Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced an update regarding the Phase 2 IMAGINE-DR
clinical trial (MK-8507-13), which is evaluating the
investigational combination of MK-8507, a non-nucleoside reverse
transcriptase inhibitor, and islatravir (ISL), a nucleoside reverse
transcriptase translocation inhibitor, as a once-weekly oral
treatment for HIV-1 infection. MK-8507 and islatravir, alone and in
combination, are investigational and not approved for use.
Decreases in total lymphocyte and CD4+ T-cell counts were
observed in study participants randomized to receive ISL+MK-8507. A
review by the external Data Monitoring Committee (eDMC) determined
that this effect was related to treatment with the combination of
ISL+MK-8507; the greatest decreases were seen in the arms of the
study receiving the highest doses of MK-8507 (200 mg and 400 mg).
At the recommendation of the eDMC, Merck is stopping dosing in the
trial, with continued monitoring of study participants. The company
has notified investigators and paused development of MK-8507. Merck
remains confident in islatravir’s overall profile and is continuing
with development of islatravir across a range of settings including
in treatment of patients living with HIV and in pre-exposure
prophylaxis (PrEP). None of these other programs combine islatravir
with MK-8507.
“Merck remains resolute in its commitment to help address the
unmet needs of people living with HIV and continue to do our part
in the global efforts to help end the HIV pandemic, which includes
the ongoing development of islatravir,” said Dr. Joan Butterton,
vice president, infectious diseases, Global Clinical Development,
Merck Research Laboratories. “All clinical studies provide
important learnings to help us in the fight against HIV, and we are
grateful to the patients and investigators for their
contributions.”
In light of the findings from the MK-8507-013 study, Merck
conducted a review of trends in total lymphocyte and CD4+ T-cell
counts in company-sponsored clinical trials of ISL across all
indications and dosing regimens. A dose-dependent decrease in
lymphocyte counts was observed in an ongoing Phase 2 trial
(MK-8591-016), which is evaluating monthly ISL (60 mg and 120 mg)
for PrEP in participants at low-risk of HIV-1 infection. In this
population of HIV-1 uninfected participants, the mean decreases
were in the normal range and there was no increase in clinical
adverse events (AEs) related to infection. In addition, a small,
treatment related mean decrease in CD4+ T-cell counts was observed
through Week 48 in two Phase 3 trials, ILLUMINATE SWITCH A and
ILLUMINATE SWITCH B (MK-8591A-017 and MK-8591A-018), which are
evaluating doravirine 100 mg in combination with ISL 0.75 mg daily
(DOR/ISL) in HIV-1 virologically suppressed participants. There was
no increased incidence of AEs related to infections in participants
receiving DOR/ISL relative to comparators through Week 48.
Investigators for these trials have been informed and the trials
are continuing. Full results from ILLUMINATE SWITCH A and
ILLUMINATE SWITCH B will be presented at an upcoming medical
meeting.
Merck has an expansive HIV clinical development program
evaluating islatravir across a variety of dosing regimens, for both
the treatment of HIV-1 in combination with other antiretroviral
agents and for the prevention of HIV-1 as a monotherapy. Merck
recently announced positive topline results from the ILLUMINATE
SWITCH A and ILLUMINATE SWITCH B Phase 3 clinical trials. As
previously reported, at 48 weeks, both trials met their primary
efficacy endpoint of percentage of participants with HIV-1 RNA
levels ≥50 copies/mL, demonstrating that antiviral efficacy was
comparable between DOR/ISL and different antiretroviral therapy
regimens (ILLUMINATE SWITCH A) and between DOR/ISL and
bictegravir/emtricitabine/tenofovir (ILLUMINATE SWITCH B).
About IMAGINE-DR
The IMAGINE-DR clinical trial was a Phase 2, randomized,
controlled, double-blind, dose-ranging study, designed to evaluate
a switch to MK-8507 and ISL in combination as a once-weekly oral
treatment in adults with HIV-1 who have been virologically
suppressed for greater than or equal to six months on
bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF)
once-daily. The study had been fully enrolled with 161 participants
and was ongoing.
About PIFELTRO™ and DELSTRIGO™
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.
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.
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 (MK-8591) is Merck’s investigational nucleoside
reverse transcriptase translocation inhibitor under evaluation in
more than 10 clinical trials. For treatment, islatravir is being
evaluated in combination with other antiretrovirals, including the
ILLUMINATE clinical trials program for a once-daily regimen. In the
IMPOWER clinical trials, islatravir is also being studied for
pre-exposure prophylaxis (PrEP) of HIV-1 infection as a single
agent across a variety of formulations, including an oral
once-monthly regimen.
Our Commitment to HIV
For more than 35 years, Merck has been committed to scientific
research and discovery (R&D) in HIV. Today, we are developing a
series of antiviral options designed to help people manage HIV and
protect people from HIV, with the goal of reducing the growing
burden of infection worldwide. We remain committed to working
hand-in-hand with our partners in the global HIV community to
address the complex challenges that impede progress toward ending
the epidemic.
About Merck
For over 130 years, Merck, known as MSD outside 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 2020
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 (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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