Pepinemab helps cognition in early Huntingtons in SIGNAL trial | Post-hoc analysis supports phase 3 trial in diagnosed patients

A phase 2 trial of pepinemab failed to significantly improve certain cognitive abilities in people with prodromal-to-early-onset Huntington’s disease, failing to meet a primary study objective. But the data indicated that patients diagnosed in the early stages of the disease, those with cognitive and functional impairment at the start of the study, achieved significant benefits.

Pepinemab also prevented brain tissue loss and increased metabolism in this early Huntington’s group, but not in patients in the prodromal or pre-diagnosis phase of the disease. It was found to be generally safe and well tolerated in the treated groups.

People with early-stage Huntington’s disease could benefit the most from the experimental treatment, and the trial results “provide rationale and direction for the design of a Phase 3 study and encourage further development of the drug.” pepinemab in patients diagnosed with [early-manifest Huntington’s disease]“, wrote the researchers.

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The study, “Blockade of SEMA4D by pepinemab antibodies in early Huntington’s disease: a randomized, placebo-controlled phase 2 trialwas published in natural medicine.

Pepinemab is being developed by Vaccinex to treat Huntington’s disease and other neurological disorders. It is designed to block the activity of SEMA4D, a signaling molecule present at higher levels in the brains of people with Huntington’s disease.

Pepinemab aims to prevent damaging brain changes

The drug is thought to work in part by normalizing the function of a set of brain support cells called astrocytes, thereby preventing the blood vessel, metabolic and inflammatory changes that contribute to nerve cell loss in Huntington’s disease.

The two-part Phase 2 SIGNAL trial (NCT02481674), which concluded in August 2020, evaluated the safety, tolerability, and potential efficacy of pepinemab in adults with late prodromal Huntington’s disease or early manifest. Its first part tested six monthly infusions of pepinemab against a placebo in 36 patients. The results here, reported before the trial ended, indicated that pepinemab may improve brain metabolism, prevent brain shrinkage, and relieve motor and cognitive symptoms compared to placebo.

Now, a research team has analyzed data in people from the second part of the trial, including post-hoc analyzes of early-stage patients with and without obvious cognitive or other problems. The second part of SIGNAL recruited 256 people at 30 sites in the United States and Canada – 179 with early-stage Huntington’s disease and mild to moderate functional impairments, and 86 with prodromal disease. Prodromal patients tested positive for the mutation that causes Huntington’s disease, but did not yet have motor symptoms warranting a diagnosis of Huntington’s.

Participants in both groups were randomized to receive monthly intravenous infusions of pepinemab 20 mg/kg or placebo for 18 months, followed by a safety check for three months.

The treatment was generally safe and well tolerated, with no overall difference in the frequency of adverse events reported between the pepinemab and placebo groups. Most treatment-related events were rated as mild or moderate by study investigators.

The trial had two main efficacy goals, both of which were assessed in the 179 people with an early-stage Huntington’s diagnosis. One of the objectives examined changes from baseline in cognition with treatment using two components of the Huntington’s Disease Cognitive Assessment Battery (HD-CAB), one a test of executive function and the other an assessment of timing and psychomotor coordination. The other efficacy endpoint was changes in score on the Clinical Global Impression of Change (CGIC), which assesses changes in planning ability and memory associated with disease progression.

Data from the front-line SIGNAL trial, reported in late September 2o2o, indicated that pepinemab-treated people with early-onset Huntington’s disease tended to show greater cognitive improvements from measurements taken early in the study (baseline) than those of the placebo group. But these differences were not statistically significant, meaning they could have been due to chance, and the trial did not meet its main efficacy endpoints.

Details of SIGNAL trial benefits seen with diagnosed Huntington’s disease

Other analyses, however, suggested that cognitive gains were significant among the subset of these early-stage patients with baseline cognitive impairment, as assessed by the Montreal Cognitive Assessment (MoCA). On this 30-point scale, people with scores of 26 or higher are considered to have normal cognition, while those with scores below 26 are considered impaired.

Little difference in HD-CAB scores was seen in patients with normal cognitive abilities at study entry, regardless of pepinemab or placebo assignment. Significant differences, however, were seen among pepinemab-treated patients who entered the trial with “some degree of cognitive impairment” – MoCA scores below 26 – compared to those who also had such deficits on placebo.

“There was a consistent decline in HD-CAB scores in the placebo group over 18 months of treatment,” the researchers noted, while these scores “in the pepinemab group did not fall below baseline at any time. moment”.

Similarly, no differences in CGIC scores between pepinemab and placebo were observed in patients with normal functional abilities, ranging from managing personal finances to self-care and activities of daily living, at the start of the study. But among those with baseline functional impairment, fewer pepinemab-treated patients experienced declines in CGIC – reflecting disease progression – over the course of the study.

“This is consistent with the hypothesis that potentially greater treatment benefit may be detected in subjects with somewhat more advanced disease and could be an important consideration in the design of further studies,” the authors wrote. researchers, noting that their post-hoc analyzes were in smaller groups of patients than the trials’ initial analyses.

Additional exploratory cognitive measures also tended to show improvements in the pepinemab group compared to placebo. Fewer patients who received pepinemab reported apathy, a behavioral symptom of Huntington’s disease that has been linked to cognitive declines.

Pepinemab did not outperform placebo on measures of motor performance. “It is possible that later stages of motor progression are affected by treatment but may be less important” in patients with mild to moderate disease, the team noted.

MRI scans showed that pepinemab significantly prevented brain atrophy, or tissue loss, compared to a placebo in early Huntington patients. Additionally, while an expected decline in metabolic activity in several brain regions was observed in placebo-treated patients, those who received pepinemab showed increased metabolic activity in most brain regions assessed.

No differences in cognition, apathy, brain atrophy and metabolism were observed in prodromal patients.

Combined with the finding that early Huntington patients with existing cognitive impairment were the most likely to benefit from treatment, these data suggest that pepinemab may target previously unperturbed cellular processes very early in the disease, the researchers suggested.

The results of the SIGNAL trial, while failing a primary efficacy endpoint, “overall encourage the continued development of pepinemab,” the researchers concluded, noting that patients with clear cognitive and functional difficulties may benefit the most. of the treatment.

“Key observations suggesting a trend of benefit…collectively suggest clinically relevant changes in patients with early-stage Huntington’s disease,” the scientists concluded.

It should be noted that Vaccinex researchers participated in this study, which was led by researchers working at SIGNAL trial sites and others at scientific institutions.

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