Clinical trial NCT03374202: Safety and Tolerability of AAV8 Delivery of a Broadly Neutralizing Antibody in Adults Living With HIV: a Phase 1, Dose-escalation Trial
Official title: VRC 603: A Phase I Dose-Escalation Study of the Safety of AAV8-VRC07 (VRC-HIVAAV070-00-GT) Recombinant AAV Vector Expressing VRC07 HIV-1 Neutralizing Antibody in Antiretroviral-Treated, HIV-1 Infected Adults With Controlled Viremia
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: HIV-1 Infected Adults With Controlled Viremia
Keywords: ARV Therapy
Broadly Neutralizing
Gene Transfer
Monoclonal Antibody
AAV8
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2017-12-15
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

The Human Immunodeficiency Virus (HIV) attacks the immune system. Scientists have created a gene that could be transferred to the cells of people with HIV. The gene should tell the cells to make an antibody called VRC07. This antibody fights HIV. The VRC07 gene is packaged into a man-made version of a virus called AAV8.

Objectives:

To see if AAV8-VRC07 is safe. To study if it causes cells to produce the VRC07 antibody.

Eligibility:

Adults ages 18-65 who are HIV infected but in general good health and have been taking the same HIV medicine for at least 3 months

Design:

Participants were screened in a different protocol.

Participants received the study product on day 1. It was injected one or more times in the upper arm or thigh using a needle. Participants weight was measured to calculate the dose.

Women may have had a pregnancy test.

For 7 days after getting the study product, participants checked their temperature with a thermometer. They noted any symptoms in an electronic or paper diary.

Participants will have study visits. At each one, they will have a physical exam and medical history. They will have blood drawn and may have saliva collected.

The study visit schedule is as follows:

For 12 weeks: 1 visit a week

For the next 12 weeks: 1 visit every other week

Then about 1 visit a month

After 1 year in the study: a visit every 6 months for the next 4 years.

Total study participation is 5 years.

Detailed description: Design: This is a Phase I study of the safety and tolerability of AAV8-VRC07 (VRC-HIVAAV070-00-GT) expressing VRC07 human monoclonal antibody with broad HIV-1 neutralizing activity in HIV-1 infected adults. It is a dose-escalation study to examine pharmacokinetics of VRC07 expression following intramuscular (IM) administration of AAV8-VRC07 in participants on anti-retroviral therapy (ARV). The hypotheses are: 1) AAV8-VRC07 will be safe for human administration and will not elicit hypersensitivity or anti-drug antibody (ADA) to VRC07; and 2) intramuscular delivery of AAV8-VRC07 will result in production of biologically active VRC07 antibody at a concentration in serum that is measurable and safe.

Description: AAV8-VRC07 was developed by VRC, NIAID, NIH, and manufactured by the Clinical Vector Core, Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania (PA). It is composed of an AAV8 recombinant vector expressing genes encoding the heavy and light chains of the VRC07 monoclonal antibody. AAV8-VRC07 was supplied at 2.84 x 10\^13 vector genomes (vg)/mL.

Participants: HIV-1 infected adult volunteers (18 to 65 years old) on a stable antiretroviral regimen for more than or equal to 3 months, with controlled viremia, under the care of a physician, and without additional clinically significant medical conditions.

Study Plan: There are 3 dose escalation groups. Sequentially enrolled participants were assigned to the dosage level being evaluated at the time of enrollment. All injections were administered intramuscularly (IM) by needle and syringe. Cumulative safety data were reviewed weekly by a Protocol Safety Review Team (PSRT) that included an Independent Safety Monitor (ISM) while injections were being administered. Safety, including reactogenicity and unsolicited adverse events (AEs), laboratory findings, pharmacokinetics, and VRC07 antibody levels in blood were assessed after the injection and summarized for an interim analysis at 4 weeks post injection. The second participant in each dose group was injected after the 4 weeks safety assessment for the first participant. Decisions regarding dose escalation and participant enrollments were based on safety data and the VRC07 concentration in blood at 4 weeks after product administration. The pharmacokinetics of VRC07 at each dose level was evaluated to determine the dose that would result in antibody production that achieves at least 50 mcg/mL VRC07 concentration in serum at 4 weeks post injection with a target set point of more than or equal to 5 mcg/mL at 12 weeks post injection.

Eligibility criteria: INCLUSION CRITERIA:

A volunteer must have met all of the following criteria:

* Able and willing to complete the informed consent process.
* 18 to 65 years of age.
* HIV-1 infected.
* On a stable antiretroviral regimen for greater than or equal to 3 months.
* Available for clinical follow-up through the last study visit.
* Based on history and examination, must be in general good health with no evidence of clinically significant lab abnormalities and without additional clinically significant medical conditions as per exclusion criteria.
* Willing to maintain or establish a relationship with a primary health care provider for medical management of HIV infection while participating in the study.
* Willing to have blood samples collected, stored indefinitely, and used for research purposes.
* Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
* Laboratory tests assessing individual's health will be conducted within 84 days prior to enrollment and values must meet the following criteria:

  1. White blood cell count (WBC) 2,500-12,000/mm\^3;
  2. WBC differential either within institutional normal range or accompanied by approval of the Principal Investigator (PI) or designee;
  3. Platelets = 125,000-400,000/mm\^3;
  4. Hemoglobin greater than or equal to 10.0 gm/dL;
  5. Creatinine less than or equal to 1.25 x upper limit of normal (ULN);
  6. Alanine aminotransferase (ALT) less than or equal to 1.1 x ULN;
  7. Aspartate aminotransferase (AST) less than or equal to 1.1 x ULN; and,
  8. Viral Load (VL) less than or equal to 50 copies/mL and a CD4 count greater than or equal to 300/mcL (microliter).

     Male-Specific Criteria:
* Males must agree to use condoms for all sexual activity of any reproductive potential for 52 weeks after receiving the study product.

Female-Specific Criteria:

* If a woman is sexually active with a male partner and has no history of hysterectomy, tubal ligation or menopause, she must agree to use either a prescription birth control method or a barrier birth control method from the time of study enrollment through study Week 52, or to be monogamous with a partner who has had a vasectomy.
* Negative beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be of reproductive potential.

EXCLUSION CRITERIA:

A volunteer would have been excluded if one or more of the following conditions applied:

* Previous receipt of monoclonal antibody whether licensed or investigational.
* Previous receipt of gene therapy product.
* Ongoing AIDS-related opportunistic infection (including oral thrush).
* Active injection drug use or active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
* A titer of pre-existing antibodies to AAV8 capsid is greater than 1:90.
* Weight \> 115 kg for Group 3 participants only.
* History of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis within the 2 years prior to enrollment that has a reasonable risk of recurrence.
* Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with IM injections or blood draws.
* Active liver disease such as chronic hepatitis.
* Hypertension that is not well controlled by medication.
* Woman who is breast-feeding or planning to become pregnant during the study participation.
* Receipt of any investigational study agent within 28 days prior to enrollment.
* Current infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
* Any other chronic or clinically significant medical condition that in the opinion of investigator would jeopardize the safety or rights of the volunteer, including, but not limited to: diabetes mellitus type I; OR clinically significant forms of asthma, autoimmune disease, psychiatric disorders, heart disease, or cancer.

Primary outcomes:
measure: Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of AAV8-VRC07 Product Administration
timeFrame: 7 days after AAV8-VRC07 product administration, at approximately Week 1
measure: Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of AAV8-VRC07 Product Administration
timeFrame: 7 days after AAV8-VRC07 product administration, at approximately Week 1
measure: Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following AAV8-VRC07 Product Administration
timeFrame: Day 0 through 8 weeks after AAV8-VRC07 product administration
measure: Number of Participants With Abnormal Laboratory Measures of Safety Following AAV8-VRC07 Product Administration
timeFrame: Day 0 through 8 weeks after AAV8-VRC07 product administration
measure: Geometric Mean Endpoint Titer of Anti-AAV8 Antibodies
timeFrame: Day 0 through 44 Weeks after AAV8-VRC07 product administration
measure: Number of Participants Who Attained A 50 mcg/mL VRC07 Serum Concentration
timeFrame: Day 0 through 52 Weeks after AAV8-VRC07 product administration
measure: Geometric Mean Concentration of VRC07 Serum Antibodies (PK ELISA)
timeFrame: Day 0 through 52 Weeks after AAV8-VRC07 product administration
measure: Number of Participants With Serious Adverse Events (SAEs) Following AAV8-VRC07 Product Administration
timeFrame: Day 0 through 5 Years (260 weeks) after AAV8-VRC07 product administration
measure: Number of Participants With New Chronic Medical Conditions Following AAV8-VRC07 Product Administration
timeFrame: Day 0 through 5 Years (260 weeks) after AAV8-VRC07 product administration
measure: Number of Participants Who Produced VRC07 Anti-drug Antibodies (ADA)
timeFrame: Day 0 through 5 Years (260 weeks) after AAV8-VRC07 product administration
Secondary outcomes:
measure: Geometric Mean Value of CD4 Cell Counts
timeFrame: Day 0 through 44 Weeks after AAV8-VRC07 product administration
measure: Viral Load
timeFrame: Day 0 through 44 Weeks after AAV8-VRC07 product administration
measure: Concentration of VRC07 Serum Antibodies (Singulex Assay)
timeFrame: Day 0 through 52 weeks after AAV8-VRC07 product administration
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Joseph P Casazza, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lynch RM, Boritz E, Coates EE, DeZure A, Madden P, Costner P, Enama ME, Plummer S, Holman L, Hendel CS, Gordon I, Casazza J, Conan-Cibotti M, Migueles SA, Tressler R, Bailer RT, McDermott A, Narpala S, O'Dell S, Wolf G, Lifson JD, Freemire BA, Gorelick RJ, Pandey JP, Mohan S, Chomont N, Fromentin R, Chun TW, Fauci AS, Schwartz RM, Koup RA, Douek DC, Hu Z, Capparelli E, Graham BS, Mascola JR, Ledgerwood JE; VRC 601 Study Team. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Sci Transl Med. 2015 Dec 23;7(319):319ra206. doi: 10.1126/scitranslmed.aad5752.
citation: Balazs AB, Ouyang Y, Hong CM, Chen J, Nguyen SM, Rao DS, An DS, Baltimore D. Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nat Med. 2014 Mar;20(3):296-300. doi: 10.1038/nm.3471. Epub 2014 Feb 9.
citation: Casazza JP, Cale EM, Narpala S, Yamshchikov GV, Coates EE, Hendel CS, Novik L, Holman LA, Widge AT, Apte P, Gordon I, Gaudinski MR, Conan-Cibotti M, Lin BC, Nason MC, Trofymenko O, Telscher S, Plummer SH, Wycuff D, Adams WC, Pandey JP, McDermott A, Roederer M, Sukienik AN, O'Dell S, Gall JG, Flach B, Terry TL, Choe M, Shi W, Chen X, Kaltovich F, Saunders KO, Stein JA, Doria-Rose NA, Schwartz RM, Balazs AB, Baltimore D, Nabel GJ, Koup RA, Graham BS, Ledgerwood JE, Mascola JR; VRC 603 Study Team. Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial. Nat Med. 2022 May;28(5):1022-1030. doi: 10.1038/s41591-022-01762-x. Epub 2022 Apr 11.