Gene Therapy Pioneer uniQure Faces Market Skepticism Amid Clinical Data Confusion and $317M Market Cap

On December 19, gene therapy company uniQure updated and announced interim data from its European Phase I/II clinical trial of the gene therapy AMT-130 for Huntington’s disease, with data derived from a 30-month follow-up of 39 patients.

Walid Abi-Saab, Chief Medical Officer at uniQure, stated, “Based on the evaluation of trends from clinical study data, AMT-130 appears highly promising. Patients with Huntington’s disease have demonstrated efficacy and stability following treatment with this one-time gene therapy, with some patients now having been followed for more than two years. Compared to a natural history control group matched using asynchronous standards, we observed favorable trends with AMT-130 in motor skills, functional independence, and composite scores.”

Although uniQure expressed optimism about the updated data, Wall Street analysts remained unconvinced. They identified confusing aspects in the new results. For instance, while the study is evaluating the efficacy of two doses of AMT-130, the lower dose appears to be more effective and exhibits less variability than the higher dose. Meanwhile, the duration of efficacy for both doses remains unclear.

uniQure’s AMT-130 is undergoing industry scrutiny and rigorous examination. Following the release of the latest clinical data, uniQure’s stock price fell by 10%, dropping below $7 per share, with a market capitalization of $317 million.

Latest Data on AMT-130

Huntington’s disease is a rare hereditary neurodegenerative disorder characterized by choreiform involuntary movements, accompanied by progressive cognitive and psychiatric impairments and dementia. This autosomal dominant genetic disorder is caused by mutations in the huntingtin (HTT) gene, which lead to misfolding of the HTT protein. The misfolded proteins aggregate within the nuclei of neuronal cells in the brain, resulting in neurodegeneration. Although the etiology of Huntington’s disease is well established, there are currently no approved therapies capable of delaying onset or slowing disease progression.

uniQure’s AMT-130 is an adeno-associated virus serotype 5 (AAV5)-based gene therapy designed to silence the mutant HTT gene. It produces a microRNA that inhibits the production of the defective HTT protein. AMT-130 is uniQure’s first clinical program focused on central nervous system (CNS) diseases and one of its most closely watched projects.

Since mid-2020, uniQure has been conducting Phase I/II studies of AMT-130 in the United States and Europe, respectively.

In the United States, based on this ongoing multicenter Phase I/II clinical trial, uniQure enrolled a total of 26 patients with early-stage Huntington’s disease, including an initial low-dose cohort of 10 patients (6 treated and 4 controls) with up to 30 months of follow-up, and a high-dose cohort of 16 patients (10 treated and 6 controls) with up to 18 months of follow-up. Patients were randomly assigned to receive either AMT-130 treatment or sham surgery.

In Europe, the Phase I/II clinical trial of AMT-130 enrolled a total of 13 patients with early-stage Huntington’s disease. Six patients received AMT-130 in the initial low-dose cohort, and seven patients received AMT-130 in the high-dose cohort.

Newly disclosed data show that patients receiving high-dose AMT-130 experienced preservation or improvement in neurological function 18 months after treatment, compared with baseline. This was measured using a rating scale known as the cUHDRS, which assesses motor, cognitive, and behavioral functions in patients with Huntington’s disease.

In the low-dose cohort, assessments using the Total Functional Capacity (TFC) and Total Motor Score (TMS) scales demonstrated that neurological function was preserved at 30 months following AMT-130 treatment.

Meanwhile, across all three rating scales, treatment with AMT-130 demonstrated a “favorable trend” compared with the natural history control group. This natural history cohort, established by uniQure with assistance from a nonprofit research organization, comprised 31 patients with early-stage Huntington’s disease who were similar to those enrolled in the AMT-130 study. uniQure leverages natural history data to better understand disease progression in the absence of intervention.

Given the design of AMT-130, uniQure is also measuring biomarkers for this disease. The study has been quantifying the levels of mutant huntingtin protein (mHTT) present in the cerebrospinal fluid surrounding the brain and spine.

uniQure stated that the average change in mHTT “remains variable,” and the company claimed that, because AMT-130 is administered deep within the brain, this measurement is not considered to substantially represent mHTT levels in the target brain regions. Previously, the company disclosed that mHTT levels differed between the two dose groups in the study. In the low-dose group, they decreased by an average of 8% after two years of treatment, whereas in the high-dose group, they increased by an average of 40% after one year of treatment.

uniQure’s research also mapped levels of “neurofilament light chain,” a molecule shown to indicate the extent of damage to the brain and nervous system. The study revealed that after 30 months of treatment, average levels of this molecule decreased by 6.6%. In the high-dose group, levels returned close to baseline by month 18.

Regarding safety, uniQure reported four serious adverse events in the high-dose cohort that were considered related to AMT-130. Three cases involved central nervous system (CNS) inflammation, and one case involved severe headache, which was subsequently also attributed to CNS inflammation. Patients experiencing these inflammatory symptoms improved after treatment with glucocorticoids. Six patients in the high-dose cohort received perioperative steroid therapy during AMT-130 administration to mitigate the risk of inflammation.

Why Is the Market Unresponsive?

Regarding the newly disclosed data, Edward Wild, lead investigator at University College London, stated that one thing is clear: any recommendation that improves or delays the progression of Huntington’s disease is good news for patients. Executives at uniQure have also been encouraged by the clinical data to date.

However,Wall Street analysts have raised questions about these data, stating in Mizuho Securities’ recent report on the June clinical data for AMT-130 that the current clinical studies appear to be “more qualitative than quantitative.” Mizuho also pointed out that the inconsistent trends between the low-dose and high-dose groups observed in the June data were likewise present in this latest data update.

Market skepticism regarding the AMT-130 data also stems from the clinical data released by uniQure this June.

In June 2023, uniQure announced interim data from the Phase I/II clinical trial of AMT-130 in the United States. The clinical trial data showed that mHTT levels in patients receiving the low dose began to rebound, while changes in mutant protein levels were more pronounced in the high-dose group, with a 40% increase in mutant protein levels one year after treatment.This set of data contradicts the positive figures released in June 2022.

In June 2022, early study results released by uniQure showed that mHTT protein levels decreased by approximately 50% in patients receiving the low dose of AMT-130 after one year of treatment. A comparison with data announced in June 2023 revealed that mHTT levels in this low-dose cohort rebounded over two years, ending up only 8% lower than baseline.Analysts have raised doubts, describing the data set as “confusing.” The December update still fails to dispel concerns surrounding the June data.

Therefore, in stark contrast to the euphoric surge of nearly 20% in its stock price when the data were announced in 2022, uniQure’s shares plummeted 40% this June, hitting a six-year low and closing at $12.

In fact, the clinical trials of AMT-130 have not been smooth sailing.

In August 2022, uniQure disclosed serious adverse events associated with AMT-130 in its Q2 earnings report. Three patients were hospitalized due to severe side effects following treatment; these three cases occurred among patients who received higher doses of AMT-130 in the Phase I/II clinical trial.

Three hospitalized patients presented with multiple symptoms, but all experienced nausea or vomiting. Two of these cases occurred in Europe. The first patient was hospitalized due to fever, vomiting, mania, and involuntary limb movements. Magnetic resonance imaging (MRI) revealed swelling in certain regions of the treated patient’s brain. Another patient reported similar vomiting and other symptoms during hospitalization and was diagnosed with ocular swelling associated with elevated intracranial pressure and cerebrospinal fluid pressure. The last case occurred in the United States, where a patient was hospitalized twice weekly due to severe headaches and was subsequently reclassified as an adverse event. After the second hospitalization, a cerebrospinal fluid leak was identified as being triggered by the lumbar puncture required for the trial. Although the patient made a full recovery, follow-up MRI still showed residual pressure in certain areas of the treated brain.

uniQure therefore postponed further studies on the high-dose cohort while investigating the causes of the adverse events. Following the decision to partially suspend the clinical trial, the company’s stock price fell 32.5%, from $25.54 per share to $17.25. The clinical trial was not resumed and advanced until November 2022.

Therefore,Despite uniQure’s confidence in the therapeutic potential of AMT-130, market skepticism is evident. This stems from the subpar and difficult-to-interpret clinical data released this June, the failure of the latest data update to alleviate market confusion, and the fact that more critical efficacy data for AMT-130 have yet to be released.

Nevertheless, uniQure continues to advance AMT-130. Abi-Saab stated that discussions with the FDA were expected in early 2024, during which the FDA would provide guidance on the next steps for the program.