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ICAAC 2013: Researchers Present Data on New NNRTIs AIC292 and MK-1439

A pair of next-generation HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) demonstrated promising activity in early studies, researchers reported last week at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013) in Denver. AIC292 showed good antiviral activity in early laboratory, animal and human studies. MK-1439, now in Phase 2b, is likely to interact with ritonavir, but not tenofovir.

AIC292

Researchers are eager to develop new antiretrovirals that have a high barrier to resistance and low cross-resistance with existing drugs. Given the high effectiveness and good tolerability of existing medications, they must also simple to administer -- ideally once-daily -- and suitable for combining in fixed-dose coformulations to minimize pill burden.

Holger Zimmerman from AiCuris in Wuppertal, Germany -- a Bayer spin-off focusing in infectious disease therapies -- gave a late-breaker presentation on AIC292, an NNRTI belonging to a novel chemical class known as diarylpyrazole-[imidazolidinone]-carboxamides.

In early laboratorystudies AIC292 demonstrated potent and selective activity against various HIV-1 clinical isolates with both CCR5 and CXCR4 tropism (using 2 different co-receptors to enter cells).

In this analysis, AIC292 was evaluated in vitro using cell-based assays against wild-type HIV (lacking resistance mutations) and multiple NNRTI-resistant strains. It was also tested in combination with marketed antiretroviral drugs from the nucleotide/nucleoside, NNRTI, protease inhibitor, and integrase inhibitor classes.

In addition, AIC292 was studied in an in vivo model using mice with surgically implanted foam grafts containing human cells. Toxicity studies were done in rats and dogs. Finally, the first Phase 1 clinical trial evaluated the new drug in 2 groups of 8 healthy HIV negative volunteers whoreceived either AIC292 at single ascending doses or placebo.

Results

• ACI292 showed good activity at low nanomolar concentrations against wild-type HIV and viruses with a variety of NNRTI-resistance mutations, including the highly prevalent K103N, Y181C, and G190A substitutions.
• Tested against a panel of viruses carrying double, triple, or quadruple NNRTI-resistance mutations, AIC292 worked better than currently approved drugs in its class.
• AIC292 proved highly active against HIV bearing the L100I mutation, which is associated with resistance to the second-generation NNRTIs efavirenz (Sustiva or Stocrin), etravirine (Intelence), and rilpivirine (Edurant); Zimmerman described these viruses as "hypersusceptible" to AIC292, adding that the molecular mechanism is not yet known.
• AIC292 demonstrated a high barrier to resistance, remaining active against wild-type and NNRTI-resistance HIV for more than a month when used as monotherapy; at least 2 mutations are required to confer resistance.
• When studied in combination with existing antiretrovirals, AIC292 showed no antagonistic activity with any of the 21 tested drugs from all classes.
• On the contrary, AIC292 demonstrated additive or slightly synergistic activity --meaning the drugs work better together than their added individual effects would predict -- in all combinations.
• In the mouse model, during 5 days of treatment, AIC292 again demonstrated potent activity, with once-daily administration comparing favorably to twice-daily dosing of efavirenz, etravirine, or rilpivirine.
• AIC292 appeared well-tolerated in different laboratory human cell lines and in animals, with "no noteworthy findings" observed in 4-week toxicity studies in rats and dogs.
• In the Phase 1 trial, AIC292 was shown to be safe and well-tolerated at doses up to 1400 mg; there were "only a limited number of adverse events" (not specified), with no concerns related to vital signs, electrocardiograms, or laboratory safety parameters.
• Looking at pharmacokinetics, AIC292 had protein-binding levels similar to other NNRTIs.
• AIC292 did not inhibit major CYP450 enzymes involved in drug metabolism, suggesting low potential for drug-drug interactions, and testing against 68 different receptors showed low potential for "off-target activity."
• In humans AIC292 had a half-life of about 20 hours, suggesting it is suitable for once-daily administration.

"AIC292 represents a promising novel drug with the antiviral properties of a next-generation NNRTI for the treatment of HIV-1 infection," the researchers concluded. "Preclinical data support further clinical evaluation."

MK-1439

At the same session Matt Anderson from Merck presented findings from a study looking at interactions between the novel NNRTI MK-1439 and 2 widely used antiretrovirals, ritonavir (Norvir) and tenofovir disoproxil fumarate (Viread, also in the Truvada, Atripla, Eviplera, and Stribild coformulations).

In studies to date, MK-1439 has shown good antiviral potency, safety and tolerability. As reported at last year's ICAAC, MK-1439 works well against NNRT-resistant viruses with the K103N, Y181C, and G190A mutations. At this year's Retrovirus conference Anderson reported that MK-1439 demonstrated robust activity and good tolerability as monotherapy in a Phase 1b trial and had minimal central nervous system (CNS) toxicity -- a common concern with efavirenz.

MK-1439 is primarily metabolized by oxidation via the CYP3A4 enzyme in the liver, which may lead to interactions with other drugs processed by the same pathway. Early pharmacokinetic studies suggested that MK-1439 did not inhibit or significantly induce drug-metabolizing CYP enzymes, and it did not meaningfully alter midazolam levels.

Conversely, researchers wanted to know if other antiretroviral drugs that act as CYP3A4 inhibitors or inducers would have clinically significant effects on MK-1439. CYP3A4 inhibitors slow drug processing, which can lead to higher concentrations and intensified side effects; this is the principle behind "boosting" other antiretrovirals with the potent CYP3A4 inhibitors ritonavir or cobicistat. CYP3A4 inducers, in contrast, speed up processing and can lead to low drug levels that do not adequately control viral replication.

Ritonavir is both a strong inhibitor and an inducer of CYP3A4. Tenofovir has more "idiosyncratic interaction potential" that does not follow a consistent pattern, the researchers noted as background.

Merck investigators performed 2 open-label, fixed-sequence studies -- 1 for ritonavir, 1 for tenofovir -- each enrolling 8 healthy HIV negative volunteers. All were men and ages ranged from 21 to 50 years.

In the ritonavir study, during the first period participants received a single 50 mg dose of MK-1439. During the second period, after a 7-day washout, they received 100 mg twice-daily ritonavir for 20 days, with a second single 50 mg dose of MK-1439 taken with the morning ritonavir dose on day 14.

In the tenofovir study, during the first period volunteers received a single 100 mg dose of MK-1439. During the second period, again after a 7-day washout, they received 300 mg once-daily tenofovir for 18 days, with a second single 100 mg dose of MK-1439 taken with tenofovir on Day 14.

Blood samples were collected before and after dosing during each treatment period. Researchers measured pharmacokinetic parameters including overall plasma concentration (area under the curve, or AUC), 24-hour minimum or trough plasma concentration (C_24hr), maximum plasma concentration (C_max), time to reach maximum concentration (T_max), and half-life, or time needed to eliminate half the drug. They also evaluated adverse events, vital signs, electrocardiograms, and laboratory safety values.

Results

• All participants in the ritonavir study, and all but 1 in the tenofovir study, completed the trial; that single individual stopped due to diverticulitis considered not related to the study drug.
• Co-administration of MK-1439 with either ritonavir or tenofovir was generally safe and well-tolerated, with no serious adverse events or CNS side effects seen in either study.
• Most participants (8 in the ritonavir study, 4 in the tenofovir study) reported mild-to-moderate adverse events of limited duration, a majority of which were deemed possibly drug-related.
• No significant effects on vital signs, electrocardiograms, or laboratory safety measurements were observed in either study. 
• Co-administration with ritonavir approximately tripled overall AUC and trough concentrations of MK-1439, although the maximum concentration only rose by about 30% (geometric mean ratios 3.54, 2.91, and 1.31, respectively).
• Time to reach C_max increased from 3.5 to 5.0 hours, while apparent half-life more than doubled, from 13.9 to 34.9 hours.
• Co-administration with tenofovir, in contrast, had little effect on MK-1439 levels: AUC and C_24hr concentrations of MK-1439 remained about the same, with a small decrease in C_max (geometric mean ratios 0.97, 0.95 and 0.82, respectively).
• T_max (2.5 vs 3.0 hours) and apparent half-life (14.4 vs 15.8 hours) were also similar.

These findings "[suggest] that ritonavir has a limited effect on MK-1439 bioavailability and absorption, but a significant effect on MK-1439 elimination, due to inhibition of CYP3A4," the researchers concluded. "Co-administration with MK-1439 has no clinically meaningful effect on the pharmacokinetics of MK-1439."

Responding to audience questions, Anderson indicated that the clinical dose of MK-1439 has not yet been determined. He added that it is not yet clear whether dose adjustment will be required when using MK-1439 with ritonavir or cobicistat. "We need to know the clinical bounds of meaningful change -- not just pharmacokinetics -- which will come from clinical trials," he said.

9/17/13

References

S Wildum, D Paulsen, K Thede, H Zimmerman et al. Antiviral activity of AIC292, a novel next-generation HIV- 1 nonnucleoside reverse transcriptase inhibitor. 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Denver, September 10-13, 2013. Abstract H1464b.

MS Anderson, J Gilmartin, A Mitselos, et al. Effect of ritonavir and tenofovir on the pharmacokinetics of MK-1439, a novel HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Denver, September 10-13, 2013. Abstract H-1462.