therapy for patients who develop symptoms of the disease in adulthood.

Strensiq's dosing is dependent on the specific patients, but can involve multiple subcutaneous injections per week, while the clinical data for efzimfotase alfa suggests it could be given by injection once every two weeks.

AZ and Alexion's update notes that the new longer-acting ERT showed statistically significant improvements in bone health in treatment-naïve paediatric patients enrolled in the placebo-controlled MULBERRY trial, while an open-label study, CHESTNUT, showed that switching patients from Strensiq to efzimfotase alfa could be done safely, maintaining the therapeutic benefits.

The data was less positive in the HICKORY trial in patients aged 12 and over who had been previously untreated with Strensiq, as the drug was unable to show a significant improvement in its primary endpoint, the six-minute walk test (6MWT), compared to placebo.

AZ said that there was a trend towards improvement on that measure that was undermined by better-than-expected performance in the placebo group, and there was a "nominally significant" improvement in fatigue, a secondary endpoint.

Lead HICKORY investigator Kathryn Dahir of Vanderbilt Health's metabolic bone disorders programme said the results "highlight the heterogeneity of the disease and the value of assessing a range of clinically meaningful endpoints across diverse patient populations."

She added that the results point to "a clinically relevant impact on mobility, physical function, pain, and fatigue, demonstrating the potential for efzimfotase alfa to improve outcomes for patients living with this disease."

AZ said the results across all HPP age ranges are "clinically meaningful," noting that the three phase 3 trials are the first to include patients with both paediatric- and adult-onset HPP with heterogeneous manifestations beyond bone.

There is potential competition to Strensiq and efzimfotase alfa in development from AM Pharma, which is developing another ERT – ilofotase alfa – that is in phase 1b testing.