Robust pipeline of ART drugs in development

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The Conference on Retroviruses and Opportunistic Infections (CROI 2017) included presentations on several new investigational antiretroviral drugs in development, reflecting a more robust pipeline, says a HIV and Hepatitis report.

Although modern antiretroviral therapy (ART) is highly effective and well-tolerated by most people living with HIV, having more available drugs that work in different ways offers more options for putting together optimal regimens.

The report says some of the experimental agents discussed at CROI represent novel drug classes that work differently than existing antiretrovirals, including capsid inhibitors in early studies and monoclonal antibodies now in late-stage human trials.

Other presentations focused on next-generation candidates in familiar antiretroviral classes. Given that widely used approved drugs are very effective for HIV treatment, researchers are seeking incremental benefits in the areas of improved tolerability and convenience – such as long-acting drugs – as well as new options for HIV pre-exposure prophylaxis, or PrEP.

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) work by adding a defective building block that terminates the DNA chain when HIV’s reverse transcriptase enzyme tries to copy viral genetic material.

The report says Kirsten White from Gilead Sciences presented findings on GS-9131, a NRTI that works against HIV with resistance to other drugs in this class. GS-9131 is a pro-drug of the adenosine nucleotide analog GS-9148. Gilead’s tenofovir disoproxil fumarate and tenofovir alafenamide are also adenosine nucleotide analogs; all other approved NRTIs are nucleoside analogs, which require an additional processing step to become active.

GS-9131 is converted to the active GS-9148 diphosphate in lymphocytes. It appears to have a low potential for mitochondrial toxicity and minimal accumulation in the kidneys, which is a drawback of tenofovir.

In laboratory cell cultures GS-9131 showed potent activity against all major HIV-1 subtypes (A, B, C, D, E, F, group O and N) and also against HIV-2. Potency was not affected by NRTI resistance mutations including K65R, M184V, multiple thymidine analog mutations, or the T69 insertion. It had a high barrier to resistance, with multiple mutations required to confer reduced susceptibility. It demonstrated additive to synergistic activity, and so far no drug interactions, with several other antiretrovirals. “GS-9131 is an attractive candidate for once-daily dosing in combination with other antiretrovirals in patients with NRTI resistance and limited treatment options,” the researchers concluded.

A pair of studies looked at Merck’s MK-8591, also known as EFdA, a long-acting nucleoside reverse transcriptase translocation inhibitor that binds to the polymerase active site of HIV reverse transcriptase, the report says.

Research presented at last year’s CROI showed that MK-8591 was highly potent in animal and human studies. A single oral dose produced desired intracellular drug concentrations for more than a week, and a long-acting injectable formulation may maintain effective drug levels for up to 6 months.

Jay Grobler from Merck reported that MK-8591 reached high concentrations in lymphoid tissue in rats, suggesting the potential to fight ongoing HIV replication in lymph nodes. The drug also showed good distribution to rectal and vaginal tissues in monkeys, shedding light on its potential suitability for PrEP.

“The levels of MK-8591-[triphosphate] achieved in both rectal and vaginal tissue are comparable to the levels of tenofovir diphosphate observed in rectal tissue from human subjects treated with tenofovir disoproxil fumarate,” the researchers concluded. “Given the significantly greater potency of MK-8591 (IC50=0.2 nM) compared to TDF (IC50=73 nM), these data suggest utility of MK-8591 for prophylaxis in both men and women.”

In a separate study Merck researchers showed that MK-8591 is also a highly potent inhibitor of HIV-2. The drug is about 5 times more active against HIV-2 than against HIV-1, and virus with certain antiretroviral resistance mutations was found to be “hyper-susceptible” to MK-8591.

Robert Murphy from Northwestern University and colleagues presented findings on a new non-nucleoside reverse transcriptase inhibitor (NNRTI), elsulfavirine or VM1500A, being developed by San Diego-based Viriom. After promising early studies, a 20 mg once-daily oral dose of the elsulfavirine pro-drug Elpida was selected for further study. This drug appears to have long-acting potential, with a half-life of about 8 days.

Researchers conducted a Phase 2b clinical trial comparing once-daily Elpida versus efavirenz (Sustiva), both with tenofovir DF/emtricitabine (the drugs in Truvada) in 120 previously untreated people with HIV.

At week 48 of therapy 81% of Elpida recipients and 74% of efavirenz recipients had HIV RNA <50 copies/mL. Among participants with baseline viral load above 100,000 copies/mL, response rates were 78% and 68, respectively. No patients experienced virological failure, defined as 2 consecutive viral loads over 400 copies/mL.

Drug-related adverse events were about half as frequent in the Elpida group compared to the efavirenz group (37% vs 78%, respectively), and only 1 Elpida recipient discontinued early due to adverse events compared to 7 in the efavirenz group. The same was true for central nervous system side effects (27% vs 50%, respectively).
“This 48-week study demonstrated equivalent virologic and immunologic efficacy of ART regimens including Elpida or efavirenz in ART-naive HIV-1 infected patients,” the researchers concluded. “Elpida was significantly safer than efavirenz-based therapy offering a better tolerated alternative to efavirenz-based ART.”

Based on these findings, Viriom is now testing once-weekly oral and longer-acting injected formulations of elsulfavirine, as well as coformulations, according to a company press release.

The report says turning to HIV protease inhibitors, John Link from Gilead presented findings on GS-PI1, a novel protease inhibitor with potential for unboosted once-daily oral dosing.

Although Gilead dominates the HIV drug market overall, it does not yet have an approved protease inhibitor. Existing protease inhibitors must be used with a pharmaco-enhancer or booster, which increases the likelihood of interactions with other drugs. GS-PI1 showed potent activity against HIV in laboratory cell cultures. It had greater activity against resistant virus than atazanavir (Reyataz) or darunavir (Prezista). It had a high barrier to resistance in vitro. GS-PI1 had good oral bio-availability and half-life of 13-14 hours in rats and dogs.

GS-PI1 “represents a new generation of HIV protease inhibitor with potential for combination in an unboosted single-tablet regimen,” the researchers concluded.

Finally, looking at integrase inhibitors, researchers presented data on a new longer-acting formulation of cabotegravir using nanoparticles.

As previously reported, long-acting injectable cabotegravir plus rilpivirine administered once every 4 or 8 weeks maintained viral suppression at week 48 in people who switched from standard ART regimens with undetectable viral load. Injectable cabotegravir alone is also being studied for PrEP, but researchers found that the drug was absorbed faster than expected, meaning PrEP would probably have to be given every 2 months rather than every 3.

The new formulation of cabotegravir, dubbed NMCAB, administers the drug in tiny nanoparticles designed to release it more slowly. In laboratory cell cultures NMCAB was efficiently taken up by macrophages, with sustained slow release over 30 days. It showed sustained antiretroviral activity for up to 30 days — better than the older injectable cabotegravir formulation. NMCAB was eliminated more slowly in mice, resulting in drug levels up to 300 times higher at 6-8 weeks post-injection than those seen with the older formulation.

The researchers indicated that they are also working on a long-acting nanoparticle formulation of the widely used approved integrase inhibitor dolutegravir (Tivicay).

Abstract 1
There remains a need for an NRTI with potent activity against HIV-1 virus with NRTI resistance. GS-9131 is a monoamidate prodrug of the nucleotide analog GS-9148 (phosphonomethoxy-2′-fluoro-2′,3′-dideoxydidehydroadenosine). GS-9131 undergoes conversion in lymphocytes to GS-9148 diphosphate, a potent inhibitor of HIV-1 RT. GS-9148 has a low potential for mitochondrial toxicity and renal accumulation. Here we report on the antiviral activity and resistance profile of GS-9131.
GS-9131 was subjected to extensive in vitro evaluation of antiviral activity and resistance profile. The PhenoSense HIV assay was used to compare the activity of GS-9131 and the NRTIs (ZDV, ddI, d4T, FTC, ABC, and TFV) against HIV-1 variants with all major types of NRTI resistance mutations. GS-9131 activity was also determined against 14 HIV-1 clinical isolates and 1 HIV-2 isolate in peripheral blood mononuclear cells.
GS-9131 had potent activity against laboratory strains of HIV-1 both in primary cells and T-cell lines (EC50 = 25-200 nM) and exhibited potent antiretroviral activity against HIV-1 isolates of subtypes A, B, C, D, E, F, group O and N (EC50 0.29-113 nM). GS-9131 also had potent activity against HIV-2 (EC50 = 21 nM) and showed low cytotoxicity in multiple cell types including renal cells (CC50 > 100 µM). The activity of GS-9131 was not affected by the presence of RT mutations K65R, L74V, M184V or their combinations (EC50 fold change < 1). Viruses with 4 or more thymidine analog mutations (TAMs), including one with the T69-insertion, showed minimal changes (0.68 to 1.5-fold) in susceptibility to GS-9131, a change smaller than any other tested NRTI. Passaging of HIV-1 in the presence of the parent drug GS-9148 selected for a primary K70E mutation in combination with D123N and T165I, or the poorly fit Q151L mutation in combination with K70E, L74I, and L187F/M in RT; these variants conferred <3-fold and 50-fold reduced susceptibility to GS-9131, respectively. GS-9131 (GS-9148) was synergistic in combination studies with AZT, FTC, ABC, efavirenz, the integrase inhibitors bictegravir and dolutegravir, and the PI lopinavir, and additive with TFV and TAF.
GS-9131 exhibits potent in vitro antiretroviral activity and a favorable resistance profile including lower levels of resistance than approved NRTIs. GS-9131 is an attractive candidate for further clinical development with a potential for once daily dosing and efficacy in patients with NRTI resistance.

Kirsten L White, Nicolas Margot, Kirsten Stray, Helen Yu, George Stepan, Constantine Boojamra, Richard Mackman, Adrian Ray, Michael D Miller, Tomas Cihlar

Abstract 2
MK-8591 is a long acting nucleoside reverse transcriptase translocation inhibitor (NRTTI) that has demonstrated potent antiviral activity in HIV-1 infected subjects administered a once-weekly (QW) 10 mg dose as monotherapy in a clinical trial and in SIV-infected rhesus macaque models. MK-8591 extended duration dosing potential was suggested by the long-intracellular half-life of MK-8591-triphosphate (MK-8591-TP) in peripheral blood mononuclear cells (PBMCs) in vitro and in preclinical models. Here we describe the tissue distribution of MK-8591 and its anabolites in rats by quantitative whole body autoradiography and in rhesus vaginal and rectal mucosa by biopsy.
Wistar Hannover rats dosed orally at 50 mpk (mg/kg) of [14C]-MK-8591 were sacrificed at 0.5 hr and 24 hr, cryo-sectioned (40 μm thick sagittal), and phosphor imaged for 4 days. Radioactivity in tissues was quantified using the blood standards along with Raytest AIDA image analysis software. For rectal and vaginal tissue distribution studies, monkeys were dosed 3.9 mpk orally on days 1 and 8. PBMCs were isolated from blood collected at day 1, 7, 14, and 21. Colorectal and vaginal biopsies were collected on days 7 (pre-dose) and 14, pooled separately, and snap-frozen with liquid nitrogen. PBMC and biopsy samples were analyzed by LC-MS/MS.
In rats, MK-8591 distributed widely within 30 min of dosing and was notably enriched in lymphoid tissue (75.9 nmol-eq/g) compared to blood (lymph node:blood ratio = 2.7). MK-8591 remained enriched in lymphoid tissue at 24 hr (11.1 nmol-eq/g; lymph node:blood ratio = 7.1). In rhesus macaques, on days 7 and 14, levels of MK-8591-TP in rectal tissues (36 pmol/g and 31 pmol/g) were similar to those measured in vaginal tissue (49 pmol/g and 78 pmol/g).
The levels of MK-8591-TP achieved in both rectal and vaginal tissue are comparable to the levels of tenofovir diphosphate observed in rectal tissue from human subjects treated with tenofovir disoproxil fumarate. Given the significantly greater potency of MK-8591 (IC50=0.2 nM) compared to TDF (IC50=73 nM), these data suggest utility of MK-8591 for prophylaxis in both men and women. In addition, as lymphoid tissues are sites of active HIV replication and persistence, the observation that MK-8591 is enriched in lymphoid tissues in rats suggests the potential to address the ongoing replication of HIV in lymph nodes.

Jay Grobler, Carolyn McHale, Carol Freddo, Dan Dreyer, Li Sun, Marissa Vavrek, Sheila Breidinger, Kerry Fillgrove, Daria Hazuda, Ming-Tain Lai

Abstract 3
EFdA (4´-ethynyl-2-fluoro-2´-deoxyadenosine; MK-8591; Merck & Co.) is an investigational NRTI that blocks HIV-1 replication in culture with 50% effective concentrations (EC50) in the low-nanomolar to picomolar range. EFdA is highly active against HIV-1 and SIV in humanized mice and rhesus macaques, respectively, and a single 10-mg dose of EFdA demonstrated potent antiviral activity for 10 days in a phase 1b proof-of-concept clinical trial. However, studies evaluating the activity of the EFdA against HIV-2 are lacking, and the ability of the drug to inhibit NRTI-resistant mutants of HIV-2 is unknown.
HIV-1 and HIV-2 isolates from antiretroviral-naïve individuals were tested against EFdA in single-cycle infections of MAGIC-5A cells. Site-directed mutants of HIV-2 reverse transcriptase (RT) were generated in a full-length plasmid clone (pROD9) and were evaluated for EFdA resistance in the single-cycle assay. 50% cytotoxic concentrations (CC50) for EFdA were determined using a CellTiter-Glo® luminescence kit.
EFdA inhibited HIV-2 infection of MAGIC-5A cells with mean EC50 values (± SD) of 0.58 ± 0.13 nM for 6 group A isolates and 0.55 ± 0.16 nM for 6 group B isolates (range = 0.34–0.83 nM for all 12 HIV-2 strains tested). In contrast, the mean EC50 for 6 HIV-1 isolates, including group M subtype A, B, C and D strains and the group O isolate MVP5180-91, was 2.0 ± 0.43 nM (range = 1.29–2.54 nM; p < 0.0001 for HIV-1 vs. HIV-2, Mann-Whitney test). In spreading infections of CEMss cells, EC50 values for HIV-2 ROD9 and HIV-1 NL4-3 were 38 and 120 pM, respectively. EFdA was fully active against HIV-2 RT mutants K65R and Q151M (EC50 = 0.17 ± 0.04 nM and 0.31 ± 0.05 nM, respectively), whereas the M184V variant was 10-fold resistant to the drug. Similar levels of resistance (12–16-fold) were seen for HIV-2 mutants that harbored M184V plus one or more additional NRTI resistance-associated changes in RT, including a patient-derived clone encoding K65R+N69S+V111I+Q151M+M184V. The CC50 for EFdA in MAGIC-5A cells was >100 nM.
EFdA is the most potent inhibitor of HIV-2 replication described to date and is more active against HIV-2 than against HIV-1 in culture. EFdA also inhibits multi-NRTI–resistant HIV-2 mutants with single-cycle EC50 values ≤ 10 nM. These data indicate that EFdA should be evaluated in clinical studies involving HIV-2–infected individuals.

Vincent Wu, Robert Smith, Sara Masoum, Dana Raugi, Selly Ba, Moussa Seydi, Jay Grobler, Geoffrey Gottlieb

Abstract 4
Elpida® (VM1500) is the prodrug of Elsulfavirine (VM1500A), a new potent non-nucleoside reverse transcriptase inhibitor with unique pharmacokinetic properties (T1/2 is ~8 days). A 20 mg once daily dosing was chosen for further study based on 12-week efficacy, pharmacology and safety data.
Compare the efficacy and safety of an ART regimen including Elpida or Efavirenz (EFV) plus tenofovir/emtracitabine (TDF/FTC). Phase IIb randomized, placebo-controlled, double-blind, multicenter study in ART-naïve HIV-1-infected patients treated for 48 weeks. Patients were randomized 1:1 to receive; 1) Elpida 20 mg QD, or 2) EFV 600 mg QD. All patients were treated with TDF/FTC.
120 patients enrolled, 60 Elpida/60 EFV. Baseline plasma HIV RNA median was 4.7-4.8 log10 copies/ml; median CD4+ T lymphocyte count was 349 and 379 cells/mm3 for Elpida and EFV respectively. A total of 55/60 (91.7%) Elpida and 47/60 (78.3%) EFV (p=0.041) completed treatment. At Week 48 of therapy 45/55 (81%) of Elpida and 35/47 (73.7%) of EFV patients had HIV-1 RNA values 100 000 copies/ml, with HIV RNA 400copies/ml. CD4+ T lymphocyte counts increased at Week 48 by 179 and 182 cells/mm3 respectively. Median CD4/CD8 ratio increased in both groups from 0.41 to 0.78 and from 0.34 to 0.63 respectively. Study drug-associated adverse events were observed in N22/60 (36.7%) of Elpida patients and 45/58 (77.6%) of EFV patients (p <0.0001). AEs of special interest (CNS disorders, skin disorders) with a frequency > 5% occurred in 31.7% and 62.1% of patients respectively (p = 0.008). The most frequent were headache (15% and 24.1%), dizziness (6.7% and 27.6%), sleep disorders (5% and 20.7%). Only EFV patients had abnormal dreams (17.2%), skin rash (17.2%), and pruritus (5.2%). Only 5 patient discontinued Elpida (2 AE [1 pregnancy], 1 lack of compliance, 1 LTFU, 1 withdrew consent), and 13 patients discontinued EFV (7 AE, 5 LTFU, 1 withdrew consent) because of drug-related AEs.
Elpida was significantly better tolerated than EFV-based therapy offering a safer alternative to EFV-based ART.

Robert Murphy, Alexey V Kravchenko, Elena Orlova-Morozova, Firaya Nagimova, Oleg Kozirev, Tatyana Shimonava, Marina Deulina, Natalia Vostokova, Olga Zozulya, Vadim Bichko

Abstract 5
Background: HIV protease inhibitors (PIs) represent an important antiretroviral class largely due to their low potential to select for clinical resistance. Despite extensive discovery and development efforts over the past 30 years, all marketed PIs suffer from high rates of hepatic oxidative metabolism, leaving none that are suitable for once-daily (QD) dosing without pharmacokinetic boosting. Here we describe a novel, potent HIV PI that exhibits a high resistance barrier, exceptional metabolic stability, and has the potential for use as an unboosted, QD oral agent for the treatment of HIV infection.
Methods: Antiretroviral EC[sub]50[/sub] and Hill-coefficient values were measured in a cytopathic MT4 T-cell assay. PI cross-resistance was assessed against a panel of atazanavir (ATV) and darunavir (DRV) resistance-associated HIV-1 mutants (RAMs). Predicted drug clearance (CL) was measured in human liver microsomes with added cofactors. Oral and intravenous pharmacokinetic studies were conducted in rat and dog.
Results: GS-PI1 is a potent inhibitor of HIV replication in MT4 cells with an EC50 of 4.9 nM (ATV and DRV EC50 values are 10.7 and 7.5 nM, respectively), a Hill-slope of 5.0, and a protein-adjusted EC95 of 310 nM. Similar antiretroviral potency was observed in PBMCs. GS-PI1 potency was reduced Conclusion: GS-PI1 represents a new class of HIV protease inhibitor possessing favorable potency, resistance barrier, and in vivo half-lives relative to marketed HIV PIs and has been designed to achieve metabolic stability without pharmacokinetic boosting. GS-PI1 has the potential for once-daily oral dosing without boosting in the treatment of HIV infection.

John O Link, Darryl Kato, Michael Moore, Andrew Mulato, Bernard Murray, Judy Mwangi, Nathan D Shapiro, George Stepan, Yujin Wang, Zheng-Yu Yang

Abstract 6
Significant interest in long-acting parenteral (LAP) antiretroviral drugs (ARVs) has set the bar for future HIV/AIDS care. LAP ARVs can improve treatment adherence and positively affect drug resistance and systemic toxicity patterns. Cabotegravir (CAB), a potent HIV integrase inhibitor, now in phase II clinical trials as a LAP (CAB-LAP), currently demonstrates sustained plasma drug levels in humans up to 52 days after single intramuscular dose. We proposed that CAB-LAP could be modified to further reduce injection volumes and improve pharmacokinetic (PK) profiles. To this end, a nanoformulated prodrug of CAB (called NMCAB) was made to extend the drug half-life and antiretroviral activities and enabled the creation of a long-acting dolutegravir (DTG).
CAB was chemically conjugated to myristoyl chloride, increasing its hydrophobicity. NMCAB was produced by high-pressure homogenization with poloxamer 407. Uptake and retention were tested in human monocyte-derived macrophages (MDM). Antiretroviral activity was evaluated by HIV reverse transcriptase (RT) activity and HIV-1p24 expression. Pharmacokinetics of NMCAB was evaluated in Balb/C mice and compared to parent drug formulations after a single intramuscular injection of 15 or 45 mg/kg. The plasma drug levels were monitored for two months.
NMCAB was efficiently taken up by MDM with sustained slow release of up to 30 days. Notably, the parent drug formulations were eliminated after a single day of treatment. Drug crystals were observed by transmission electron microscopy in NMCAB treated MDM, but not in cells treated with parent drug. NMCAB showed sustained antiretroviral activity in MDM as determined by both RT activity and HIV-1p24 staining for up to 30 days after drug removal. In contrast, parent drug formulations failed to inhibit viral growth one day after drug loading. In in vivo studies, NMCAB showed reduced burst release but was cleared more slowly, resulting in drug levels at later time points being up to 100 times higher than the parent drug formulations (Figure). Replicate results were seen for a created DTG prodrug and will be discussed.
Both CAB and DTG prodrugs were successfully synthesized and encapsulated into nanoparticles with clear improvements as a LAP formulation for antiretroviral therapy.

Tian Zhou, Benson Edagwa, JoEllyn McMillan, Howard E Gendelman

HIV and Hepatitis material
CROI 2017 abstract 436
CROI 2017 abstract 435
CROI 2017 abstract 440
CROI 2017 abstract 452LB
CROI 2017 abstract 433
CROI 2017 abstract 439
Viriom Inc material

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