Readout for AZ's hypoparathyroidism drug raises questions

 A drug at the heart of AstraZeneca's takeover of Amolyt has hit the mark in a phase 3 trial, but could be undermined by an efficacy result that doesn’t seem to match up to its main rival.

The CALYPSO trial of eneboparatide hit its primary endpoint by showing that the drug was more effective than placebo at normalising serum calcium levels in people living with hypoparathyroidism, a rare condition caused by a deficiency of parathyroid hormone (PTH) that leads to imbalances in calcium and phosphorus levels in the blood, in turn leading to tissue and organ damage.

Eneboparatide, a PTH 1 receptor agonist, helped 31.1% of patients bring their serum calcium levels into the normal range and come off calcium and vitamin D supplements at 24 weeks, which was significantly better than the 5.9% of patients who achieved that objective with placebo.

The issue for AZ is that Ascendis Pharma's already-marketed Yorvipath (palopegteriparatide) seemed to perform much better against a similar endpoint in the pivotal PaTHway trial, with normalisation of serum calcium levels seen in 79% of patients treated with the drug versus 5% of the placebo group, after 26 weeks.

AZ teased the results of CALYPSO a few months ago, without going into details, and waited until the European Congress of Endocrinology (ECE) this week to reveal the data, including a 52-week follow-up period that showed the benefits of treatment were maintained.

Immunogenicity at fault?

Trying to compare two studies with different protocols and patient populations can always be prone to misinterpretation, and AZ emphasised that CALYPSO is the largest phase 3 trial ever conducted in adult hypoparathyroidism and showed "meaningful and sustained benefits in calcium regulation, symptom burden, physical function and bone health" that were sustained for a year.

That said, the data reveal that eneboparatide caused immunogenic reactions in "the majority of patients," according to AZ, which added that this had resulted in "reduced treatment effects in some patients" that could be offset by giving supplements and raising the dose of the drug.

Immunogenicity leads to the creation of patient antibodies against the drug itself, reducing its ability to exert its pharmacological effects.

Gianluca Pirozzi, head of AZ's Alexion rare disease subsidiary, said that the results support "eneboparatide’s potential to address the broad burden of this complex rare disease and help close persistent gaps in care, given the limited treatment options available."

AZ also pointed to a beneficial impact of eneboparatide on normalising urinary calcium in patients with elevated levels at baseline, with 56.6% of patients seeing levels return to normal ranges at week 24 versus 20% of those in the control group.

That is an important result, as supplements can increase the risk of excess calcium in the urine, and in turn lead to progressive kidney dysfunction and failure from calcium deposition and kidney stones.

There has been no word from AZ on plans to file for approval of eneboparatide, which was the focus of the purchase of French pharma Amolyt two years ago for $800 million upfront and $250 million in potential milestones.

Yorvipath could also face competition from MBX Bio's canvuparatide (formerly MBX 2109), which is due to start a phase 3 trial later this year after hitting the mark in a phase 3 trial. Canvuparatide can be dosed subcutaneously once a week, while both Yorvipath and eneboparatide require a daily injection.

https://pharmaphorum.com/news/readout-azs-hypoparathyroidism-drug-raises-questions