Pepinemab Demonstrates Cognitive Benefit in Huntington Disease

Article

The results support continued development in Alzheimer disease and in patients with mid-stage Huntington disease who suffer from greater cognitive deficits.

Maurice Zauderer, PhD

Topline results from the early manifest treatment arm (Cohort B1; n = 179) of the phase 2 SIGNAL trial (NCT02481674) demonstrated that treatment with pepinemab (Vaccinex) benefitted cognitive change in patients with early manifest and prodromal Huntington disease (HD).1

Despite the study not meeting its pre-specified co-primary end points, the results of each of the 2 cognitive assessments demonstrated a strong trend for beneficial change on the One Touch Stockings of Cambridge (OTS; P = .028) and Practice Transition Accreditation Program (PTAP; P = .06) tests. Both cognitive assessments reflect changes in planning ability and memory associated with disease progression.

“The results reported today strongly support a cognitive benefit to treatment with pepinemab and indicate that treatment with pepinemab antibody potentially targets cortical centers, including those that govern cognition,” Maurice Zauderer, PhD, president and chief executive officer, Vaccinex, said in a statement. “We believe the data, therefore, suggest that patients at a somewhat more advanced stage of HD may derive the greatest benefit from pepinemab.”

There was no statistically significant difference between the placebo and pepinemab-treated groups in terms of the trend of benefit on the Clinical Global Impression of Change (CGIC), but investigators noted this could be caused by the small sample size for the phase 2 study.

Pepinemab, a humanized monoclonal antibody that binds and blocks the activity of semaphoring 4D (SEMA4D) was found to be well-tolerated with low treatment discontinuation and study drop-out rates over the extended 18-month treatment period.

Previously reported results of Cohort A, which evaluated the safety of pepinemab, met the primary end point. Additionally, those from Cohort A treated with pepinemab (n = 11) demonstrated an increase in fluorodeoxyglucose as measured by positron emission tomography (FDG-PET) in multiple cortical regions of interest compared to placebo (n = 8). The estimated difference between the mean FDG-PET index was 0.78 (±0.31; 95% CI, 0.11–1.40; P = .025).2

In addition to increases in FDG-PET, preservation of brain matter, represented by reduced atrophy, and improvement in multiple motor and cognitive assessments were also observed in Cohort A.

Participants in Cohort A were assigned randomly to receive either pepinemab 20-mg/kg or a placebo intravenously once a month for 6 months. After that, all patients received the therapy for an additional 5 months, followed by a 3-month safety follow-up period.

The design of Cohort B was informed by the results of Cohort A and enrolled 265 subjects, 179 early manifest patients and 86 late prodromal subjects for randomized treatment of at least 18 months duration.

Zauderer further noted that “the insights gained from this study also suggest that pepinemab might be an important treatment option for Alzheimer’s and other neurodegenerative diseases known to primary affect frontal cortex and to impact cognition. As previously reported, imaging data indicate that these are the brain regions most affected by pepinemab treatment.”

SEMA4D, which is blocked by pepinemab, can interact with astrocytes, impairing normal support functions such as glucose transport, which has had clear associations to Alzheimer disease (AD) brain pathology and symptoms. According to Vaccinex, the company intends to initiate the SIGNAL-AD trial (NCT04381468), a phase 1, placebo-controlled study of pepinemab for the treatment of Alzheimer disease (AD).3

There is also evidence suggesting pepinemab could serve as a potential treatment for disorders such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Vaccinex recently completed a phase 1, randomized, placebo-controlled, single-ascending dose study in 50 adult patients with MS. The therapy was found to be well tolerated among 40 patients treated with single doses of pepinemab ranging from 1 to 20 mg/kg.

Pepinemab was previously granted orphan drug and fast track designations in 2016.4,5

The company noted that additional results including a broader examination of motor activity and outcomes for a smaller group of 86 prodromal subjects will be reported at the upcoming 2020 Huntington’s Study Group Conference on October 30.

REFERENCES
1. Top-line results of the phase 2 SIGNAL study in Huntington’s disease support potential for cognitive benefit of pepinemab. News release. Rochester, NY: Vaccinex. September 22, 2020. Accessed September 22, 2020. https://www.biospace.com/article/releases/top-line-results-of-phase-2-signal-study-in-huntington-s-disease-support-potential-for-cognitive-benefit-of-pepinemab/
2. Vaccinex delivers virtual presentation at the Advances in Alzheimer’s and Parkinson’s therapies AAT-AD/PD Focus Meeting 2020. News release. Rochester, NY: April 7, 2020. Accessed September 20, 2020. https://www.globenewswire.com/news-release/2020/04/07/2012756/0/en/Vaccinex-Delivers-Virtual-Presentation-at-the-Advances-in-Alzheimer-s-and-Parkinson-s-Therapies-AAT-AD-PD-Focus-Meeting-2020.html
3. Pepinemab Neurology. Vaccinex website. http://www.vaccinex.com/pipeline/pepinemab-neurology/. Accessed September 22, 2020.
4. Vaccinex receives FDA fast track designation for VX15 antibody for the treatment of Huntington’s disease. News release. Rochester, NY: Vaccinex. August 1, 2016. Accessed September 22, 2020. http://www.vaccinex.com/vaccinex-receives-fda-fast-track-designation-for-vx15-antibody-for-the-treatment-of-huntingtons-disease/
5. Vaccinex receives orphan drug designation from US FDA for its lead antibody product candidate, VX15, as a potential treatment for Huntington’s disease. News release. Rochester, NY: Vaccinex. August 23, 2016. Accessed September 22, 2020. http://www.globenewswire.com/news-release/2016/08/23/866257/0/en/Vaccinex-Inc-Receives-Orphan-Drug-Designation-from-U-S-FDA-for-its-Lead-Antibody-Product-Candidate-VX15-as-a-Potential-Treatment-for-Huntington-s-Disease.html

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