NEW YORK – Despite interim Phase I/II clinical trial data that made market analysts skittish, UniQure on Wednesday said it will start making late-stage development plans for its Huntington's disease gene therapy with regulators.
The candidate, AMT-130, is a gene therapy that uses an adeno-associated virus type 5 vector to deliver an artificial microRNA designed to silence the huntingtin gene and inhibit production of the mutant huntingtin protein. According to Amsterdam-based UniQure, the gene therapy has been generally well tolerated and appeared to preserve clinical function in Huntington's disease patients in the Phase I/II trial.
"We're very encouraged by these interim clinical results," Ricardo Dolmetsch, UniQure's president of R&D, said on a call with market analysts and investors Wednesday. "There's an early indication of a potentially positive clinical effect in this relatively small group of patients treated with AMT-130 with one and two years of follow-up."
The company is planning to begin late-stage clinical trial discussions with regulators early next year.
However, investors appeared skeptical after seeing inconsistent biomarker data readouts from the trial's high-dose cohort. On Wednesday, the company's stock price on the Nasdaq hit a 52-week low of $10.51, and though it regained a little ground to close at $11.62, that was still 40 percent below Tuesday's close.
There were 10 patients with early-manifest Huntington's disease in the low-dose cohort of the study and 16 patients in the high-dose cohort; all patients received either AMT-130 or a placebo imitation surgery. Participants were blinded for one year in the core study and were unblinded during the five-year follow-up period.
Clinical function was generally preserved for patients receiving low-dose AMT-130 after 24 months compared to baseline measurements; the same was true for those in the high-dose treatment cohort at 12 months.
Patients in the low-dose cohort reported benefits on various clinical function measurement scales including a 1.8-point mean improvement in the Total Motor Score; a mean improvement of 0.8 points in Total Functional Capacity; and a mean improvement of 0.9 points in the composite Unified Huntington's Disease Rating Scale at 24 months compared to the natural history cohort developed by UniQure. At 12 months, patients in the high-dose cohort experienced mean improvements of 2.7 points, 0.5 points, and 1 point in these respective scales.
In the control group, patients experienced worse Total Motor Score at 12 months compared to baseline and the natural history cohort, but Total Functional Capacity and composite Unified Huntington's Disease Rating Scale were preserved.
Investigators also evaluated multiple biomarkers, including neurofilament light chain (NfL), which is associated with neurodegeneration. NfL is also the surrogate endpoint upon which the US Food and Drug Administration recently granted accelerated approval to Biogen's Qalsody (tofersen) for a genetic form of amyotrophic lateral sclerosis; the drug showed in clinical trials that it reduced NfL levels in patients.
"Our view is that neurofilament light [chain], which … has been viewed by the FDA as a potential surrogate endpoint, in conjunction with supportive trending clinical data, can serve as the basis of an accelerated approval," UniQure CEO Matt Kapusta said on the call, hinting at one possible regulatory path forward.
Patients treated with UniQure's AMT-130 experienced temporary increases in NfL after treatment, suggesting worsening neurodegeneration in the wake of the neurosurgical procedure to administer the therapy delivered directly to the brain. That trend later reversed for many patients, and in the low-dose treatment cohort, mean NfL was 12.9 percent below baseline at 24 months.
However, NfL levels in the high-dose treatment cohort were variable. At 12 months, patients experienced a mean increase of 51.5 percent compared to baseline, although NfL levels were declining toward baseline, according to Dolmetsch. Four of eight high-dose treatment patients who had at least 12 months of follow-up had lower NfL levels compared to baseline, he added.
"This is significant, because it suggests that we may be having an effect on disease progression," Dolmetsch said.
Similar trends were observed when measuring mutant huntingtin protein (mHTT). In the low-dose treatment cohort, mHTT was lower than what it was at baseline with a mean reduction of 8.1 percent at 24 months. However, in the high-dose treatment cohort, there was a mean increase of 39.7 percent compared to baseline at 12 months. The control group experienced a 4.7 percent increase in mHTT at 12 months.
Since the drug is administered into a relatively small region of the brain, it's possible mHTT is lowered there, but not at a level to be detected by assays measuring mHTT broadly, Dolmetsch said.
There were two serious adverse events, post-operative delirium and major depression, in the low-dose treatment cohort and one such event, back pain, in the high-dose treatment cohort. Investigators determined that none of the adverse events were due to AMT-130, however. There was one serious adverse event, deep vein thrombosis, in the control group.
"The treatment-emergent adverse events were transient and were mostly related to the surgery or to the lumbar puncture," which was needed for the NfL cerebrospinal fluid analysis, Dolmetsch said. The most common adverse events in the treatment groups were procedural headache and procedural complications.
UniQure plans to enroll 10 more patients into a third cohort in the second half of the year to assess safety of both AMT-130 doses combined with perioperative immunosuppression.
On the heels of the interim study results, UniQure also said it plans to enroll 15 early-manifest Huntington's disease patients in an open-label Phase Ib/II study of AMT-130 in Europe. Six patients have already joined the low-dose cohort, and the company expects to enroll the remaining nine patients into the high-dose cohort in Q3.
Results from the US and EU trials will inform the optimal dose of AMT-130 for a Phase III study or confirmatory trial if UniQure decides to pursue accelerated approval, the company said. "We look forward to advancing clinical development and beginning discussions with regulators by early next year," Kapusta said.