AZ makes case for hypophosphatasia drug after phase 3 miss

AstraZeneca has already filed for approval of its therapy for ultra-rare disease hypophosphatasia (HPP), after missing the mark in a phase 3 trial, but reckons the totality of the data could get the drug over the line with a broad label.

AZ's rare disease unit Alexion presented the full dataset from the HICKORY trial of enzyme replacement therapy (ERT) efzimfotase alfa in patients aged 12 and older with HPP, saying that issues with the trial design and execution resulted in it missing its primary endpoint.

The main problem was that the study saw an unexpectedly high placebo response rate, particularly among adult subjects, which was exacerbated by imbalances between the groups in baseline mobility performance that compromised its ability to demonstrate a significant improvement with efzimfotase alfa on the primary endpoint – the six-minute walk test (6MWT).

At week 25, AZ's drug achieved a least squares (LS) mean difference of 17.05 metres change from baseline in 6MWT compared to placebo, which was not a statistically significant difference.

That said, 45.2% of the efzimfotase alfa group achieved the minimum clinically important difference (MCID) from baseline in 6MWT – set at 43 metres in adolescents and 31.1 metres in adults – compared to 30% of the placebo arm, which scraped over the threshold for statistical significance.

Meanwhile, efzimfotase alfa demonstrated nominally significant improvement in the key secondary endpoint of FACIT-Fatigue, achieving a nominally significant LS mean difference of 5.74 compared with placebo.

AZ's marketing application for efzimfotase alfa includes data from two phase 3 trials in paediatric populations aged from two to 11, MULBERRY and CHESTNUT, which showed the drug's efficacy in patients who had switched from treatment with its older ERT Strensiq (asfotase alfa).

Now, the question is whether the FDA – which is due to deliver a decision on efzimfotase alfa's filing in the first half of next year after a priority review – will consider approving the drug for all HPP patients aged two and over, or limit its use to those aged under 12.

HICKORY's lead investigator, metabolic bone disorder specialist Kathryn Dahir of Vanderbilt Health, said there is a pressing need for new treatments for adolescents and adults with HPP, in whom the disease has "far-reaching impact on physical function and emotional wellbeing, potentially impairing people's ability to live independently, form connections, and sustain employment."

HPP is characterised by defective mineralisation of bone, along with impaired calcium and phosphate regulation, which leaves patients at risk of bone malformations like rickets, muscle weakness, neurologic symptoms, generalised fatigue, and pain.

It affects people of all ages, with adults estimated to account for around 80% of all cases in the US, so the population covered by HICKORY will be key to making efzimfotase alfa a commercial success and hit its sales target of $3 billion to $5 billion.

Strensiq remains a big earner for AZ, with sales rising 18% last year to $1.68 billion, but is due to start losing patent protection around the end of this decade or in the early 2030s. Efzimfotase alfa offers much less frequent dosing – subcutaneous injections every two weeks, rather than multiple times per week – and requires a lower injection volume, with less tendency to cause injection site reactions.

"The HICKORY Phase III trial builds on the positive results from the MULBERRY and CHESTNUT trials and demonstrates the potential of efzimfotase alfa to address the diverse and complex clinical manifestations of HPP across a broad population of patients," said Alexon's head of development, regulatory, and safety, Gianluca Pirozzi.

"We look forward to bringing this potential new therapy with favourable tolerability and dosing convenience to the HPP community, including those with limited treatment options."

Image by Dr. Manuel González Reyes from Pixabay