The U.S. Food and Drug Administration granted Rare Pediatric Disease designation to Rezolute for RZ358, a potential treatment for congenital hyperinsulinism, an ultra-rare, genetic, endocrine disorder in which the pancreas secretes excess insulin.

Caused by at least 10 known genetic mutations, congenital hyperinsulinism (HI) appears in 1 in 25,000 to 1 in 50,000 live births, with a greater prevalence in certain populations such as among Ashkenazi Jews. Congenital HI is characterized by excess insulin secretion, which causes repeated episodes of low blood sugar, or hypoglycemia. The condition often goes unnoticed in infants, putting them at risk of complications of recurring hypoglycemic events, including developmental delays, seizures, coma and even death.

There are currently no approved therapies specifically for congenital HI and existing medical options are often sub-optimal, ineffective in some groups, or associated with substantial side effects that discourage compliance.

RZ358, a human monoclonal antibody, is designed to restore healthy levels of insulin action. The drug binds to an allosteric site on the insulin receptor to counteract the effects of elevated insulin at its target tissues by diminishing the binding and downstream signaling of insulin at its receptor. This unique mechanism of action gives properties of reversibility and graded activity, which are dependent on the extent of insulin elevation.

Rezolute began a four cohort, global, multi-center, open label phase 2b study of RZ358 in pediatric patients with congenital HI who are at least two years old in February 2020, and dosed its first patient just a few weeks before the full weight of the Covid-19 pandemic was felt around the world.

“Like most of us in the world, clinical studies hit a strong pause given the demand and burden within hospitals,” said Nevan Elam, CEO of Rezolute. While we had the first patient enrolled and receiving treatment, we just paused.”

Fortunately for the company, the pandemic hit at the beginning of the trial rather than midstream, so it has just lost time. Rezolute plans to resume the study this summer and still plans to complete it in the first half of 2021 with topline data in the second half of next year.

“What we are seeing now is a phased in approach as different regions in the world open up,” said Elam. “Because we are in 10 different countries, we see differences in the various regions and we hope we will benefit from that when we resume the study.”

Elam says there is a lot of interest from key opinion leaders in studying RZ358, as well as from families.

“Because it is an ultra-rare disease, the families are keenly aware that the therapy we are bringing forward has the potential to significantly alter the treatment modality for the children and there is a lot of interest in participating in the study,” he said. “Having said that, one of the things we have to observe and will have to be sensitive to in conducting this study is having patients, in particular children, participate while we are still riding alongside the pandemic. That is probably the single greatest unknown.”

The phase 2b study will evaluate four sequential ascending dose cohorts of six to eight patients with congenital HI greater than 2 years old, with a primary endpoint of time in glycemic range assessed by continuous glucose monitoring (CGM), and secondary endpoint assessments by CGM, blood glucometer, and modified overnight fasting.

The FDA grants Rare Pediatric Disease designation for serious or life-threatening diseases with manifestations in individuals aged from birth to 18 years, including access to the FDA’s expedited review and approval process. The designation makes RZ538 eligible for a Rare Pediatric Disease Priority Review voucher upon approval of the therapy by the FDA.

The vouchers can be used to reduce the time of an FDA new drug approval review to six months from ten months. The vouchers are potentially lucrative because they are transferable. Most recently, Sarepta sold its priority review voucher to Vifor Pharma $111 million in February 2020.

RZ358 has also received Orphan Drug designation in the United States and European Union.

Photo: Nevan Elam, CEO of Rezolute

Editor’s note: This story was updated to correct the most recent sales of a priority review voucher.

 

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