Week 48 Data Met Safety and Efficacy
Endpoints in Adults with HIV-1 Infection Currently on
Antiretroviral Therapy
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced positive top-line results from two pivotal
Phase 3 trials of the investigational, once-daily oral fixed dose
combination pill of doravirine/islatravir (DOR/ISL) in adults with
HIV-1 infection who are virologically suppressed on different
antiretroviral therapy regimens (ART; ILLUMINATE SWITCH A) or
bictegravir/emtricitabine/tenofovir (BIC/FTC/TAF; ILLUMINATE SWITCH
B). 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 ART (ILLUMINATE SWITCH A) and between DOR/ISL and
BIC/FTC/TAF (ILLUMINATE SWITCH B). The safety and tolerability
profile of DOR/ISL during the trials to date are consistent with
the previously reported Phase 2 studies. 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; DOR/3TC/TDF). Islatravir is
Merck’s investigational nucleoside reverse transcriptase
translocation inhibitor under evaluation for the treatment of
people living with HIV-1 infection in combination with other
antiretrovirals. Detailed findings from these studies will be
presented at a future scientific congress and will form the basis
of global regulatory applications.
“Merck is committed to investigating potential treatment options
to help address the evolving needs of people living with HIV,” said
Dr. Joan Butterton, vice president, global clinical development,
infectious diseases, Merck Research Laboratories. “We are
encouraged by the results from the Phase 3 ILLUMINATE SWITCH A and
B trials, in which the DOR/ISL dual regimen efficacy was comparable
to certain commonly used three-drug regimens. We will continue to
study doravirine/islatravir in diverse populations of people living
with HIV and look forward to sharing data from these trials.”
The ILLUMINATE clinical trial program is evaluating DOR/ISL in a
broad patient population, which includes people with HIV-1 who are
virologically suppressed on ART, those who are heavily treatment
experienced and those who are new to HIV treatment. The clinical
trial program also includes pediatric participants with HIV-1
weighing at least 35 kg who are virologically suppressed and have
not previously been treated. Merck is committed to enrolling
diverse people in our HIV-1 clinical trials, especially among
communities who may be disproportionately impacted by HIV, such as
women and those within the Black and Latinx communities.
Indications and Usage for 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 ILLUMINATE SWITCH A
The ILLUMINATE SWITCH A (MK-8591A-017) (NCT04223778) Study is a
Phase 3, randomized, active-controlled, open-label clinical trial
to evaluate a switch from antiretroviral therapy (ART) to
investigational, oral, once-daily DOR/ISL (100 mg/0.75 mg)
(MK-8591A), in adults with HIV-1 who are virologically suppressed.
Participants (n=672) were randomized 1:1 to either switch to
DOR/ISL or continue with their current baseline ART regimen through
Week 48. At Week 48, all participants receive DOR/ISL through Week
96 of the trial. 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
study intervention due to AEs) endpoints were assessed at Week
48.
About ILLUMINATE SWITCH B
The ILLUMINATE SWITCH B (MK-8591A-018) (NCT04223791) Study is a
Phase 3, randomized, double-blind clinical trial to evaluate a
switch from BIC/FTC/TAF to investigational, oral, once-daily
DOR/ISL (100 mg/0.75 mg), in adults with HIV-1 who are
virologically suppressed. Participants (n=641) were randomized 1:1
to either switch to DOR/ISL or continue on BIC/FTC/TAF through Week
144. The primary efficacy (percentage of participants with HIV-1
RNA levels ≥50 copies/mL) and safety (number of participants
experiencing AEs and discontinuing study intervention due to AEs)
endpoints were assessed at Week 48.
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. An overview of the islatravir treatment and
prevention development program is available here.
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
Information for DELSTRIGO (doravirine/3TC/TDF) at:
https://www.merck.com/product/usa/pi_circulars/d/delstrigo/delstrigo_ppi.pdf
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