Huntington's disease(Mitorx Therapeutics)

UniQure has been working on a gene therapy for Huntington’s disease for some time, and as the field has suffered through multiple failures, the company’s program has been set back. The biotech announced Monday morning that back in July, it had observed “suspected, unexpected severe adverse reactions”, or SUSARs, in two patients after they were treated with the “higher dose” of a gene therapy candidate, AMT-130, in a European Phase Ib/II clinical trial. A third patient, who was treated back in March in the US, had their side effect deemed not related to the candidate, but it then was reclassified as a severe adverse reaction after review. As a result, it’s halted dosing in the high dose cohort. Execs said that the FDA and EMA had been notified, but no specific dialogue has been made with those agencies yet. Execs added in a conference call Monday morning they decided to pause dosing after consulting with the trial’s independent data safety monitoring board (or DSMB). “The DSMB does not view these events as a dose-limiting toxicity and thus far in our investigation, we have not yet identified the root cause of these events,” uniQure execs said on the conference call. They added that they have started a safety review that is expected to end in Q4 this year, and are considering potential risk mitigation plans over the next 2-3 months. Shares for the gene therapy biotech suffered after the announcement, with $QURE down more than 30% so far on the Nasdaq. The patients were hospitalized, with the US patient suffering severe headache and vomiting. They were admitted seven days after undergoing a procedure for the drug candidate, in which AAV is injected into the striatum, a part of the brain linked to the basal ganglia and Huntington’s disease, via 3 holes over a matter of several hours. The patient’s hospital admission was originally determined to be related to the procedure, not the drug. After being treated with analgesics and a diagnostic lumbar puncture, the patient was discharged and then returned to the hospital two days later with a recurring headache, attributed to a leak of cerebrospinal fluid after that lumbar puncture. The patient was treated with a blood patch (blood injected into the spinal canal to patch the leak) and then has fully recovered, according to the biotech. For the patients in Europe, it was a similar story. Both of those patients were admitted to the hospital around 12 days after the procedure, with the first patient experiencing what the biotech described as “motor and other vital symptoms.” That patient is still reported to have small deficits in fluency, memory and attention. The second European patient reported vomiting and raised intracranial pressure, being admitted around 12 days after that patient’s procedure. Following admission, the patient was found to have papilledema, or optic disc swelling, but no edema (aka swelling) in the striatum along the tracks of the holes drilled into the brain. That patient received prophylactic antibiotics and a lumbar puncture to remove 20 cc’s of cerebral spinal fluid — which led to symptoms resolving and the patient was then discharged. The company is keeping its research at the lower dose of the gene therapy ongoing, as CEO Matt Kapusta and head of R&D Ricardo Dolmetsch tell Endpoints News that no SAEs had been reported at that dose. “The event really is something that happens acutely, when you infuse somebody with a gene therapy. We think it only happens at our high dose. Because we never saw it at a low dose,” Dolmetsch told Endpoints. The biotech’s R&D chief went on to say that so far, the company thinks that the most likely thing is something unique to the patients, but they don’t know for sure, yet. Kapusta reiterated to Endpoints that this setback would not impact the company’s planned data disclosures, scheduled for 2023. So far, the biotech had enrolled 36 patients, 26 dosed with the candidate (low and high dose) and 10 on placebo with up to 1-2 years of follow-up data. All but 5 patients in the high-dose cohort have already been dosed. The hunt for a working treatment for Huntington’s disease has been a proverbial minefield. The genetic disease where nerve cells begin to break down in people in their 30s and 40s has so far stumped many a biotech and pharma — such as Roche last year, when it stopped dosing of tominersen in its Phase III, Ionis-partnered trial after the high dose made patients’ disease even worse. Days after that development, Wave Life Sciences also reported the failure of its Huntington’s candidate, sending the company’s share price down 28% in the immediate aftermath of the news.