Phase I, Open-Label, Dose-Escalation Study of a Human Monoclonal Antibody, VRC-HIVMAB091-00-AB (N6LS), Administered Intravenously or Subcutaneously With or Without Recombinant Human Hyaluronidase PH20 (rHuPH20)

Background:

The experimental product in this study, N6LS, is a human monoclonal antibody. Antibodies are one way that the human body fights infection. Monoclonal means that all the antibodies in the product are the same. N6LS is directed against the HIV virus. There is no HIV in the N6LS study product and you cannot get HIV from this product. This study is the first time N6LS is tested in humans. It was given into a vein in the arm (intravenously, IV) or as an injection underneath the skin (subcutaneously, SC). The study also tested N6LS mixed with an enzyme, rHuPH20 (recombinant human hyaluronidase). rHuPH20 increases the spread of fluids injected underneath your skin (subcutaneously, SC) and allows for the rapid delivery of large volume injections that can be given with a single needle. It was given as a SC infusion using a small needle attached to an infusion pump. Study products were only given to healthy adults who are not infected with HIV.

Objective:

The main purpose of the study is to see if N6LS alone and N6LS mixed with rHuPH20 is safe in healthy adults. Another goal is to learn how amounts of N6LS in the body change over time.

Study Plan:

Assigned study groups depended on the dose of product, the numbers of times the product was given (once or three times at 12-week intervals), and how the product was given (IV or SC). Blood samples for research were collected at most of the visits. There were about 14 clinic visits over 6 months for all groups who got one dose of product, and about 26 clinic visits over 12 months for the groups who got three doses of product.

Study Design:

This is the first study in healthy adults of the N6LS monoclonal antibody (MAb). It was a dose-escalation study to examine safety, tolerability, dose, and pharmacokinetics (PK) of N6LS administered intravenously (IV) and subcutaneously (SC) to healthy adults. For SC administration, N6LS was administered alone or co-administered with the permeation enhancer rHuPH20 enzyme. Primary hypotheses are that N6LS administration to healthy adults will be safe by the IV and SC routes, alone and with rHuPH20 co-administration. A secondary hypothesis is that all N6LS administrations will be detectable in human sera with a definable half-life

Product Description:

N6LS (VRC-HIVMAB091-00-AB) is a human MAb targeted to the HIV-1 CD4 binding site. It was developed by the VRC/NIAID/NIH and manufactured under current Good Manufacturing Practice (cGMP) regulations at the VRC Vaccine Pilot Plant operated under contract by the Vaccine Clinical Materials Program (VCMP), Leidos Biomedical Research, Inc., Frederick, MD. The product was provided as a sterile aqueous buffered solution in 10 mL glass vials at a concentration of 100 mg/mL and volume of 6.25 mL.

Each vial of ENHANZE™ Drug Product (EDP) contains 0.5 mL of rHuPH20 formulated at a concentration of 1 mg/mL (approximately 110,000 U/mL rHuPH20). rHuPH20 is a tissue permeability modifier that depolymerizes hyaluronan (HA), increasing the dispersion of a substance into the subcutaneous space, which enables SC delivery of co-administered antibody (-ies) at higher dose volumes (e.g., \>10 mL) that cannot be administered quickly without rHuPH20. EDP is manufactured by Ajinomoto Althea, Inc. (San Diego, CA) for Halozyme Therapeutics, Inc. (San Diego, CA) and is supplied in 2 mL glass vials as a sterile, single-dose, injectable liquid.

Subjects:

Healthy adults, 18-50 years of age.

Study Plan:

This open-label study included 8 dose groups to assess N6LS alone given as a single IV infusion at the 5, 20, or 40 mg/kg dose level (Groups 1,3 and 4); a single SC injection at the 5 mg/kg dose level (Group 2); or in 3 administrations, spaced 12 weeks apart by SC injection at the 5 mg/kg dose level (Group 5), or by IV infusion at the 20 mg/kg dose level (Group 6). Two additional groups assessed N6LS given as a single SC injection mixed with rHuPH20 (2000 U/mL) at 5 mg/kg (Group 7) or 20 mg/kg (Group 8) doses. Enrollment opened with Groups 1, 2 and 5; and was followed by the sequential activation of Groups 3, 4, and 6. With implementation of the two SC N6LS+rHuPH20 arms as a protocol amendment, Group 7 opened first to accrual, followed by Group 8.

Study Duration:

Study participation was approximately 24 weeks for participants in Groups 1-4, 7 and 8; and 48 weeks for participants in Groups 5 and 6.

Eligibility Criteria:
INCLUSION CRITERIA:

A volunteer must have met all of the following criteria:

1. Willing and able to complete the informed consent process.
2. 18 to 50 years of age.
3. Based on history and examination, must be in good general health and without history of any of the conditions listed in the exclusion criteria.
4. Willing to have blood samples collected, stored indefinitely, and used for research purposes.
5. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
6. Screening laboratory criteria within 84 days prior to enrollment meeting the following criteria:

   * White blood cell count (WBC): 2,500-12,000/mm\^3.
   * WBC differential: Within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval.
   * Platelets: 125,000-400,000/mm\^3.
   * Hemoglobin: Within institutional normal range or accompanied by PI or designee approval.
   * Creatinine: less than or equal to 1.1 x Upper Limit of Normal (ULN).
   * Alanine aminotransferase (ALT): less than or equal to 1.25 x ULN.
   * Aspartate aminotransferase (AST): less than or equal to 1.25 x ULN.
   * Negative for HIV infection by an FDA approved method of detection.

   Female-Specific Criteria:
7. If a woman is of reproductive potential and sexually active with a male partner, then she agrees to use an effective means of birth control from the time of study enrollment until the last study visit, or to be monogamous with a partner who has had a vasectomy.
8. 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:

1. Prior receipt of licensed or investigational monoclonal antibody.
2. Weight \> 115 kg.
3. Any 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 during the study.
4. Hypertension that is not well controlled.
5. Woman who is breast-feeding, or planning to become pregnant during the study participation.
6. Receipt of any investigational study agent within 28 days prior to enrollment.
7. Any other chronic or clinically significant medical condition that in the opinion of investigator would jeopardize the safety or rights of the subject including (but not limited to): diabetes mellitus type I, chronic hepatitis; OR clinically significant forms of drug or alcohol abuse, asthma, autoimmune disease, infectious disease, psychiatric disorders, heart disease, or cancer.
8. Known hypersensitivity to hyaluronidase or any of the excipients in ENHANZE™ Drug Product (EDP).