Trials met efficacy success criteria for
non-inferiority of DOR/ISL to comparator antiretroviral therapies
in adults with virologically suppressed HIV-1
Safety profiles were generally comparable
between DOR/ISL and other therapies in these trials
Merck (NYSE: MRK), known as MSD outside of the United States and
Canada, today announced topline results from two pivotal Phase 3
trials of the investigational, once-daily, oral, two-drug,
single-tablet regimen of doravirine/islatravir [DOR/ISL (100
mg/0.25 mg)] in adults with HIV-1 infection that is virologically
suppressed on different antiretroviral therapy regimens [baseline
antiretroviral therapy (bART)]; MK-8591A-051 or
bictegravir/emtricitabine/tenofovir alafenamidei [BIC/FTC/TAF (50
mg/200 mg/25 mg)]; MK-8591A-052.
The success criterion for the primary efficacy hypothesis, as
measured by the percentage of participants with HIV-1 RNA levels
≥50 copies/mL at Week 48, was met in both trials. DOR/ISL was
demonstrated to be non-inferior to bART in open-label trial
MK-8591A-051 and non-inferior to BIC/FTC/TAF in double-blind trial
MK-8591A-052. The superiority criteria were not met in trial
MK-8591A-052. Primary safety objectives of both trials were also
met.
The company is planning to present detailed findings from these
trials at a future scientific congress and will also plan to file
these data with regulatory authorities. In the U.S., doravirine is
approved for the treatment of adults with HIV-1 in combination with
other antiretrovirals, as a single agent (PIFELTRO) and a component
of a single-tablet regimen [DELSTRIGO; doravirine, lamivudine, and
tenofovir disoproxil fumarate (DOR/3TC/TDF)].
“We are encouraged by the results from these Phase 3 trials
evaluating a once-daily, oral, two-drug, single-tablet regimen of
doravirine and islatravir,” said Dr. Eliav Barr, senior vice
president, head of global clinical development and chief medical
officer, Merck Research Laboratories. “We are committed to
advancing our clinical programs for islatravir in combination with
other antiretrovirals as potential options to help address the
needs of people living with HIV.”
Islatravir (MK-8591), Merck’s investigational nucleoside reverse
transcriptase translocation inhibitor (NRTTI), exhibits both
transcriptase and translocation inhibition (which prevents
nucleotide binding and incorporation to the DNA chain, resulting in
immediate chain termination) and delayed chain termination (which
prevents nucleotide incorporation even in the event of
translocation). Islatravir is being evaluated in multiple early and
late-stage clinical trials in combination with other antiretroviral
therapies for the treatment of HIV-1. In addition to the
MK-8591A-051 and MK-8591A-052 trials, ongoing Phase 3 trials of
DOR/ISL include MK-8591A-053 in people with HIV who had not
previously received treatment (treatment-naïve), and MK-8591A-054
evaluating open-label DOR/ISL (100 mg/0.25 mg) in individuals who
participated in earlier Phase 3 trials of DOR/ISL (100 mg/0.75
mg).
About MK-8591A-051 (NCT05631093)
MK-8591A-051 is a Phase 3, randomized, active-controlled,
open-label clinical trial evaluating a switch to investigational,
oral, once-daily DOR/ISL (100 mg/0.25 mg) in adults with HIV-1
infection that has been virologically suppressed using ART.
Participants (n=551) were randomized 2:1 to either switch to
investigational DOR/ISL or continue with their current bART regimen
through Week 48. After Week 48, all participants receive DOR/ISL
through Week 144 of the trial. After Week 144, eligible
participants may continue on DOR/ISL and continue trial treatment
until Week 240 or when DOR/ISL becomes commercially accessible
(whichever comes first). The primary efficacy (percentage of
participants with HIV-1 RNA levels ≥50 copies/mL) and safety
(number of participants experiencing adverse events (AEs) and
discontinuing trial intervention due to AEs) endpoints were
assessed at Week 48.
About MK-8591A-052 (NCT05630755)
MK-8591A-052 is a Phase 3, randomized, active-controlled,
double-blind clinical trial evaluating a switch to investigational,
oral, once-daily DOR/ISL (100mg /0.25mg) in adults with HIV-1
infection that has been virologically suppressed using BIC/FTC/TAF
(50 mg/200 mg/25 mg). Participants (n=513) were randomized 2:1 to
either switch to DOR/ISL or continue on BIC/FTC/TAF through Week
144. After Week 144, eligible participants may continue on DOR/ISL
and continue trial treatment until Week 240 or when DOR/ISL becomes
commercially accessible (whichever comes first). The primary
efficacy (percentage of participants with HIV-1 RNA levels ≥50
copies/mL) and safety (number of participants experiencing AEs and
discontinuing trial intervention due to AEs) endpoints were
assessed at Week 48.
Indications and usage for PIFELTRO and DELSTRIGO in the
U.S.
PIFELTRO 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 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.
Selected Safety Information
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 people with concomitant HIV-1 and HBV who
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.
Contraindications
PIFELTRO and DELSTRIGO are contraindicated when coadministered
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.
Warnings and Precautions
Severe Skin Reactions
Severe skin reactions, including Stevens-Johnson syndrome
(SJS)/toxic epidermal necrolysis (TEN), have been reported during
the postmarketing experience with doravirine-containing regimens.
Discontinue PIFELTRO or DELSTRIGO, and other medications known to
be associated with severe skin reactions, immediately if a painful
rash with mucosal involvement or a progressive severe rash
develops. Clinical status should be closely monitored, and
appropriate therapy should be initiated.
New or Worsening Renal Impairment
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 people living with HIV 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.
Bone Loss and Mineralization Defects
In clinical trials in adults living with HIV, 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
Immune reconstitution syndrome can occur, including the
occurrence of autoimmune disorders with variable time to onset,
which may necessitate further evaluation and treatment.
Drug Interactions
Because DELSTRIGO is a complete regimen, coadministration with
other antiretroviral medications for the treatment of HIV-1
infection is not recommended.
Coadministration of PIFELTRO with efavirenz, etravirine, or
nevirapine is not recommended.
If DELSTRIGO is coadministered 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 coadministered 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.
Dosage and Administration/Specific Populations
Renal Impairment
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.
Adverse Reactions
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 participants in the
PIFELTRO group and 3% in the darunavir+ritonavir (DRV+r) group had
adverse events leading to discontinuation of study medication.
By week 96 in DRIVE-AHEAD, 3% of adult participants in the
DELSTRIGO group and 7% in the efavirenz (EFV)/emtricitabine
(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-C
and 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 24 in LDL-C
and 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 in the 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 participants 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 participants in the DRIVE-SHIFT trial.
Overall, the safety profile in virologically-suppressed adult
participants was similar to that in participants with no ARV
treatment history.
Serum ALT and AST Elevations: In the DRIVE-SHIFT trial, 22% and
16% of participants 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 participants 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
participants in the delayed switch group experienced ALT and AST
elevations of greater than 1.25 X ULN through 24 weeks on their
baseline regimen.
Pregnancy/Breastfeeding
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.
Inform individuals with HIV-1 infection of the potential risks
of breastfeeding, including: (1) HIV-1 transmission (in
HIV-1–negative infants), (2) developing viral resistance (in
HIV-1–positive infants), and (3) serious adverse reactions in a
breastfed infant similar to those seen in adults.
About Islatravir (MK-8591) and Merck’s HIV Research
Islatravir (MK-8591) is Merck’s investigational nucleoside
reverse transcriptase translocation inhibitor (NRTTI) under
evaluation in multiple ongoing early and late-stage clinical
studies in combination with other antiretrovirals for the treatment
of HIV-1. Studies with islatravir are designed to offer different
dosing options as potential daily and once-weekly treatments. For
an overview of Merck’s HIV treatment and prevention clinical
development program, please click here.
Merck’s Commitment to HIV
For more than 35 years, Merck has been committed to scientific
research and discovery in HIV leading to scientific breakthroughs
that have helped change HIV treatment. Our work has been pioneering
in the development of new options across multiple drug classes to
help those impacted by 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 want to ensure people are not defined by
HIV and our work focuses on transformational innovations,
collaborations with others in the global HIV community, and access
initiatives aimed at the goal of helping to end the HIV epidemic
for everyone.
About Merck
At Merck, known as MSD outside of the United States and Canada,
we are unified around our purpose: We use the power of leading-edge
science to save and improve lives around the world. For more than
130 years, we have brought hope to humanity through the development
of important medicines and vaccines. We aspire to be the premier
research-intensive biopharmaceutical company in the world – and
today, we are at the forefront of research to deliver innovative
health solutions that advance the prevention and treatment of
diseases in people and animals. We foster a diverse and inclusive
global workforce and operate responsibly every day to enable a
safe, sustainable and healthy future for all people and
communities. For more information, visit www.merck.com and connect
with us on X (formerly Twitter), Facebook, Instagram, YouTube and
LinkedIn.
Forward-Looking Statement of Merck & Co., Inc., Rahway,
N.J., USA
This news release of Merck & Co., Inc., Rahway, 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 candidates that
the candidates 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 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 Annual
Report on Form 10-K for the year ended December 31, 2023, 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,
lamivudine, and tenofovir disoproxil fumarate) at:
https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_pi.pdf
and Patient Information for DELSTRIGO (doravirine, lamivudine,
and tenofovir disoproxil fumarate)
https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_ppi.pdf
i bictegravir/emtricitabine/tenofovir alafenamide (BIKTARVY) is
a registered trademark of Gilead Sciences, Inc.
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version on businesswire.com: https://www.businesswire.com/news/home/20241219661570/en/
Media Contacts: Julie Cunningham (617) 519-6264 Deb
Wambold (215) 779-2234 Investor Contacts: Peter Dannenbaum
(732) 594-1579 Steven Graziano (732) 594-1583
Merck (NYSE:MRK)
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