Pepinemab Aids Cognition With Early Huntington’s 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 Huntington’s disease, not meeting a primary study goal. But data indicated that diagnosed patients in early disease stages, those with existing cognitive and functional impairments at the study’s start, did gain some significant benefit.

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

People with early manifest Huntington’s may benefit most from the investigational treatment, and trial findings “provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with [early-manifest Huntington’s disease],” the researchers wrote.

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the study,”Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: a randomized, placebo-controlled, phase 2 trial,” was published in Nature Medicine.

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

Pepinemab aims to prevent damaging changes to brain

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

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 or early manifest Huntington’s disease. Its first part tested six once monthly pepinemab infusions against a placebo in 36 patients. Findings here, reported before the trial’s end, indicated that pepinemab could improve brain metabolism, prevent brain shrinkage, and ease motor and cognitive symptoms relative to the placebo.

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

Participants in both groups had been randomized to monthly into-the-vein infusions of pepinemab at 20 mg/kg or to a placebo for 18 months, followed by a three-month check for safety.

Treatment was generally safe and well-tolerated, with no overall differences in the frequency of adverse events reported between the pepinemab or placebo groups. Most treatment-emergent events were deemed mild or moderate by study investigators.

The trial had two primary efficacy goals, both assessed in the 179 people with an early-stage Huntington’s diagnosis. One goal looked at changes from study start 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 goal was score changes on the Clinical Global Impression of Change (CGIC), which evaluates changes in planning ability and memory associated with disease progression.

Top-line SIGNAL trial data, reported in late September 2o2o, indicated that pepinemab-treated people with early Huntington’s tended to show greater cognitive improvements from measures taken at the study’s start (baseline) than those in the placebo group. But these differences were not statistically significant, meaning they could be due to chance, and the trial failed to meet its primary efficacy endpoints.

Details of SIGNAL trial benefits seen with diagnosed Huntington’s

Further analyses, however, suggested that cognitive gains were significant among the subset of these early-stage patients with baseline cognitive impairments, 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 were seen in patients with normal cognitive abilities at the study’s start regardless of pepinemab or placebo assignment. Significant differences, however, were observed among pepinemab-treated patients who began the trial with “some degree of cognitive deficit” — MoCA scores below 26 — relative to those also with such deficits on a placebo.

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

Similarly, no differences in CGIC scores between pepinemab and placebo were observed for patients with normal functional abilities, ranging from managing personal finances to self-care and daily life activities, at the start of the study. But among those with baseline functional impairments, fewer pepinemab-treated patients experienced CGIC declines — reflective of disease progression — during the study.

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

Additional exploratory cognitive measures also tended to show improvements in the pepinemab group relative to placebo. Few patients given pepinemab reported apathy, a behavioral symptom of Huntington’s that has been linked to cognitive declines.

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

MRI scans showed evidence that pepinemab significantly prevented brain atrophy, or tissue loss, relative to a placebo among the early Huntington’s patients. Further, while an expected decline in metabolic activity across several brain regions was observed among placebo-treated patients, those given pepinemab showed increased metabolic activity in most evaluated brain regions.

Differences in cognition, apathy, brain atrophy and metabolism were not observed among prodromal patients.

Combined with the finding that early Huntington’s patients with existing cognitive impairments were most likely to benefit from the treatment, these data suggest pepinemab may target cellular processes not yet disturbed very early in disease, the researchers suggested.

SIGNAL trial results, while failing at a primary efficacy goal, overall “encourage continued development of pepinemab,” the researchers concluded, noting that patients with evident cognitive and functional difficulties may stand to benefit most from the treatment.

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

Of note, researchers at Vaccinex took part in this study, which was led by investigators working SIGNAL trial sites and others at scientific institutions.

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