Sign up to resume Huntington's gene therapy trial |...

Sign up to resume Huntington’s gene therapy trial |…

A data safety monitoring board has recommended that enrollment of the highest dosage group be resumed in the European Phase 1/2 trial of AMT-130 in people with Huntington’s disease, but with additional security measures in place.

UniQure, the developer of the investigational treatment, announced in August that enrollment in this high-dose group was voluntarily halted after unexpected side effects were reported in three patients shortly after receiving the treatment.

The reactions, which occurred in two patients included in the open-label European trial (NCT05243017) and one in a US placebo-controlled trial (NCT04120493), were not seen in patients treated with a lower dose.

Now, after reviewing all available safety, biomarker and imaging data from both trials, the committee has recommended that treatment continue, but with additional clinical visits and other measures to ensure participant safety. .

The European trial is still recruiting participants at sites in Germany, Poland and the UK

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“Patient safety will always be our top priority, and we are grateful for the close collaboration between our clinical team, the study investigators and, most importantly, the patients, who have all been instrumental in achieving of our thorough investigations,” Matt Kapusta, CEO of uniQure, said in a company press release. “We look forward to completing patient enrollment in the higher dose cohort of the European study in the first half of 2023 and remain on track to announce data from the US Phase I/II study in the second quarter of 2023. .”

In Huntington’s disease, mutations in the huntingtin leads to an abnormal form of the protein huntingtin building up to toxic levels inside nerve cells, disrupting their function.

AMT-130 is designed to stop the production of this abnormal protein by binding to and causing the breakdown of a template molecule, called mRNA, which carries the genetic information needed to make it. The treatment is given via a single infusion directly into an area of ​​the brain called the striatum, which is particularly affected by Huntington’s disease.

The European trial was designed to test two doses of AMT-130 in 15 early Huntington patients, six who would receive the low dose (6 x 10^12 vector genomes) and nine a high dose (6 x 10^13 vector genomes).

At the time of the break, all six patients had been treated with the lowest dose and four had received the highest dose.

In the US trial, which was already fully enrolled at the time of the break, participants were placed in one of two dosing groups. In the low-dose group, six people received AMT-130 and four received mimic surgery. Of those in the high dose group, 1o received AMT-130 and six the sham procedure.

The primary objective of both studies is to assess the safety and tolerability of AMT-130.

Changes in levels of mutant huntingtin and neurofilament light chain (NfL), a biomarker of nerve cell damage, will be measured in blood and cerebrospinal fluid (CSF) that surrounds the brain and spinal cord . Disease progression, quality of life and imaging data are also collected.

Side effects reported with AMT-130

In July, uniQure reported to health authorities that three of the 14 people who had so far received the high dose had serious adverse effects, leading to the pause in enrollment in the European trial.

Two patients in Europe had localized inflammatory responses and associated symptoms. Severe headache and associated symptoms in one patient in the US trial were initially deemed unrelated to treatment and later reclassified as a severe reaction to AMT-130.

All three patients have since recovered.

Just before the break, uniQure announced positive preliminary results from the US study, which showed that the low dose was generally well tolerated and led to a 53.8% reduction in CSF mutant huntingtin levels after a year in four patients with evaluable data.

Additionally, while NfL levels initially increased after surgery in treated patients, they returned to near pre-surgical levels after one year, while levels remained stable for those who underwent sham surgery.

Participants continue to be followed for four additional years of follow-up. According to uniQure, a participant who originally had the sham surgery has since crossed over and received the low dose of AMT-130.

“We believe AMT-130 has the potential to positively impact patients with this devastating disease for which there are currently no approved treatments,” Kapusta said.

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