| |
New PrEP Long-Acting MK-8591, for HIV Treatment Too
|
| |
| |
Download the PDF here
New Long Acting Potent Nuke MK-8591 + Doravirine Phase 2B Study Starts (2017)
New Journal of Infectious Diseases,
07 June 2019 -
Once-weekly Oral Dosing of MK-8591 Protects Male Rhesus Macaques from Intrarectal SHIV109CP3 Challenge - free
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiz271/5513016?searchresult=1
Background:
Antiretroviral agents are efficacious when taken as prescribed for pre-exposure prophylaxis (PrEP) against HIV-1 infection [1, 2]. Fixed-dose combination tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) prevents HIV-1 infection in high risk individuals when administered daily [3]. Efficacy has also been demonstrated with "on demand" dosing [4]. In clinical trials, outcomes have been closely linked to adherence [5-9]. In high-risk heterosexual women [10] [11], TDF/FTC was ineffective and studies were halted due to futility, likely due to the observation that less than 30% of participants were adherent to the treatment regimen based on plasma drug concentration determinations. In the initial studies of men who have sex with men, overall efficacy was 44%, with a clear gap between those adherent, 90%, and those who were not [2]. Regimens that improve adherence are likely to represent important advances in the field. Identifying alternatives to daily oral PrEP has become a research priority and MK-8591 is one such compound [12]
MK-8591 (4' -ethynyl-2-fluoro-2' -deoxyadenosine, EFdA) is a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI). Its unique mechanisms of action and distinct pharmacology distinguish MK-8591 from approved antiretroviral agents [13-16]. MK-8591 has structural features that contribute to its pharmacologic attributes, 4'-ethynyl, 3'-hydroxyl, and 2-fluoro groups. The 4' -ethynyl group binds tightly to a conserved hydrophobic pocket in HIV-1 reverse transcriptase and interferes with translocation of the extended primer resulting in immediate chain termination [17-19]. The 3'-hydroxyl group, found in naturally occurring nucleotides, contributes to very high binding affinity for reverse transcriptase (RT). Finally, the 2-fluoro on the adenine base ring renders the drug less susceptible to deamination by adenosine deaminase contributing to its long intracellular half-life (t1/2) [20].
These unique structural elements and mechanisms of action confer MK-8591 with high antiviral potency and unique pharmacology making low-dose, infrequent dosing feasible. The potential for extended duration dosing with MK-8591 was first demonstrated in rhesus macaques (RMs). MK-8591-triphosphate (MK-8591-TP), the active metabolite of MK-8591 [21], exhibited a 50-hour intracellular t1/2 in peripheral blood mononuclear cells
(PBMC) [22]. When administered to SIVmac251-infected RMs, 2 once-weekly doses ranging from 3.9 to 18.2 mg/kg resulted in a 1.8 log10 reduction in plasma SIV RNA. The 3.9 mg/kg/week dose, provided a mean MK-8591-TP trough level at 168 hours of 0.53 pmol/106 PBMC, and was on the plateau of treatment efficacy. This informed the initial proof of concept experiments using MK-8591 dosing once weekly (QW) in prophylaxis as described here [22].
Efficacy with weekly MK-8591 dosing has also been demonstrated in the clinic. In humans, MK-8591-TP has a long intracellular t1/2 (78.5 to 128 hours in PBMC) [23]. Single oral doses of MK-8591 of 0.5 mg to 30 mg reduced plasma HIV-1 levels from 1.2 to 1.8 log10 at day 7 to 10 in HIV-1 infected individuals [24]. The MK-8591-TP trough level required for virologic efficacy was consistent with that observed in SIVinfected RMs. At the 10 mg dose, which was well on the plateau of virologic response, MK-8591-TP trough level was approximately 1 pmol/106 PBMCs. At steady state, daily oral dosing of 0.25 mg MK-8591 provides approximately the same PBMC MK-8591-TP trough level as after a single 10 mg dose [24].
SHIV109CP3 [25], a pathogenic clade C SHIV swarm raised from a SHIV clone, SHIVC109.PB4 which contains an HIV-1 envelope from a recently infected Zambian individual was used as the challenge stock for these studies. This SHIV is CCR5- tropic and readily transmissible by the mucosal route. SHIV109CP3 was recovered from the third passage in a rapidly progressing RM. This virus replicates to high levels in vivo, and during acute infection depletes CD4+ T cells in the peripheral blood and the gastrointestinal lymphoid tissue of infected macaques [25].
Here we present the first pre-clinical studies of MK-8591 as a potential PrEP agent in the RM-SHIV low dose intrarectal challenge model, using doses of MK-8591 administered weekly.
Discussion:
The protection against SHIV109CP3 infection provided by low-dose, weekly administration of MK-8591 demonstrates its potential as a next generation PrEP agent. Intracellular levels of MK-8591-TP at or above 102 fmol/106 PBMC resulted in complete protection in this model. The EC90 is estimated to be 24 fmol/106 PBMC which was achieved with a 0.1 mg/kg oral weekly dose. For comparison, it has been estimated that the EC90 of TDF is 22.6 fmol/106 PBMC in RMs treated with oral TDF/FTC and 16 fmol/106 PBMC in men participating in the iPrEx study [28]. The dose of MK-8591 required to obtain a target concentration of 24 fmol/106 PBMC in humans, assuming dose proportionality below 0.5 mg (the lowest dose for which human pharmacokinetic data are available) is approximately 0.25 mg weekly and less than 0.01 mg daily.
The projected dose required to achieve efficacious drug levels for prophylaxis against HIV infection are therefore approximately 30,000-fold lower than that demonstrated for TDF. The low daily dose requirement, coupled with the long t1/2 of MK-8591-TP in humans, provides the opportunity for flexibility with regard to both dosing frequency and potentially, route of administration.
MK-8591 has been evaluated in clinical trials in HIV-1 infected and uninfected individuals. MK-8591-TP exhibited an intracellular half-life of approximately 100 hrs [23, 24]. In these studies, MK-8591-TP levels were well above the predicted EC90 for prophylaxis in excess of a month and suggests the potential for use with oral dosing regimens that are less frequent than QW and perhaps may couple efficacy with forgiveness for late or missed dosing.[30]
There is current enthusiasm for developing long-acting formulations as PrEP. Cabotegravir (CAB), a potent integrase strand transfer inhibitor, has been formulated as an injectable nanosuspension and is in Phase 3 efficacy testing in both men who have sex with men and high-risk women [31]. It is administered intramuscularly every 8 weeks after an every 4 week loading dose. Long acting injectable formulations have complicated clinical development plans. Currently, oral dosing is required prior to the administration of the first injection to rule out drug hypersensitivity as once injected the drug cannot be easily removed. There are also concerns regarding the pharmacokinetic "tail", the circulating levels of CAB that persist below efficacious levels in individuals when they cease treatment, which may increase the risk of resistance should infection occur [32]. This risk has prompted current clinical trials to include the use daily oral TDF/FTC for a year after the last CAB injection. If dosed orally, the projected pharmacologic "tail" of MK-8591 is predictably shorter than intramuscularly administered CAB, however, this remains hypothetical as final decisions regarding dosing and route of MK-8591 have yet to be made as the drug is amenable to dosing in an extended release formulation.
Extended release of MK-8591 from implants formulated using a drug eluting polymeric matrix has been demonstrated in both rats and non-human primates [33] MK-8591 release from these formulations is driven by dissolution and diffusion out of the matrix. Implants have some advantages over oral therapies as well as injectables in that they are potentially much longer lasting, can be removed in the event of untoward adverse events, and once removed do not have the pharmacokinetic tail associated with injectable formulations. MK-8591, because it has a substantially lower dose requirement may have longer durations of release from implants and lower frequency of dosing than for other agents (e.g. tenofovir alafenamide) for which these types of drug delivery systems are being pursued [34].
In summary, MK-8591 demonstrates robust efficacy as prevention in the RM/SHIV intrarectal challenge model. The SHIV/RM low dose intrarectal challenge model has successfully predicted the clinical activity of TDF/FTC as PrEP in high risk MSM [35] and our findings are encouraging. MK-8591 combines antiviral potency and pharmacokinetics that translate to flexibility in dosing level, route and frequency of administration. Given these favorable attributes, clinical development of MK-8591 is highly anticipated and much will be learned in the near future regarding its efficacy and safety as a potential addition to the armamentarium in both HIV-1 therapy and prevention.
-------------------------------------------
CROI 2018: LOW DOSE MK-8591 PROTECTS RHESUS MACAQUES AGAINST RECTAL SHIV INFECTION
Low-Dose Oral MK-8591 Protects Monkeys From Rectal SHIV Infection
"The researchers concluded that MK-8591 remains completely protective against rectal SHIV at doses of 1.3 and 0.43 mg/kg weekly..."suggesting MK-8591 utility in extended-duration prophylaxis against HIV infection.....strong antiviral activity with weekly oral dosing"
Weekly oral MK-8591 protects male rhesus macaques against repeated low dose intrarectal challenge with SHIV109CP3
New Long Acting Potent Nuke MK-8591 + Doravirine Phase 2B Study Starts - (09/27/17)
Efficacy of MK-8591 against diverse HIV-1 subtypes and NRTI-resistant clinical isolates - (10/30/18)
MK-8591 Concentrations at Sites of HIV Transmission and Replication - (02/23/17)
The levels of MK-8591-TP achieved in both rectal and vaginal tissueare comparable to the levels of tenofovir diphosphate observed in rectaltissue from human subjects treated with tenofovir disoproxil fumarate. Given the significantly greater potency of MK-8591 (IC50 = 0.2 nM)compared with TDF (IC50 = 73 nM), these data suggest utility ofMK-8591 for prophylaxis in both men and women. As lymphoid tissues are sites of active HIV replication and persistence,the observation that MK-8591 is enriched in lymphoid tissues in ratssuggests the potential to address the ongoing replication of HIV in lymph nodes. 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-8591extended-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 wedescribe the tissue distribution of MK-8591 and its anabolites in rats by quantitative whole-bodyautoradiography and in rhesus vaginal and rectal mucosa by biopsy.
Antiviral Activity of EFdA [MK-8591] Against NRTI-Sensitive and -Resistant Strains of HIV-2 - (02/24/17)
"potential pre-exposure prophylaxis agent to prevent HIV transmission in women and their infants......MK-8591 (or EFdA) is a NRTI with very potent in vitro activity against HIV....Viral suppression was maintained for at least 7 days after the last dose. This study provides proof of concept for a once weekly oral dosing strategy of MK-8591....."Our data demonstrated that EFdA efficiently prevents both vaginal and oral HIV transmission. Together with EFdA's relatively low toxicity and high potency against drug-resistant HIV strains, these data support further clinical development of EFdA as a potential pre-exposure prophylaxis (PrEP) agent to prevent HIV transmission in women and their infants."
|
|
| |
| |
|
|
|
