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A Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Single Suspension Injection of Investigational Capsid Inhibitors Compared to Placebo in Healthy Adults; HIV Pipeline: GSK/ViiV, Gilead, Merck
Study Overview
Brief Summary:
The primary purpose of the study is to investigate safety and tolerability following single ascending subcutaneous (SC) and intramuscular (IM) doses of capsid inhibitor in healthy participants. The study will also describe the pharmacokinetics following single ascending SC and IM doses of capsid inhibitor in healthy participants.
A Phase 1 Double-Blind (Sponsor-unblinded), Placebo-Controlled, Randomized, Single Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of a Parenterally Administered Suspension of Investigational Capsid Inhibitors in Healthy Adults
First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4004280 in Healthy Participants
Study Overview
Brief Summary:
This FTIH study aims to evaluate the safety, tolerability and PK of the novel investigational Human immunodeficiency virus (HIV)-1 capsid inhibitor VH4004280 in healthy adults. The study will be conducted in 3 parts: Part 1 will investigate single ascending doses (SAD), Part 2 will investigate multiple ascending doses and drug-drug interaction (MAD/MAD DDI) Part 3 will investigate single dose relative bioavailability (RBA) of a new formulation of VH4004280.
GSK drops one of 2 maturation inhibitors in HIV pipeline
April 26 2023
GSK's weighty HIV pipeline just got slightly lighter as the British Big Pharma decided not to progress a once-promising candidate into late-stage trials.
The asset in question, dubbed GSK3640254, was a so-called maturation inhibitor, a type of antiretroviral medicine designed to prevent the HIV replication process by blocking key enzyme activity and causing the formation of immature virus particles. The candidate had demonstrated antiviral activity, safety and tolerability in a phase 2a study back in 2021, but the anticipated phase 2b findings never appeared.
The move to cull GSK3640254 was revealed in a presentation (PDF) to coincide with GSK's first-quarter earnings results this morning.
The company made the decision that the candidate was not differentiated enough in the daily oral HIV market, Fierce Biotech has learned. Another limit on the drug's potential effectiveness was its food effect, a term for the reduced effectiveness of certain drugs if taken soon after a meal.
All of GSK's HIV assets are developed by ViiV Healthcare, its HIV unit that also lists Pfizer and Shionogi as shareholders. ViiV spoke positively about GSK3640254 back in 2021, describing phase 2a results as demonstrating the unit's "commitment to researching and developing a broad range of innovative approaches to treating HIV."
"Because there are no treatments available that target this specific stage of the HIV life cycle, maturation inhibitors may help meet a critical need, particularly for individuals who are treatment-experienced," ViiV head of R&D Kimberly Smith, M.D., said at the time. Still, Fierce Biotech understands that removing the candidate is not expected to have any wider impact on GSK's HIV pipeline, which still includes a maturation inhibitor in the form of VH3739937, currently in phase 1. It's joined by the HIV capsid protein inhibitors VH4004280 and VH4011499 as well as the HIV integrase inhibitor VH4524184. GSK also lists one HIV drug in phase 2 development: the broadly neutralizing antibody VH3810109, which showed promise in a midstage trial in October.
GSK and ViiV can point to other recent successes on the HIV front, with Cabenuva, a combination of the approved drugs cabotegravir and rilpivirine that is administered monthly or every other month, approved in 2021.
GSK's ViiV gives early look at HIV broadly neutralizing antibody's power, eyes long-acting combo trial
oct 25 2022
Existing HIV antiretroviral therapies are mostly small-molecule drugs that require daily medication. Broadly neutralizing antibodies (bNAbs) hold promise as potential longer-term options, and GSK's ViiV Healthcare has provided encouraging early proof-of-concept data for such a candidate.
The drug, called N6LS, came to GSK through a licensing deal with the National Institutes of Health in 2019. It targets the gp120 protein on the HIV envelope, blocking the virus from binding to CD4 on T cells and therefore preventing viral entry. In the phase 2a BANNER study, a single dose of 40 mg/kg infusion of N6LS led to a virologic response in all eight treatment-naïve HIV patients. That means the patients had at least a 0.5 log10 copies/mL fall in viral load. The median viral count reduction was 1.72 log10 copies/mL, according to data presented at the 30th HIV Glasgow conference. The drug's performance represents a "nice drop" in viral load, ViiV's head of R&D, Kimberly Smith, M.D., said in an interview with Fierce Biotech. To put the number in context, GSK's integrase inhibitor Tivicay (dolutegravir), which Smith said is so far the most potent FDA-approved antiretroviral therapy based on its viral reduction data, showed a median 2.5 log10 copies/mL reduction in a similar proof-of-concept study. The number is also comparable to or higher than some other antiretrovirals, she said.
But the data weren't all sunshine and roses. At a low, 4-mg/kg dose, N6LS failed to trigger a response in one of the six participants. That patient only saw a 0.3 log10 copies/mL reduction, while the median decrease in the low-dose cohort was 1.18 log10 copies/mL, according to GSK.
Across the two cohorts, side effects were reported in nine (56%) patients, including six that were considered drug-related. All of these effects were mild or moderate in nature. Still, GSK noted that the low dose exceeded efficacy reported by other bNAbs at similarly low doses. It at least shows that "we may be able to use smaller amounts of N6LS and have efficacy," Smith said.
"We're going to do a whole lot of research on that individual to understand why he didn't respond," the ViiV exec added.
BNAbs are typically found in some people who have been dealing with HIV infection for a long time. Although called "broadly neutralizing," bNAbs can't neutralize all HIV strains. For N6LS, early lab tests suggest that it could tackle 96% to 97% of HIV viruses, Smith noted.
This nonresponder looks to fall [fail?] in the 3% that are not covered by N6LS. GSK will study the kind of mutations the individual's virus has in the CD4 binding site that makes N6LS ineffective, Smith said. The learning could guide future clinical development in larger populations.
Before moving to large studies, GSK wants to first identify the proper dose that is both efficacious and long-lasting for at least three months and potentially six months, Smith said.
GSK's Cabenuva (cabotegravir and rilpivirine) represents the world's first full long-acting HIV regimen. But, so far, Cabenuva can be administered by a healthcare professional once every two months at the longest, and industry watchers have questioned whether that dosing schedule can really shake up existing practice that's dominated by daily orals. Various patient surveys and doctors' feedback have suggested that a self-administered, ultralong-acting therapy could attract more interest.
GSK is moving in that direction with help from Halozyme's Enhanze drug delivery technology, which has turned several marketed infused antibody therapies into under-the-skin injections.
Armed with Enhanze, GSK is already studying cabotegravir as a longer-acting injection and hopes N6LS could be one, too, as a potential combination partner for cabotegravir, Smith said. The company now plans to start a phase 2b study of N6LS in combination with other antiretrovirals in the second half of 2023, although Smith said a trial design hasn't been decided.
GSK isn't the only company working on bNAbs or long-acting HIV treatments. Gilead Sciences has won European approval for lenacapavir, or Sunlenca, a capsid inhibitor that can be given every six months. But Gilead is still searching for a long-acting combo partner for that drug.
Potential candidates Gilead is looking at include a long-acting version of bictegravir, an integrase strand transfer inhibitor that serves as the cornerstone of the company's top-selling Biktarvy. It's also studying a combination of two bNAbs, which it hopes could match up to lenacapavir's six-month dosing interval.



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