Treatment With Islatravir and Doravirine
Maintained Viral Suppression and No Viral Resistance was
Identified
Company Also Presenting Phase 1/1b Results
for MK-8507, a New Investigational Once-Weekly Oral HIV Agent;
Company Advances MK-8507 to Phase 2
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced Week 96 data from the Phase 2b trial
(NCT03272347) evaluating the efficacy and safety of islatravir, the
company’s investigational oral nucleoside reverse transcriptase
translocation inhibitor (NRTTI), in combination with doravirine
(PIFELTRO™), in treatment-naïve adults with HIV-1 infection. Week
96 findings demonstrated that the combination of islatravir and
doravirine maintained virologic suppression (as measured by the
number of study participants achieving HIV-1 RNA levels <50
copies/mL, similar to DELSTRIGO™ (doravirine/lamivudine/tenofovir
disoproxil fumarate)), and the findings were consistent with Week
48 results. Additional Week 96 data from the study show low rates
of participants meeting the definition of protocol-defined
virologic failure (PDVF) in both the islatravir plus doravirine and
the DELSTRIGO treatment arms, and no participants in either arm met
the criteria for resistance testing. Merck also announced results
from Phase 1/1b studies for MK-8507, the company’s investigational
once-weekly oral non-nucleoside reverse transcriptase inhibitor
(NNRTI), which showed that the antiviral potency and
pharmacokinetics of MK-8507 support further investigation for
once-weekly oral administration as part of combination
antiretroviral therapy. These analyses were presented as oral and
poster presentations at the virtual 2020 International Congress on
Drug Therapy in HIV Infection (HIV Glasgow 2020).
“Our commitment to medical advances in HIV can be seen in the
important data we are presenting at HIV Glasgow 2020, including
islatravir’s potential for use in combination with doravirine as a
once-daily, two-drug treatment. In addition, we are presenting data
on MK-8507, which is advancing to Phase 2 investigations in
combination with islatravir as a once-weekly oral regimen,” said
Dr. Joan Butterton, vice president, infectious diseases, Global
Clinical Development, Merck Research Laboratories. “We continue to
pursue new methods for treating HIV, as shown by our growing body
of clinical research, and we look forward to sharing new data from
our ongoing, global Phase 3 clinical trials for islatravir with
doravirine in the future.”
PIFELTRO (doravirine, 100 mg) is indicated in combination with
other antiretroviral (ARV) agents for the treatment of HIV-1
infection in adult patients with no prior ARV treatment history or
to replace the current ARV regimen in those who are virologically
suppressed (HIV-1 RNA less than 50 copies per mL) on a stable ARV
regimen with no history of treatment failure and no known
substitutions associated with resistance to doravirine.
DELSTRIGO (doravirine 100 mg/lamivudine 300 mg/tenofovir
disoproxil fumarate 300 mg) is indicated as a complete regimen for
the treatment of HIV-1 infection in adult patients with no prior
ARV treatment history or to replace the current ARV regimen in
those who are virologically suppressed (HIV-1 RNA less than 50
copies per mL) on a stable ARV regimen with no history of treatment
failure and no known substitutions associated with resistance to
the individual components of DELSTRIGO. DELSTRIGO contains a boxed
warning regarding post-treatment acute exacerbations of hepatitis B
(HBV) infection. See Selected Safety Information below.
Week 96 Efficacy and Safety Results from Phase 2b Study of
Investigational 2-Drug Regimen of Islatravir with
Doravirine
In this international, multicenter clinical trial,
treatment-naïve adult participants with HIV-1 infection were
randomly assigned (1:1:1:1) to one of four once-daily oral
treatment groups: islatravir 0.25 mg (n=29), 0.75 mg (n=30), or
2.25 mg (n=31) in combination with doravirine (100 mg) and 3TC (300
mg) compared to DELSTRIGO (n=31). After a minimum of 24 weeks of
treatment, participants in the islatravir treatment groups with
HIV-1 RNA less than 50 copies/mL who had not met protocol-defined
virologic failure (PDVF) criteria were transitioned to a two-drug
regimen consisting of the same dose of islatravir plus doravirine
(100 mg), without 3TC. At Week 96, at all dose levels, the
combination of islatravir and doravirine maintained virologic
suppression as measured by the number of study participants
achieving HIV-1 RNA levels <50 copies/mL. At Week 96, 86.2%
(25/29), 90.0% (27/30), and 67.7% (21/31) of participants
maintained HIV-1 RNA <50 copies/mL in the 0.25 mg, 0.75mg, and
2.25 mg islatravir groups, respectively, with 81.1% (73/90) of the
combined islatravir groups, as compared to 80.6% (25/31) of the
DELSTRIGO group. The numerically lower response rate for the 2.25
mg islatravir group was largely driven by discontinuations through
Week 48.
A lower rate of drug-related adverse events (AEs) occurred in
the islatravir groups (7.8%) compared with the DELSTRIGO group
(22.6%) at Week 96. No additional drug-related serious adverse
events were reported in any group between Week 48 and Week 96.
Based on these results, the 0.75 mg dose of islatravir will be used
for further clinical development.
Week 96 Protocol-Defined Virologic Failure (PDVF) Analysis
from Phase 2b Study of Investigational 2-Drug Regimen of Islatravir
with Doravirine
A Week 96 analysis of the study showed rates of PDVF were low,
and all participants who discontinued due to PDVF had HIV-1 RNA
levels <80 copies/mL, below the clinically significant level of
200 copies/mL. No participants met the criteria for resistance
testing (HIV-1 RNA >400 copies/mL). PDVF was defined as rebound
with confirmed HIV-1 RNA greater than or equal to 50 copies/mL
after suppression or non-response with confirmed HIV-1 RNA greater
than or equal to 50 copies/mL.
At Week 96, a total of seven participants met the definition of
PDVF and discontinued from the trial. As previously reported, at
Week 48, PDVF was confirmed in six participants, 5.6% (5/90; 4
rebound, 1 non-response) of the islatravir treatment groups
combined and 3.2% (1/31; rebound) of the DELSTRIGO group. Only one
additional participant in the 2.25 mg islatravir group discontinued
with PDVF (rebound). None of the participants in any treatment
group met criteria for resistance testing as all confirmed HIV-1
RNA for participants that met the definition of PDVF were <80
copies/mL. During the 42-day follow-up period, three out of seven
participants who discontinued due to PDVF continued to have
low-level viremia after switching to a new regimen.
Week 96 Renal Safety Analysis from Phase 2b Study of
Investigational 2-Drug Regimen of Islatravir with
Doravirine
A Week 96 exploratory analysis showed no renal safety concerns.
Serum creatinine was measured at each study visit, including Day 1,
Week 48, and Week 96. Estimated glomerular filtration rate (eGFR)
was calculated by the Modification of Diet in Renal Disease (MDRD)
formula.
Median changes in serum creatinine and eGFR were minimal in all
treatment groups at Week 48 and Week 96. Two participants in the
0.25 mg islatravir group had isolated instances of ≥0.5 mg/dL
increase from baseline in serum creatinine that resolved by the
next study visit: at Week 16 (1.7 mg/dL) in one participant; at
Week 60 (1.7 mg/dL) and Week 84 (1.9 mg/dL) in the other. No
participants had ≥1.0 mg/dL increase or doubling of serum
creatinine. eGFR reductions greater than 30% from baseline occurred
in 12% (11/90) of islatravir-treated participants and 16% (5/31) of
DELSTRIGO-treated participants and were transient in most cases.
eGFR <60 mL/min/1.73 m2 occurred in 4% (4/90) of
islatravir-treated participants and were transient in three (the
fourth had eGFR <60 mL/min/1.73 m2 from baseline through Week
96). No clinically meaningful changes were observed in renal
biomarkers, including urine albumin, albumin/creatinine ratio,
beta-2 microglobulin/creatinine ratio, or retinol-binding
protein/creatinine ratio. No dose-response relationship was
observed for renal effects of islatravir in combination with
doravirine, and no participant discontinued treatment due to a
renal adverse event.
Phase 1/1b Results for MK-8507
Two randomized, double-blind, placebo-controlled Phase 1
clinical trials were conducted to evaluate the safety, tolerability
and pharmacokinetics of single and multiple oral doses of MK-8507
and potential for drug-drug interaction with midazolam, a CYP3A
substrate, in healthy adult participants. In Study 1, participants
(n=16 males) received single doses of MK-8507 or placebo from 2 mg
to 400 mg. In Study 2, participants (n=24 males and females)
received single doses of MK-8507 or placebo from 400 mg to 1200 mg,
and multiple doses of MK-8507 or placebo (once-weekly for three
weeks) from 100 mg to 400 mg. At the 400 mg once-weekly dose level,
participants also received 2 mg of midazolam prior to MK-8507
dosing and co-administered with the third once-weekly dose.
The pharmacokinetics of MK-8507 support once-weekly
administration for the treatment of HIV-1 infection. MK-8507 had a
Tmax (time to maximum concentration) of two to seven hours and a
mean terminal half-life (t½) of approximately 58-84 hours.
Pharmacokinetics were approximately dose-proportional from 2 mg to
1200 mg. Adverse events reported for MK-8507 were non-serious and
mild in intensity. There were no trends in vital signs,
electrocardiograms or safety laboratory tests. The most common
adverse events were headache, cough, and rhinorrhea.
A Phase 1b open-label, proof of concept study was also conducted
to evaluate the antiviral efficacy, pharmacokinetics, safety, and
tolerability of single doses of 40 mg, 80 mg, and 600 mg of MK-8507
over seven to 14 days in 18 HIV-1 infected, antiretroviral-naïve
adult males (six participants per dosing arm). Single doses of
MK-8507 resulted in a reduction in viral load at seven days,
comparable to other NNRTIs dosed daily for the same timeframe. At
seven days post-dose, a mean (95% CI) viral load reduction of 1.22
(1.52, 0.91) log10 copies/mL at 40 mg, 1.50 (1.80, 1.19) log10
copies/mL at 80 mg, and 1.53 (1.84, 1.23) log10 copies/mL at 600 mg
was observed among participants. The pharmacokinetics were similar
to that observed in uninfected participants, with mean
concentrations at seven days post-dose of 78.1, 214, and 1400 nM at
the 40, 80 and 600 mg doses, respectively. Beginning at day 10,
following a 600 mg dose, one participant experienced viral rebound
with F227C, a NNRTI-associated resistant variant. All doses showed
low rates of adverse events, and the most common adverse events
(AEs) were nasopharyngitis (n=3) and headache (n=3). One serious AE
of diffuse large B-cell lymphoma, not considered to be related to
study drug, was reported.
The antiviral potency and human pharmacokinetics of MK-8507 are
favorable to advancing MK-8507 to Phase 2 studies of once-weekly
administration as part of combination antiretroviral therapy.
Selected Safety Information about PIFELTRO and
DELSTRIGO
Warning: Posttreatment Acute Exacerbation of Hepatitis B
(HBV)
All patients with HIV-1 should be tested for the presence of HBV
before initiating ARV therapy. Severe acute exacerbations of HBV
have been reported in patients who are coinfected with HIV-1 and
HBV and have discontinued products containing lamivudine or
tenofovir disoproxil fumarate (TDF), which are components of
DELSTRIGO. Patients coinfected with HIV-1 and HBV who discontinue
DELSTRIGO should be monitored with both clinical and laboratory
follow-up for at least several months after stopping DELSTRIGO. If
appropriate, initiation of anti-HBV therapy may be warranted.
PIFELTRO and DELSTRIGO are contraindicated when co-administered
with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers
(including the anticonvulsants carbamazepine, oxcarbazepine,
phenobarbital, and phenytoin; the androgen receptor inhibitor
enzalutamide; the antimycobacterials rifampin and rifapentine; the
cytotoxic agent mitotane; and the herbal product St. John’s wort
(Hypericum perforatum)), as significant decreases in doravirine
plasma concentrations may occur, which may decrease the
effectiveness of DELSTRIGO and PIFELTRO.
DELSTRIGO is contraindicated in patients with a previous
hypersensitivity reaction to lamivudine.
Renal impairment, including cases of acute renal failure and
Fanconi syndrome, have been reported with the use of TDF. DELSTRIGO
should be avoided with concurrent or recent use of a nephrotoxic
agent (eg, high-dose or multiple NSAIDs). Cases of acute renal
failure after initiation of high-dose or multiple NSAIDs have been
reported in patients with risk factors for renal dysfunction who
appeared stable on TDF.
Prior to or when initiating DELSTRIGO, and during treatment,
assess serum creatinine, estimated creatinine clearance, urine
glucose, and urine protein in all patients. In patients with
chronic kidney disease, also assess serum phosphorus. Discontinue
DELSTRIGO in patients who develop clinically significant decreases
in renal function or evidence of Fanconi syndrome. Discontinue
DELSTRIGO if estimated creatinine clearance declines below 50
mL/min.
In clinical trials in HIV-1 infected adults, TDF was associated
with slightly greater decreases in bone mineral density (BMD) and
increases in biochemical markers of bone metabolism. Serum
parathyroid hormone levels and 1,25 Vitamin D levels were also
higher. Cases of osteomalacia associated with proximal renal
tubulopathy have been reported with the use of TDF.
Immune reconstitution syndrome can occur, including the
occurrence of autoimmune disorders with variable time to onset,
which may necessitate further evaluation and treatment.
Because DELSTRIGO is a complete regimen, co-administration with
other antiretroviral medications for the treatment of HIV-1
infection is not recommended.
Co-administration of PIFELTRO with efavirenz, etravirine, or
nevirapine is not recommended.
If DELSTRIGO is co-administered with rifabutin, take one tablet
of DELSTRIGO once daily, followed by one tablet of doravirine
(PIFELTRO) approximately 12 hours after the dose of DELSTRIGO.
If PIFELTRO is co-administered with rifabutin, increase PIFELTRO
dosage to one tablet twice daily (approximately 12 hours
apart).
Consult the full Prescribing Information prior to and during
treatment for more information on potential drug-drug
interactions.
Because DELSTRIGO is a fixed-dose combination tablet and the
dosage of lamivudine and TDF cannot be adjusted, DELSTRIGO is not
recommended in patients with estimated creatinine clearance less
than 50 mL/min.
The most common adverse reactions with DELSTRIGO (incidence ≥5%,
all intensities) were dizziness (7%), nausea (5%), and abnormal
dreams (5%). The most common adverse reactions with PIFELTRO
(incidence ≥5%, all intensities) were nausea (7%), dizziness (7%),
headache (6%), fatigue (6%), diarrhea (6%), abdominal pain (5%),
and abnormal dreams (5%).
By Week 96 in DRIVE-FORWARD, 2% of adult subjects in the
PIFELTRO group and 3% in the DRV+r group had adverse events leading
to discontinuation of study medication.
By Week 96 in DRIVE-AHEAD, 3% of adult subjects in the DELSTRIGO
group and 7% in the EFV/FTC/TDF group had adverse events leading to
discontinuation of study medication.
In DRIVE-FORWARD, mean changes from baseline at Week 48 in
LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C) were
pre-specified. LDL-C: -4.6 mg/dL in the PIFELTRO group vs 9.5 mg/dL
in the DRV+r group. Non-HDL-C: -5.4 mg/dL in the PIFELTRO group vs
13.7 mg/dL in the DRV+r group. The clinical benefits of these
findings have not been demonstrated.
In DRIVE-AHEAD, mean changes from baseline at Week 48 in
LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C) were
pre-specified. LDL-C: -2.1 mg/dL in the DELSTRIGO group vs 8.3
mg/dL in the EFV/FTC/TDF group. Non-HDL-C: -4.1 mg/dL in the
DELSTRIGO group vs 12.7 mg/dL in the EFV/FTC/TDF group. The
clinical benefits of these findings have not been demonstrated.
In DRIVE-SHIFT, mean changes from baseline at Week 48 in
LDL-cholesterol (LDL-C) and non-HDL-cholesterol (non-HDL-C) were
pre-specified. LDL-C: -16.3 mg/dL in the DELSTRIGO group vs -2.6
mg/dL in the PI + ritonavir group. Non-HDL-C: -24.8 mg/dL DELSTRIGO
group vs -2.1 mg/dL in the PI + ritonavir group. The clinical
benefits of these findings have not been demonstrated.
In DRIVE-AHEAD, neuropsychiatric adverse events were reported in
the three pre-specified categories of sleep disorders and
disturbances, dizziness, and altered sensorium. Twelve percent of
adult subjects in the DELSTRIGO group and 26% in the EFV/FTC/TDF
group reported neuropsychiatric adverse events of sleep disorders
and disturbances; 9% in the DELSTRIGO group and 37% in the
EFV/FTC/TDF group reported dizziness; and 4% in the DELSTRIGO group
and 8% in the EFV/FTC/TDF group reported altered sensorium.
The safety of DELSTRIGO in virologically-suppressed adults was
based on Week 48 data from subjects in the DRIVE-SHIFT trial.
Overall, the safety profile in virologically-suppressed adult
subjects was similar to that in subjects with no ARV treatment
history.
Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and
16% of subjects in the immediate switch group experienced ALT and
AST elevations greater than 1.25 X ULN, respectively, through 48
weeks on DELSTRIGO. For these ALT and AST elevations, no apparent
patterns with regard to time to onset relative to switch were
observed. One percent of subjects had ALT or AST elevations greater
than 5 X ULN through 48 weeks on DELSTRIGO. The ALT and AST
elevations were generally asymptomatic, and not associated with
bilirubin elevations. In comparison, 4% and 4% of subjects in the
delayed switch group experienced ALT and AST elevations of greater
than 1.25 X ULN through 24 weeks on their baseline regimen.
There is a pregnancy exposure registry that monitors pregnancy
outcomes in individuals exposed to PIFELTRO or DELSTRIGO during
pregnancy. Healthcare providers are encouraged to register patients
by calling the Antiretroviral Pregnancy Registry (APR) at
1-800-258-4263.
Mothers infected with HIV-1 should be instructed not to
breastfeed if they are receiving PIFELTRO or DELSTRIGO due to the
potential for HIV-1 transmission.
About Islatravir (MK-8591)
Islatravir (formerly MK-8591) is Merck’s investigational
nucleoside reverse transcriptase translocation inhibitor (NRTTI)
currently being evaluated in clinical trials for the treatment of
HIV-1 infection in combination with other antiretrovirals, as well
as for pre-exposure prophylaxis (PrEP) of HIV-1 infection as a
single investigational agent, across a variety of formulations.
Our Commitment to HIV
For more than 30 years, Merck has been committed to scientific
research and discovery in HIV, and we continue to be driven by the
conviction that more medical advances are still to come. Our focus
is on pursuing research that addresses unmet medical needs and
helps people living with HIV and their communities. We remain
committed to working hand-in-hand with our partners in the global
HIV community to address the complex challenges that hinder
continued progress.
Our Commitment to Infectious Diseases
For more than 100 years, Merck has contributed to the discovery
and development of novel medicines and vaccines to combat
infectious diseases. In addition to a combined portfolio of
vaccines and antibacterial, antiviral and antifungal medicines,
Merck has multiple programs that span discovery through late-stage
development. To learn more about Merck’s infectious diseases
pipeline, visit www.merck.com.
About Merck
For more than 125 years, Merck, known as MSD outside of the
United States and Canada, has been inventing for life, bringing
forward medicines and vaccines for many of the world’s most
challenging diseases in pursuit of our mission to save and improve
lives. We demonstrate our commitment to patients and population
health by increasing access to health care through far-reaching
policies, programs and partnerships. Today, Merck continues to be
at the forefront of research to prevent and treat diseases that
threaten people and animals – including cancer, infectious diseases
such as HIV and Ebola, and emerging animal diseases – as we aspire
to be the premier research-intensive biopharmaceutical company in
the world. For more information, visit www.merck.com and connect
with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
There can be no guarantees with respect to pipeline products that
the products will receive the necessary regulatory approvals or
that they will prove to be commercially successful. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of the global outbreak of novel coronavirus disease
(COVID-19); the impact of pharmaceutical industry regulation and
health care legislation in the United States and internationally;
global trends toward health care cost containment; technological
advances, new products and patents attained by competitors;
challenges inherent in new product development, including obtaining
regulatory approval; the company’s ability to accurately predict
future market conditions; manufacturing difficulties or delays;
financial instability of international economies and sovereign
risk; dependence on the effectiveness of the company’s patents and
other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2019
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (https://www.sec.gov/).
Please see Prescribing Information for PIFELTRO (doravirine)
at:
https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_pi.pdf;
and Patient Information for PIFELTRO (doravirine) at:
https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_ppi.pdf
Please see Prescribing Information for DELSTRIGO
(doravirine/3TC/TDF) at:
https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf
and Patient Information for DELSTRIGO (doravirine/3TC/TDF)
at:
https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_ppi.pdf
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