Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV

Study Overview
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Brief Summary
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This study is designed to evaluate the safety and efficacy of lefitolimod and 3BNC117/10-1074 in HIV-1-infected individuals on ART and during ATI as intervention to reduce the HIV-1 reservoir

Official Title
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Combining a TLR9 Agonist With Broadly Neutralizing Antibodies for Reservoir Reduction and Immunological Control of HIV Infection: An Investigator-initiated Randomized, Placebo-controlled, Phase IIa Trial.

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: Saline
* Drug: Lefitolimod
* Drug: 3BNC117 and 10-1074


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented HIV-1 infection Adults age 18-65 years On ART for a minimum of 18 months. CD4+ T cell count >500 at screening HIV-1 RNA plasma level of < 50 copies/mL by standard assays for at least 15 months (a single viral load measurement > 50 but < 500 copies/mL during this time period is allowable). Able to give informed consent Viral reservoir sensitivity to 3BNC117 and 10-1074. (Sensitivity of the viral reservoir to neutralization by 3BNC117 and 10-1074 will be tested following the screening visit (i.e. prior to randomization)). Sensitivity of the viral reservoir to neutralization by 3BNC117 and 10-1074 will be tested following the screening visit (i.e. prior to enrollment and randomization). Isolated PBMCs will be analyzed using the PhenoSense HIV mAb Assay, Monogram Biosciences. The sensitivity of an individuals archieved proviruses to bNAb neutralization will be determined by the IC50 value of PBMC derived pseudovirus inhibition. Subjects that are considered sensitive to both 3BNC117 (IC90<=1.5 μg/mL) and 10-1074 (IC90<=2.0 μg/mL) AND MPI>97 AND fulfill the other inclusion/exclusion criteria will proceed to study enrolment and randomization. If sensitivity cannot be determined by the PhenoSense HIVmAb Assay, participants will be screened for 3BNC117 and 10-1074 sensitivity using HIV env sequencing carried out in-house (Aarhus, Denmark). The method was originally established and validated by Rockefeller University that already has this method implemented. The method utilizes HIV-1 DNA envelope sequencing and a mathematical prediction binding algoritm of known binding sites of the antibodies. Based on the individual HIV env sequence, proviruses are categorized as sensitive or resistant. Subjects that are determined to be sensitive to both 3BNC117 and 10-1074 (defined as at least 90% of known sequences sensitive to either bNAb) AND fulfill the other inclusion/exclusion criteria will proceed to study enrolment and randomization. Exclusion Criteria: Any significant acute medical illness requiring hospitalization in the past 4 weeks Any evidence of an active AIDS-defining opportunistic infection Any condition that, in the Investigator's opinion, will prevent adequate compliance with study therapy The following laboratory values at screening, the values can be repeated within the screening period, but test results must be available before baseline (Day 0) and checked for eligibility: Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN) // Serum total bilirubin ≥3 ULN // Estimated glomerular filtration rate (eGFR) ≤50 mL/min (based on serum creatinine) // Platelet count ≤100 x109/L // Absolute neutrophil count ≤1x109/L Hepatitis B or C infection History of: Malignancy, excluding non-melanoma skin cancers, or organ transplantation Receipt of strong immunosuppressive or systemic chemotherapeutic agents within 28 days prior to study entry Known resistance to >2 classes of ART Known hypersensitivity to the components of lefitolimod, 3BNC117, 10-1074 or their analogues Pre-existing autoimmune or antibody-mediated diseases Women who are pregnant or breastfeeding, or unwilling/ unable to use an acceptable method of contraception (if of child bearing potential) Males or females who are unwilling or unable to use barrier contraception during sexual intercourse until plasma HIV-1 RNA is undetectable using standard assays

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Participants will be randomized 1:1:1:1 in a blinded fashion to receive: Arm A: Placebo and Placebo Arm B: Lefitolimod and Placebo Arm C: Placebo and 3BNC117+10-1074 Arm D: Lefitolimod and 3BNC117+10-1074
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Arm A: Placebo/Placebo<br>This arm will receive placebo (sterile saline) for both Lefitolimod and 3BNC117 + 10-1074. | Drug: Saline<br>* Placebo<br>|
| Active Comparator: Arm B: Lefitolimod/Placebo<br>This arm will receive Lefitolimod and placebo (sterile saline) for 3BNC117 + 10-1074. | Drug: Saline<br>* Placebo<br>Drug: Lefitolimod<br>* A TLR9 agonist administered s.c. once weekly for 8 weeks.<br>* Other names: MGN1703;|
| Active Comparator: Arm C: Placebo/3BNC117 + 10-1074<br>This arm will receive 3BNC117 + 10-1074 and placebo (sterile saline) for Lefitolimod. | Drug: Saline<br>* Placebo<br>Drug: 3BNC117 and 10-1074<br>* Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval.<br>* Other names: RUhumab-001 and RUhumab-002;|
| Active Comparator: Arm D: Lefitolimod/3BNC117 + 10-1074<br>This arm will receive both Lefitolimod and 3BNC117 + 10-1074. | Drug: Lefitolimod<br>* A TLR9 agonist administered s.c. once weekly for 8 weeks.<br>* Other names: MGN1703;Drug: 3BNC117 and 10-1074<br>* Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval.<br>* Other names: RUhumab-001 and RUhumab-002;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to re-initiation of cART during analytical treatment interruption (ATI) | Time from date of cART cessation to the date of the last of three consecutive plasma HIV-1 RNA measurements >10,000 copies/mL, CD4 cell count <350 on two consecutive measurements, or end of ATI (i.e. 26 weeks after cessation of cART) - whichever comes first. | Up to 26 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs, | Subject who receives at least one dose of the IMP(s) will be included in the evaluation for safety, measured by AEs, Adverse Reactions (ARs), SAEs, Serious ARs (SARs) and (SUSAR) | Duration of the study | 
| Plasma HIV RNA doubling time | Plasma HIV RNA doubling time from first measurement >50 copies/mL to first measurement >1,000 copies/mL during the analytical treatment interruption (plasma HIV RNA measured by standard clinical assays, e.g. Cobas TaqMan; Lower limit of quantitation 20 copies/mL) | Duration of ATI (up to 26 weeks) |