Gilead, Johnson & Johnson, GSK and Others Reveal Latest HIV Drug Development Advances at IAS 2019

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The 2019 International AIDS Society Conference on HIV Science (IAS 2019) was recently held in Mexico City. At the conference, multiple pharmaceutical companies, including Gilead, GlaxoSmithKline, and Johnson & Johnson, announced the latest progress in the development of new HIV drugs.

Gilead

1. TLR7 Agonist

Gilead presented two studies on Toll-like receptor 7 (TLR7) agonists at the conference, as part of its HIV cure program. Phase I and preclinical study results indicated that the oral TLR7 agonists vesatolimod (GS-9620) and GS-986 could induce immune activation, consistent with earlier preclinical findings suggesting that TLR7 agonists, as part of combination regimens, may lead to potential viral clearance. The HIV reservoir persists even in individuals with virologic suppression, and its eradication is considered the primary obstacle to achieving an HIV cure.

• Vesatolimod is safe and pharmacologically active in individuals with HIV infection.

This was a double-blind, placebo-controlled Phase I study enrolling 48 HIV-infected individuals receiving antiretroviral therapy (ART), with a median age of 47 years (43 males) and a median treatment duration of 8.1 years. In the study, 36 patients received escalating doses of vesatolimod (1–12 mg) and 12 patients received placebo, administered once every other week. The results showed that vesatolimod stimulated a range of immune responses at higher doses. Vesatolimod was well tolerated at all dose levels, with no drug-related Grade 3 or 4 adverse events, no related serious adverse events, and no adverse events leading to discontinuation of the study drug. Drug-related adverse events were observed in 9 out of 36 subjects at doses ≥2 mg, including mild, transient flu-like symptoms, consistent with previous studies. These symptoms resolved within one day and did not occur at every dose level.

Studies have shown that vesatolimod, an immunomodulatory agent with a favorable tolerability profile, can be administered orally to individuals living with HIV. These findings support further investigation into the potential role of vesatolimod as part of combination therapy regimens aimed at achieving durable control of HIV without the need for antiretroviral therapy (ART).

• GS-986 Induces Immune-Stimulatory Responses in SIV-Infected, ART-Suppressed Rhesus Macaques

This preclinical study investigated the effects of oral GS-986 in two simian immunodeficiency virus (SIV)-infected, virologically suppressed infant rhesus macaques. At 7 months of age, the two infants received an oral dose of 0.1 mg GS-986, followed by a second dose of 0.3 mg four weeks later. Blood counts, viral loads, cytokine concentrations, and immune responses were assessed in both instances. At the 0.1 mg and 0.3 mg dose levels, GS-986 induced immune activation, characterized by increased peripheral plasma cytokines/chemokines and immune cell activation. GS-986 was well tolerated, with normal complete blood counts and maintained virologic suppression. These findings add new information to the existing preclinical data on GS-986, supporting its potential future application as an oral TLR7 agonist in patients with HIV.

2. Capsid inhibitor GS-6207

The conference also announced the first clinical data on GS-6207 for the treatment of HIV-infected individuals. The Phase Ib study data provided the first proof-of-concept that HIV capsid inhibition can lead to a significant reduction in viral load in vivo. In addition, preclinical data presented at the conference indicated that resistance to GS-6207 in vitro does not result in cross-resistance to other classes of drugs used for the treatment of HIV.

The Phase Ib study randomized HIV patients who had not previously received capsid inhibitors into two groups: one group received subcutaneous injections of GS-6207 (at doses of 50 mg, 150 mg, and 450 mg; n=6 per dose), and the other group received a placebo (n=6). The primary endpoint was the maximal reduction in HIV-1 RNA over 10 days of treatment. Results showed that the mean maximal reduction in HIV-1 RNA on Day 10 ranged from 1.8 to 2.2 log10 copies/mL across all dose groups, which was significantly greater than that observed in the placebo group (all p < 0.0001). No patients experienced serious adverse events or discontinued treatment due to adverse events. The most common adverse events were mild-to-moderate injection-site reactions (63%; 15/24), all of which were self-limiting.

GS-6207 is a long-acting antiretroviral drug that can be administered via subcutaneous injection and was recently granted Breakthrough Therapy Designation by the U.S. FDA for use in heavily treatment-experienced individuals with multidrug-resistant HIV infection.

Johnson & Johnson

Johnson & Johnson presented the latest data from the Phase I/IIa clinical study ASCENT (HPX2003/HVTN 118) at the conference. The study evaluated the efficacy of a preventive vaccine regimen based on a mosaic design strategy for preventing HIV-1 infection. The results showed that adding a bivalent Clade C and Mosaic gp140 combination to the regimen enhanced immune responses against diverse global HIV strains compared with monovalent Clade C gp140. This mosaic vaccine contains mosaic immunogens, which were created using genes from multiple HIV-1 subtypes, with the aim of providing a “global” vaccine suitable for use anywhere in the world.

The ASCENT study was conducted in Kenya, Rwanda, and the United States, enrolling a total of 152 healthy adults. In the study, participants received either: quadrivalent mosaic adenovirus serotype 26 vector (Ad26.Mos4.HIV) and bivalent Clade C/Mosaic gp140 adjuvanted with aluminum phosphate (n=100); Ad26.Mos4.HIV and monovalent Clade C gp140 with adjuvant (n=26); or placebo (n=26). The study evaluated the immunogenicity of the bivalent combination of Clade C and Mosaic gp140 versus monovalent Clade C gp140.

The results showed that at Week 52 (4 weeks after the last vaccination), both active vaccine regimens induced binding and functional antibodies against all tested antigens, namely, high immune responses against multiple HIV-1 subtypes. Notably, the bivalent combination of Clade C and Mosaic gp140 enhanced the immune response against Clade B without reducing the immune response against Clade C. Clade B is the predominant subtype in the Americas, Western Europe, and Australia, whereas Clade C is prevalent in South Africa, the Horn of Africa, and India. In the study, both active regimens were well tolerated, with no serious adverse events reported.

Merck & Co.

Merck & Co. presented Phase I study data on the nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir (formerly MK-8591) at the conference. This was a randomized, two-arm, double-blind, placebo-controlled, adaptive-design study conducted in healthy adult volunteers to evaluate the safety and pharmacokinetics of islatravir administered via a polymer drug-eluting implant. Participants were randomly assigned to receive implants containing 62 mg (n=6) or 54 mg (n=6) of islatravir, or placebo implants (n=4), subcutaneously implanted in the skin of the upper arm of the non-dominant hand. The implants were removed after 12 weeks, and participants underwent a 4-week follow-up assessment.

The results showed that both implant doses maintained intracellular islatravir concentrations in PBMCs above the calculated pharmacokinetic threshold for 12 weeks. Subsequent modeling indicated that the 62-mg islatravir implant could sustain drug levels well above the threshold for 12 months (or even longer), providing early evidence of its potential as a once-yearly PrEP regimen. The findings also demonstrated that intracellular drug concentrations could be controlled by adjusting the islatravir load in the implants. No participants discontinued treatment due to adverse events, and no serious adverse events related to the implants were reported. Pooled analyses of vital signs, electrocardiogram parameters, and safety laboratory studies revealed no clinically significant differences between islatravir and placebo, with no systemic drug-related effects observed.

Currently, islatravir is being developed for: use in combination with other antiretroviral agents as a once-daily, two-drug oral regimen for the treatment of HIV infection; and as monotherapy, including a once-yearly implant and a once-monthly oral formulation, for pre-exposure prophylaxis (PrEP).

GlaxoSmithKline

ViiV Healthcare, a subsidiary of GSK, announced positive 96-week data from the Phase III BRIGHT clinical trial of fostemsavir, a first-in-class attachment inhibitor. Fostemsavir is a prodrug of temsavir, which directly binds to the gp120 subunit within the HIV-1 envelope glycoprotein gp160 complex, thereby blocking the initial interaction between the virus and the cellular CD4 receptor. This mechanism prevents viral attachment to the CD4 receptor and entry into host cells. Currently, temsavir has not received any regulatory approval. ViiV Healthcare is developing fostemsavir in combination with other antiretroviral agents for heavily treatment-experienced individuals with multidrug-resistant HIV-1 infection.

The BRIGHT study enrolled 371 patients with treatment-experienced, multidrug-resistant HIV-1 who had resistance, intolerance, and/or contraindications to four of the six currently available classes of antiretroviral (ARV) drugs. The study comprised two cohorts (randomized and non-randomized) to evaluate the safety and efficacy of fostemsavir in combination with an optimized background therapy (OBT). In the randomized cohort, patients retained full activity to one but no more than two ARV drug classes at baseline, yet could not construct a viable ARV regimen from the remaining drug classes. These patients were randomized in a 1:3 ratio to receive either fostemsavir or placebo added to their current failing regimen for 8 days of functional monotherapy. The primary endpoint was the mean change in log10 HIV-1 RNA from Day 1 to Day 8 in the randomized cohort. Following the 8-day double-blind period, all patients in the randomized cohort received open-label fostemsavir plus OBT.

The results showed that in the randomized cohort, the rates of virologic suppression and immune response further increased from Week 48 to Week 96. The specific data are as follows:

• At Week 96, 60% of patients treated with fostemsavir plus OBT achieved virologic suppression, representing a 6% increase from Week 48;

• Based on CD4+ T-cell counts, the patient’s immune response continued to improve; at Week 96, the mean CD4+ T-cell count increased by 205 cells/mL from baseline and by 66 cells/μL from Week 48.

• At Week 96, 67% of patients with baseline CD4+ T-cell counts <200 cells/μL achieved an increase to ≥200 cells/μL, and 56% of patients with baseline CD4+ T-cell counts <50 cells/μL achieved an increase to ≥200 cells/μL;

• During the 96-week period, nearly all patients receiving fostemsavir experienced at least one adverse event, with the most common being nausea, diarrhea, and headache.

Source: Company websites