An open-label, multiple ascending dose study of the anti-CTLA-4 antibody ipilimumab in viremic HIV patients

<div><p>Expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4), a negative regulator of T-cell function, is increased in chronic HIV-1 infection. It was hypothesized that CTLA-4 blockade may enhance immune response to HIV-1 and result in better control of viremia. This open-label, multiple ascending dose study (NCT03407105)—the first to examine ipilimumab in participants with HIV-1 infection—assessed the safety, tolerability, and pharmacokinetics of ipilimumab, as well as whether ipilimumab enhanced immune response to HIV-1 and improved control of viremia. Twenty-four participants received 2 or 4 doses of ipilimumab (0.1, 1, 3, or 5 mg/kg) every 28 days. No serious adverse events (AEs) or dose-limiting toxicities were reported; one participant discontinued ipilimumab for an AE of grade 2 facial palsy. Twenty participants (83.3%) had ≥1 AE; all but 1 were grade 1 or 2. Eight participants (33.3%) had potentially immune-related AEs (7 had grade 1 diarrhea not requiring corticosteroids; 1 who had diarrhea also had transient antinuclear antibody positivity; 1 had grade 2 facial palsy requiring corticosteroids). Two participants (8.3%), one each in the 0.1- and 1-mg/kg dose groups, had a decrease from baseline HIV-1 RNA of 0.85 and 1.36 log₁₀ copies/mL. Fourteen participants (58.3%) had an increase from baseline HIV-1 RNA (mean, 0.87 log₁₀ copies/mL; range, 0.59–1.29). Of these 14 participants, all but 1 were in the higher ipilimumab dose groups (3 or 5 mg/kg). No pattern was noted regarding change from baseline in CD4 or CD8 T cells; ex vivo assessments of immune response were precluded because of inadequate cell viability. Serum concentration data for ipilimumab showed biphasic disposition, with steady state reached by dose 3. Ipilimumab treatment was well tolerated and was associated with variations in HIV-1 RNA in excess of expected repeat measures in most participants, but these were not related to combination antiretroviral therapy status or CD4 counts. The mechanism(s) underlying the increased variation in HIV-1 RNA is unclear and needs further study.</p></div

Participant disposition.

<p>Participant disposition.</p

Baseline participant characteristics.

<p>Baseline participant characteristics.</p

Data for the participants with the maximum increase or decrease in HIV-1 RNA from baseline.

<p><b>(A)</b> Participant A (ipilimumab 1 mg/kg, 2 doses); <b>(B)</b> Participant B (ipilimumab 3 mg/kg, 4 doses).</p

HIV-1 RNA change from baseline.

<p><b>(A)</b> HIV-1 RNA values for individual participants (individual squares arranged vertically represent test results from a given study day for a given participant; the 2 participants with maximum HIV-1 RNA increase and decrease, respectively, are indicated with arrows; the 14 participants with significant increases in HIV-1 RNA are indicated with asterisks; the 2 participants with significant decreases in HIV-1 RNA are indicated with double asterisks); <b>(B)</b> mean HIV-1 RNA values over time for each dose cohort.</p

CD4 count change from baseline.

<p>Individual squares arranged vertically represent test results from a given study day for a given participant.</p

Adverse events reported in ≥4% of participants (total).

<p>Adverse events reported in ≥4% of participants (total).</p

A Randomized, Double-Blind, Placebo-Controlled Assessment of BMS-936558, a Fully Human Monoclonal Antibody to Programmed Death-1 (PD-1), in Patients with Chronic Hepatitis C Virus Infection

<div><p></p><p>Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) – a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding – was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N = 54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n = 42) were randomized 5∶1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n = 5 each] or 10 mg/kg [n = 10]) or of placebo (n = 7). An additional 12 HCV treatment-naïve patients were randomized to receive 10 mg/kg BMS-936558 (n = 10) or placebo (n = 2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n = 1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA ≥0.5 log₁₀ IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log₁₀ reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4⁺, CD8⁺ and CD19⁺ cells, including both naïve and memory CD4⁺ and CD8⁺ subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20–24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted.</p><p>Trial Registration</p><p>ClinicalTrials.gov NCT00703469 <a href="http://www.clinicaltrials.gov/ct2/show/NCT00703469" target="_blank">NCT00703469</a></p></div