Analyses Add Support for Further
Investigation of Islatravir in Combination with Doravirine for
Certain Patients
Post-hoc Weight Analyses from DRIVE-SHIFT
Trial of DELSTRIGO™ (doravirine/lamivudine/tenofovir disoproxil
fumarate) Also Announced
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced new analyses from the Phase 2b trial
(NCT03272347) evaluating the safety and efficacy of islatravir, the
company’s investigational oral nucleoside reverse transcriptase
translocation inhibitor (NRTTI), in combination with doravirine
(PIFELTRO™), in adults with HIV-1 infection who had not previously
received antiretroviral treatment. The first sub-analysis further
characterized the tolerability and safety profile of islatravir in
combination with doravirine (100 mg) through Week 48 across the
three dose levels studied (0.25, 0.75, 2.25 mg). The second
sub-analysis demonstrated that participants who initiated treatment
with islatravir and doravirine in combination with 3TC and switched
to islatravir and doravirine maintained antiviral activity at Week
48 as measured by HIV-1 RNA <50 copies/mL similar to DELSTRIGO,
with low rates of protocol defined virologic failure (PDVF). These
latest findings will be made available this week in two oral
presentations during the 23rd International AIDS Conference (AIDS
2020: Virtual). The primary endpoints and full study design of the
Phase 2b Week 48 trial results were originally presented at IAS
2019.
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/3TC 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.
“These Week 48 analyses reinforce the potential for islatravir
in combination with doravirine as a two-drug regimen for people
living with HIV,” said Dr. Jean-Michel Molina, Professor of
Infectious Diseases at Paris University and Head of the Infectious
Diseases Department, Saint-Louis and Lariboisière Hospitals, Paris,
and the study’s lead investigator. “I am encouraged by the results
seen in this study and look forward to learning more about the
potential of this investigational regimen for the treatment of
HIV-1.”
“These findings add to the growing body of evidence supporting
the potential of islatravir and doravirine for the treatment of
people living with HIV. We look forward to learning more about this
treatment combination from the ongoing Phase 3 clinical development
program,” said Dr. Joan Butterton, vice president, infectious
diseases, Global Clinical Development, Merck Research Laboratories.
“Merck’s steadfast commitment to innovation persists, with the
ultimate goal of tackling unmet needs across diverse populations
and for those disproportionately affected by HIV.”
Week 48 Safety Sub-Analysis and Protocol Defined Virologic
Failure 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.
Through Week 48, a lower rate of drug-related adverse events
(AE) occurred in the islatravir groups (7.8%) compared with the
DELSTRIGO group (19.4%). From Week 0-48, similar rates of
drug-related adverse events were observed across all islatravir
groups (0.25 mg – 0.0%; 0.75 mg – 10.0%; 2.25 mg – 12.9%), with no
dose-dependent difference in the safety profile of islatravir.
Drug-related adverse events were generally more frequent in the
first 24 weeks (0.0% in the 0.25 mg islatravir group; 10.0% in the
0.75 mg islatravir group; 6.5% in the 2.25 mg islatravir group;
19.4% in the DELSTRIGO group) versus the second 24-week period of
the trial (0.0% in the 0.25 mg islatravir group; 3.3% in the 0.75
mg islatravir group; 7.4% in the 2.25 mg islatravir group; 3.6% in
the DELSTRIGO group) for all treatment arms. The most common
reported adverse events (reported by >10% participants) in the
DELSTRIGO-treated group were diarrhea (16.1%), bronchitis (12.9%)
and syphilis (12.9%). The most common reported adverse events
(reported by >10% participants) in the islatravir-treated groups
were: 0.25 mg (sinusitis, pain in extremity, headache - 10.3%,
10.3% and 13.8%, respectively); 0.75 mg (diarrhea, nausea,
bronchitis, nasopharyngitis, syphilis, vitamin D deficiency -13.3%,
13.3%, 13.3%, 13.3%, 10.0%, 13.3%, respectively); 2.25 mg
(arthralgia, headache - 12.9%, 12.9%, respectively). The majority
of all adverse events were mild and did not result in study
discontinuation. Two participants in the islatravir-treated dose
groups (both 2.25 mg) discontinued due to an AE. One participant in
the DELSTRIGO group discontinued due to a serious AE considered to
be drug related.
In the study, PDVF was defined as viral rebound (HIV-1 RNA ≥50
copies/mL after initial response at any time during the study or
confirmed HIV-1 RNA >1 log increase from the lowest HIV-1 RNA
level after a >1 log decrease in HIV-1 RNA from baseline, at any
time during the study) or non-response (≥200 copies/mL at any time
from Week 24 through Week 48 and confirmed HIV-1 RNA ≥50 copies/mL
at Week 48); PDVF had to be confirmed by an additional HIV-1 RNA
measurement within two weeks. At Week 48, rates of PDVF were low
and all participants who discontinued due to PDVF had levels of
HIV-1 RNA below the clinically significant level of 200 copies/mL.
The observed low-level viremia was comparable to levels detected in
other studies of previously untreated patients. At Week 48, 89.7%
(26/29), 90.0% (27/30) and 77.4% (24/31) of randomized participants
achieved HIV-1 RNA <50 copies/mL in the 0.25, 0.75 and 2.25 mg
islatravir groups, respectively, compared to 83.9% (26/31) with the
DELSTRIGO group. Six participants met the criteria for PDVF: two
rebounders each in the 0.25 and 0.75 mg islatravir groups, one
non-responder in the 2.25 mg islatravir group, and one rebounder in
the DELSTRIGO group. All confirmatory HIV-1 RNA levels were <80
copies/mL and none met criteria for resistance testing (>400
copies/mL). Despite changing to new regimens, three of six
participants (one each from the 0.25 and 0.75 mg islatravir groups
and one from the DELSTRIGO group) continued to have low-level
viremia with HIV-1 RNA<200 copies/mL during the 42-day
post-discontinuation assessment.
Analyses of Weight Changes in Phase 3 DRIVE-SHIFT
Trial
Separately, new findings from a post-hoc analysis of the Phase 3
DRIVE-SHIFT trial evaluating a switch to DELSTRIGO show that weight
changes among participants switching to DELSTRIGO were similar to
the average change observed in HIV negative adults in the U.S.1,2
Weight gains after switch to DELSTRIGO were 1.4 kg (95% confidence
interval [CI]; 0.8, 1.9) in the Immediate Switch Group and 1.2 kg
(95% CI: 0.4, 2.0) in the Delayed Switch Group after 2 years (144
weeks) on doravirine/3TC/TDF. The DRIVE-SHIFT trial results were
first presented at IDWeek 2018.
“The initiation of some types of antiretroviral therapy in
people living with HIV has been associated with weight gain,” said
Dr. Princy Kumar, Chief, Division of Infectious Diseases and
Tropical Medicine at MedStar Georgetown University Hospital and
Professor of Medicine and Microbiology, Georgetown University
School of Medicine, Washington, D.C. “Our post-hoc analysis of
weight changes from the Phase 3 DRIVE-SHIFT trial showed weight
changes with DELSTRIGO comparable to the average annual weight gain
observed in the general adult population.”
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.
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.
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
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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
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actual results may differ materially from those set forth in the
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Risks and uncertainties include but are not limited to, general
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including interest rate and currency exchange rate fluctuations;
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The company undertakes no obligation to publicly update any
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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
____________________ 1 Williamson DF. Descriptive epidemiology
of body weight and weight change in U.S. adults. Ann Intern Med.
1993;119(7 Pt 2):646–9. 2 Hill JO, Wyatt HR, Reed GW, Peters JC.
Obesity and the environment: where do we go from here?. Science.
2003;299(5608):853-855. doi:10.1126/science.1079857
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