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UniQure Postpones High Dose Study of Huntington’s Disease Drug

August 9, 2022

UniQure said it is postponing the study of its higher dose gene therapy for Huntington’s disease due to recent unexpected severe adverse reactions at this dose.

Photo: Matt Kapusta, CEO at UniQure

Shares dropped 30 percent on the announcement, made in its second quarter earnings report. UniQure said 12-month data on lower dose study of AMT-130 in Huntington’s disease, which was not affected by the postponement, showed the experimental gene therapy was generally well tolerated with a mean reduction of 53.8 percent of mutant Huntingtin protein (mHTT) observed in cerebral spinal fluid. The company anticipates data readouts in 2023.

“We continued to make strong progress across all of our programs highlighted by encouraging data from the lower-dose cohort in our phase 1/2 study of AMT-130 and the advancement of the U.S. and European regulatory reviews for the marketing applications for etranacogene dezaparvovec in hemophilia B,” said Matt Kapusta, CEO at UniQure. “In July, we reported to the health authorities suspected unexpected severe adverse reactions in three of the 14 patients treated with the higher dose of AMT-130,” he continued. “While these patients have fully or substantially recovered, and no clear root cause has yet been identified, we believe it’s prudent to temporarily delay additional higher-dose procedures until we put additional monitoring and treatment plans in place and complete our safety review early in the fourth quarter of 2022.”

Huntington’s disease (HD) is a rare, fatal, neurodegenerative genetic disorder that affects motor function and leads to behavioral symptoms and cognitive decline in young adults, resulting in total physical and mental deterioration. HD is caused by the expansion of CAG trinucleotide in exon 1 of a multifunctional gene coding for protein called huntingtin. Huntington’s disease affects approximately 70,000 people in the United States and Europe, making this one of the largest clinical unmet needs in the rare disease field. There are no therapies available to treat the disease, delay its onset, or slow the progression of a patient’s decline.

UniQure’s gene therapy product candidate AMT-130 consists of an AAV5 vector carrying an artificial micro-RNA specifically tailored to silence the huntingtin gene, leveraging the company’s proprietary miQURE silencing technology. The therapeutic goal is to inhibit the production of the mutant protein (mHTT). Using AAV vectors to deliver micro-RNAs directly to the brain for non-selective knockdown of the huntingtin gene represents a highly innovative and promising approach to treating Huntington’s disease.

In mid-July, UniQure reported to the appropriate regulatory agencies suspected unexpected severe adverse reactions (SUSARs) in two patients that were treated with the higher-dose of AMT-130 at a single clinical site in the European phase 1b/2 study. Both patients presented with localized inflammatory responses and other related symptoms approximately one to two weeks after their procedures. A third patient, who had previously been treated with the higher-dose of AMT-130 in the United States during March 2022, experienced severe headache and other related symptoms soon after AMT-130 administration that was initially deemed by the investigator as not related to AMT-130 but related to the procedure. Upon further review and discussion with the clinical trial’s independent Data Safety Monitoring Board following the events observed in the European study, the company has reclassified and reported the patient reaction in the U.S. trial as a SUSAR. All three patients have fully or substantially recovered after treatment and have been released from the hospital.

At this time, the Data Safety Monitoring Board does not view these findings as a dose-limiting toxicity. The DSMB has recommended temporarily delaying higher-dose enrollment pending a safety review, which is expected to take place early in the fourth quarter of 2022. The Data Safety Monitoring Board is permitting continued enrollment at the lower-dose of AMT-130, and the company expects to begin crossing over control patients from the U.S. study at this dose in the third quarter of 2022.

No impact is expected on the timing of previously guided data read-outs in 2023. In the United States phase 1/2 study, all 26 patients in the first two dose cohorts have been enrolled, and the company continues to expect to present one to two-year follow up data in the second quarter of 2023. In the European phase 1b/2 study, the six-patient lower-dose cohort is fully enrolled and the company continues to expect to present one-year follow-up data in 2023. Four of nine patients in the European study have been enrolled in the higher-dose cohort. To date, a total of 36 patients have been enrolled across the two clinical trials including 10 control patients and 26 patients treated with AMT-130, of which 14 patients received the higher-dose and 12 patients received the lower-dose.

Author: Rare Daily Staff

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