A Study in Subjects With Late Prodromal & Early Manifest HD to Assess the Safety, Tolerability, pk, and Efficacy of Pepi

NCT02481674 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: VX15/2503-N-131
• Study Type: interventional
• Target: 301
• Locations: 2 countries
• Sites: 32

Brief Summary

The purpose of this study is to evaluate the safety, tolerability, PK, and efficacy of Pepinemab in subjects with late prodromal and early manifest Huntington's disease.

Conditions

Huntington's Disease

Keywords

Prodromal Stage; Early Manifest Stage

Outcome Measures

Primary Outcomes (3)

• Revisions to SAP were made prior to un-blinding, on June 30, 2020, upon consultation with FDA.

  If primary outcome, listed below (Outcome 3), does not reach its critical p-value, the secondary outcomes will not be formally tested. If both co-primary outcomes are statistically significant, the five secondary outcomes will be formally tested following a hierarchical testing procedure.

  Prior to DBL/Study Completion

• Safety and tolerability of monthly intravenous (IV) administration of pepinemab relative to placebo in subjects with early HD (Cohort B pooled, includes Cohort B1 Early Manifest and Cohort B2 Late Prodromal HD).

  Measured by drug related adverse event frequency and laboratory test abnormalities in all subjects.

  Up to 18 months

• Efficacy of monthly IV administration of pepinemab relative to placebo in Early Manifest HD (Cohort B1)

  Co-primary outcome measured by the change from baseline in the Huntington's Disease Two-item Cognitive Family (PTAP and OTS) selected from the Huntington's Disease

  Up to 18 months

Secondary Outcomes (5)

• Clinical feature of Early Manifest HD: motor function (Q-Motor)

  Up to 18 months

• Clinical feature of Early Manifest HD: functional capacity (UHDRS-TFC)

  Up to 18 months

• Clinical feature of Early HD: functional capacity (UHDRS-TFC)

  Up to 18 months

• Clinical Feature of Early HD: motor function (Q-Motor)

  Up to 18 months

• Clinical Feature of Early HD: cognition (Huntington's Disease Two-item Cognitive Family).

  Up to 18 months

Other Outcomes (18)

• Clinical feature of HD: cognition

  Up to 18 months

• Impact of monthly IV administration of pepinemab relative to placebo on change in brain metabolic activity

  Up to 18 months

• Impact of monthly IV administration of pepinemab relative to placebo on change in brain volume

  Up to 18 months

Study Arms (2)

VX15/2503

EXPERIMENTAL

The study drug VX15/2503 will be administered via monthly intravenous infusions

Drug: VX15/2503

Placebo

PLACEBO COMPARATOR

A placebo control will be administered via monthly intravenous infusions

Drug: Placebo

Interventions

VX15/2503 DRUG

VX15/2503 (pepinemab) is a humanized IgG4 monoclonal antibody and will be administered intravenously at a dose of 20 mg/kg. The antibody is formulated at 20 mg/mL in 20 mM Sodium Acetate buffer, pH 5.4, containing 130 mM Sodium Chloride and 0.02% Polysorbate 80.

Also known as: pepinemab

VX15/2503

Placebo DRUG

Placebo consists of formulation buffer only which is 20 mM Sodium Acetate buffer, pH 5.4, containing 130 mM Sodium Chloride and 0.02% Polysorbate 80.

Placebo

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female and are at least greater than or equal to 21 years of age at Screening.
• Must fulfill one of the following criteria at Screening:
• Late prodromal HD as defined by a CAP score of greater than 200 and DCL 2 or 3.
• Early manifest HD as defined by a TFC greater than or equal to 11. Subject must have been determined to have a clinical diagnosis of HD by the Site Investigator as defined by a DCL of 4.
• Must fulfill both of the following criteria at Screening:
• Have undergone genetic testing with a known CAG repeat greater than or equal to 36.
• No features of juvenile HD (Westphal variant).
• If female must be either surgically sterile, postmenopausal, or nonlactating and nonpregnant. Female subjects of childbearing potential must practice a highly effective method of contraception.
• If male, must agree to use a reliable method of birth control (condoms with contraceptive foams or sexual abstinence) during the study and for 6 months after the last dose of study drug.
• Are willing and capable of providing informed consent for study participation, CAG genotyping (all subjects).
• Are capable of reading, writing, and communicating effectively with others.
• Are taking stable doses of any concomitant medications (including tetrabenazine and deutetrabenazine) during the 1 month prior to the Baseline Visit, with the exception of newly prescribed anxiolytics for the use of pre-medication prior to imaging at screening, which will be permitted on a case-by-case basis.
• Must meet all criteria required to move forward with the Randomization Authorization Flow (RAF) and be considered eligible by the RAF Reviewer.

You may not qualify if:

• Have participated in an investigational drug or device study within 30 days of the Baseline Visit, or 180 days if previous investigational drug was a MAb therapeutic, or previously participated in SIGNAL Cohort A. This does not apply to Cohort B subjects who are being offered the option to participate in the extension of Cohort B.
• Have had previous neurosurgery for Huntington's disease or other movement disorders.
• Are a suicide risk, as determined by meeting any of the following criteria:
• suicide attempt within one year prior to Baseline.
• suicidal ideation as defined by a positive response to question 5 on the C-SSRS (Baseline visit form) suicidal ideation section, within 60 days of the Baseline Visit.
• significant risk of suicide, as judged by the site Investigator.
• Have marked cognitive impairment with a Montreal Cognitive Assessment (MoCA) Score less than or equal to 22.
• Have a presence of clinically significant psychosis and/or confusional states, in the opinion of the site Investigator.
• Have clinically significant laboratory or ECG abnormalities at Screening, in the opinion of the site Investigator.
• Have clinically relevant hematologic, hepatic, cardiac, or renal disease.
• Have a medical history of infection with human immunodeficiency virus, hepatitis C and/or hepatitis B, or found to have an abnormality at Screening.
• Have a history of substance abuse (based on DSMIV criteria) within the past 12 months prior to Screening.
• If female are pregnant or breastfeeding.
• Have a known allergy to any ingredient in the study drug.
• Have a history of malignancy of any type within 2 years prior to Screening. A history of surgically excised non-melanoma skin cancers, and superficial bladder or prostate cancer is permitted.

Sponsors & Collaborators

• Vaccinex Inc.: lead
• Huntington Study Group: collaborator

Study Sites (32)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

University of California, San Diego

La Jolla, California, 92037, United States

Location

University of California San Francisco

San Francisco, California, 94143, United States

Location

University of Colorado - Denver

Aurora, Colorado, 80045, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20007, United States

Location

University of Florida Gainesville

Gainesville, Florida, 32611, United States

Location

Emory University School of Medicine

Atlanta, Georgia, 30329, United States

Location

Indiana University School of Medicine

Indianapolis, Indiana, 46202, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

University of Louisville

Louisville, Kentucky, 40202, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21218, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Massachusetts General Hospital

Charlestown, Massachusetts, 02129, United States

Location

University of Michigan

Ann Arbor, Michigan, 48105, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Columbia University

New York, New York, 10027, United States

Location

Columbia University

New York, New York, 10032, United States

Location

University of Rochester

Rochester, New York, 14618, United States

Location

Duke University Health Center

Durham, North Carolina, 27705, United States

Location

Wake Forest University

Winston-Salem, North Carolina, 27157, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45267, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

University of Toledo

Toledo, Ohio, 43614, United States

Location

Vanderbilt University

Nashville, Tennessee, 37232, United States

Location

University of Texas Houston Medical School

Houston, Texas, 77030, United States

Location

University of Vermont

Burlington, Vermont, 05401, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

University of Washington and VA Puget Sound Health Care System

Seattle, Washington, 98195, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

University of Alberta

Edmonton, Alberta, T6G 2R3, Canada

Location

University of British Columbia

Vancouver, British Columbia, V6T 1Z4, Canada

Location

Centre hospitalier de l'Université de Montréal (CHUM)

Montreal, Quebec, H2X 0C1, Canada

Location

Related Publications (4)

• Southwell AL, Franciosi S, Villanueva EB, Xie Y, Winter LA, Veeraraghavan J, Jonason A, Felczak B, Zhang W, Kovalik V, Waltl S, Hall G, Pouladi MA, Smith ES, Bowers WJ, Zauderer M, Hayden MR. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol Dis. 2015 Apr;76:46-56. doi: 10.1016/j.nbd.2015.01.002. Epub 2015 Feb 3.

  PMID: 25662335 BACKGROUND

• Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington's Disease Clinical Trials Corner: November 2022. J Huntingtons Dis. 2022;11(4):351-367. doi: 10.3233/JHD-229006.

  PMID: 36463457 DERIVED

• Feigin A, Evans EE, Fisher TL, Leonard JE, Smith ES, Reader A, Mishra V, Manber R, Walters KA, Kowarski L, Oakes D, Siemers E, Kieburtz KD, Zauderer M; Huntington Study Group SIGNAL investigators. Pepinemab antibody blockade of SEMA4D in early Huntington's disease: a randomized, placebo-controlled, phase 2 trial. Nat Med. 2022 Oct;28(10):2183-2193. doi: 10.1038/s41591-022-01919-8. Epub 2022 Aug 8.

  PMID: 35941373 DERIVED

• Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: August 2018. J Huntingtons Dis. 2018;7(3):279-286. doi: 10.3233/JHD-189003.

  PMID: 30103342 DERIVED

Related Links

• Nonclinical research article: Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease.

MeSH Terms

Conditions

Huntington Disease; Prodromal Symptoms

Interventions

pepinemab

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Andrew Feigin, MD

  The Marlene & Paolo Fresco Institute for Parkinson's & Movement Disorders-NYU Langone Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 19, 2015
• First Posted: June 25, 2015
• Study Start: July 1, 2015
• Primary Completion: August 1, 2020
• Study Completion: August 1, 2020
• Last Updated: May 2, 2022

Record last verified: 2022-04

Locations

CA (3); US (29)