Approvals Based on Findings from the Phase 3
DRIVE-SHIFT Trial Evaluating a Switch to DELSTRIGO
Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced that the U.S. Food and Drug Administration
(FDA) approved supplemental New Drug Applications (sNDAs) for
PIFELTRO™ (in combination with other antiretroviral agents) and
DELSTRIGO™ (as a complete regimen) that expand their indications to
include adult patients with HIV-1 infection who are virologically
suppressed (HIV-1 RNA less than 50 copies per mL) on a stable
antiretroviral regimen with no history of treatment failure and no
known substitutions associated with resistance to PIFELTRO or the
individual components of DELSTRIGO.
PIFELTRO (doravirine, 100 mg) is a non-nucleoside reverse
transcriptase inhibitor (NNRTI) to be administered in combination
with other antiretroviral agents. DELSTRIGO is a once-daily
fixed-dose combination tablet of doravirine (100 mg), lamivudine
(3TC, 300 mg) and tenofovir disoproxil fumarate (TDF, 300 mg).
DELSTRIGO contains a boxed warning regarding post-treatment acute
exacerbation of hepatitis B virus (HBV) infection. DELSTRIGO and
PIFELTRO do not cure HIV-1 infection or AIDS. PIFELTRO and
DELSTRIGO were approved in the United States on August 30, 2018 for
the treatment of HIV-1 infection in adults with no prior
antiretroviral treatment history.
PIFELTRO and DELSTRIGO are contraindicated when co-administered
with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers
as significant decreases in doravirine plasma concentrations may
occur, which may decrease the effectiveness of PIFELTRO and
DELSTRIGO (doravirine/lamivudine (3TC)/tenofovir disoproxil
fumarate (TDF)). DELSTRIGO is contraindicated in patients with a
previous hypersensitivity reaction to 3TC. For more information,
please see “Selected Safety Information” below.
“Thanks to developments in HIV science, more treatment options
are becoming available to address the medical needs of people
living with HIV,” 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. “The
expanded indications offer certain people with HIV-1 infection, and
their doctors, the choice to switch their current antiretroviral
therapy to DELSTRIGO or PIFELTRO in combination with other
antiretroviral agents.”
Immune reconstitution syndrome can occur in patients treated
with combination antiretroviral therapy, including the occurrence
of autoimmune disorders with variable time to onset, which may
necessitate further evaluation and treatment. 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, as cases of acute
renal failure after initiation of high-dose or multiple
non-steroidal anti-inflammatory drugs (NSAIDs) have been reported
in patients with risk factors for renal dysfunction who appeared
stable on TDF.
Data Supporting the sNDA Approvals of PIFELTRO (doravirine)
and DELSTRIGO
The FDA’s approval of the sNDAs of PIFELTRO and DELSTRIGO was
based on findings from DRIVE-SHIFT, the Phase 3 randomized,
international, multicenter, open-label trial evaluating a switch to
DELSTRIGO in virologically suppressed participants (HIV-1 RNA
<50 copies/mL) on a baseline regimen for at least six months
prior to trial entry with no history of virologic failure. The
baseline regimen consisted of two nucleoside reverse transcriptase
inhibitors (NRTIs) in combination with a protease inhibitor plus
either ritonavir or cobicistat, or elvitegravir plus cobicistat, or
an NNRTI.
In DRIVE-SHIFT, 670 participants were randomized to begin
treatment with DELSTRIGO immediately on Day 1 (immediate switch
group, ISG; N=447) or after 24 weeks (delayed switch group, DSG;
N=223). In the trial, the primary efficacy comparison was between
the DELSTRIGO ISG at Week 48 and the baseline regimen DSG at Week
24. Two percent in the DELSTRIGO ISG had HIV-1 RNA ≥50 copies/mL at
Week 48 compared to 1% in the baseline regimen DSG at Week 24
(treatment difference: 0.7%, 95% confidence interval: -1.3, 2.6).
In addition, 91% of participants who switched to DELSTRIGO on Day 1
(ISG) had HIV-1 RNA <50 copies/mL at Week 48. Ninety-five
percent of participants who continued on their baseline regimen
(DSG) had HIV-1 RNA <50 copies/mL at Week 24.
At Week 24, participants who switched to DELSTRIGO
(doravirine/lamivudine (3TC)/tenofovir disoproxil fumarate (TDF))
on Day 1 showed statistically significant differences in changes
from baseline in fasting LDL-cholesterol (LDL-C) and
non-HDL-cholesterol (non-HDL-C) compared to those who continued on
a boosted protease inhibitor regimen (LDL-C: -16.3 mg/dL vs. -2.6
mg/dL, treatment difference: -14.5, 95% confidence interval: -18.9,
-10.1, p<0.0001; non-HDL-C: -24.8 mg/dL vs. -2.1 mg/dL,
treatment difference: -22.8, 95% confidence interval: -27.9, -17.7,
p<0.0001). The clinical benefit of these findings has not been
demonstrated.
Overall, the safety profile in virologically suppressed adult
participants was similar to that in participants with no
antiretroviral treatment history. The safety of DELSTRIGO and
PIFELTRO in participants infected with HIV-1 with no antiretroviral
treatment history were evaluated in the Phase 3 DRIVE-AHEAD and
DRIVE-FORWARD clinical trials, respectively. In DRIVE-AHEAD, the
rate of discontinuation of treatment due to adverse events was
lower in the DELSTRIGO treatment group than in the efavirenz
(EFV)/emtricitabine (FTC)/TDF treatment group (3% and 6%,
respectively). Clinical adverse reactions of all grades occurring
in ≥5 percent of participants in the DELSTRIGO treatment group
included dizziness (7%), nausea (5%) and abnormal dreams (5%). No
adverse reactions of Grade 2 or higher (moderate or severe)
occurred in ≥2 percent of participants treated with DELSTRIGO. In
DRIVE-FORWARD, the rate of discontinuation of therapy due to
adverse events in either treatment group was low (2% in the
PIFELTRO group and 3% in the DRV+r group). Clinical adverse
reactions of all grades occurring in ≥5 percent of participants in
the PIFELTRO treatment group included nausea (7%), headache (6%),
fatigue (6%), diarrhea (5%) and abdominal pain (5%). No adverse
reactions of Grade 2 or higher (moderate or severe) occurred in ≥2
percent of participants treated with PIFELTRO. In the DRIVE-SHIFT
trial, 22% and 16% of participants in the immediate switch group
experienced ALT and AST elevations of greater than 1.25 X ULN,
respectively, through 48 weeks on DELSTRIGO. For these ALT and AST
elevations, no apparent time 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.
“Today’s approvals provide doravirine treatment options for
people living with HIV-1 who are virally suppressed, reflecting
Merck’s continued commitment to research and development of HIV
treatments,” said Dr. George Hanna, vice president and therapeutic
area head of infectious diseases, Global Clinical Development,
Merck Research Laboratories. “We are thankful to the researchers
and HIV community for their collaboration that made this
possible.”
PIFELTRO (doravirine) and DELSTRIGO (doravirine/lamivudine
(3TC)/tenofovir disoproxil fumarate (TDF)) can be co-administered
with a wide range of non-antiretroviral agents, and PIFELTRO can be
co-administered with a wide range of antiretroviral agents.
PIFELTRO and DELSTRIGO cannot be co-administered with enzalutamide,
carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin,
rifapentine, mitotane or St. John’s wort. If DELSTRIGO is
co-administered with rifabutin, patients should take one tablet of
DELSTRIGO once daily, followed by one tablet of PIFELTRO
approximately 12 hours after the dose of DELSTRIGO. If PIFELTRO is
co-administered with rifabutin, patients need to increase the
PIFELTRO dosage to one tablet twice daily approximately 12 hours
apart. Use of PIFELTRO with efavirenz, etravirine, or nevirapine is
not recommended.
No clinically significant drug interactions have been observed
following the co-administration of doravirine and the following
drugs: dolutegravir, ritonavir, TDF, 3TC, elbasvir and grazoprevir,
ledipasvir and sofosbuvir, ketoconazole, aluminum
hydroxide/magnesium hydroxide/simethicone containing antacid,
pantoprazole, atorvastatin, an oral contraceptive containing
ethinyl estradiol and levonorgestrel, metformin, methadone, and
midazolam.
For DELSTRIGO, no clinically significant drug interactions have
been observed in studies conducted in healthy participants between
TDF and the following medications: entecavir, methadone, oral
contraceptives, sofosbuvir or tacrolimus. If DELSTRIGO
(doravirine/lamivudine (3TC)/tenofovir disoproxil fumarate (TDF))
is co-administered with ledipasvir/sofosbuvir or
sofosbuvir/velpatasvir, monitor for adverse reactions associated
with TDF. Co-administration of single doses of 3TC and sorbitol
resulted in a sorbitol dose-dependent reduction in 3TC exposures.
When possible, avoid use of sorbitol-containing medicines with
3TC-containing medicines, such as DELSTRIGO.
Overall Viral Resistance Profile
In the DRIVE-SHIFT clinical trial, there were six participants
in the immediate switch group (n=447) and two participants in the
delayed switch group (n=209) who met the protocol-defined virologic
failure criteria (HIV-1 RNA ≥50 copies/mL). Two of the six
virologic failures in the immediate switch group had available
resistance data and neither developed detectable genotypic or
phenotypic resistance to doravirine, lamivudine, or TDF during
treatment with DELSTRIGO (doravirine/lamivudine (3TC)/tenofovir
disoproxil fumarate (TDF)). One of the two virologic failures in
the delayed switch group had available resistance data and
developed the RT M184M/I substitution and phenotypic resistance to
emtricitabine and lamivudine during treatment with their baseline
regimen.
In the DELSTRIGO and PIFELTRO (doravirine) treatment arms of the
two Phase 3 trials DRIVE-AHEAD and DRIVE-FORWARD (n=747), a total
of 11 participants showed the emergence of doravirine-associated
resistance substitutions, among the 28 participants in the
resistance analysis subset (participants with HIV-1 RNA >400
copies per mL at virologic failure or early study discontinuation
and having resistance data). Of these 11 participants, seven showed
both genotypic and phenotypic resistance to doravirine, with at
least a 100-fold reduction in susceptibility to doravirine. The
other four participants had substitutions that were associated with
less than twofold reduction in susceptibility to doravirine.
In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial
(n=364), 12 participants showed the emergence of
efavirenz-associated resistance substitutions among 20 participants
in the resistance analysis subset. In the darunavir + ritonavir
(DRV+r) treatment arm of the DRIVE-FORWARD trial (n=383), no
participants showed the emergence of DRV+r associated resistance
substitutions among the nine participants with resistance data.
Cross-resistance has been observed among NNRTIs, including
doravirine. Treatment-emergent doravirine resistance-associated
substitutions can confer cross-resistance to efavirenz,
rilpivirine, nevirapine and etravirine.
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 (doravirine/lamivudine (3TC)/tenofovir
disoproxil fumarate (TDF)) and PIFELTRO (doravirine).
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 (doravirine/lamivudine (3TC)/tenofovir
disoproxil fumarate (TDF)) is a complete regimen, co-administration
with other antiretroviral medications for the treatment of HIV-1
infection is not recommended.
Co-administration of PIFELTRO (doravirine) 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 (doravirine/lamivudine (3TC)/tenofovir
disoproxil fumarate (TDF)) 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 (5%), abdominal pain (5%),
and abnormal dreams (5%).
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 (doravirine) 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 Merck
For more than a century, Merck, a leading global
biopharmaceutical company 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.
Through our prescription medicines, vaccines, biologic therapies
and animal health products, we work with customers and operate in
more than 140 countries to deliver innovative health solutions. We
also demonstrate our commitment to increasing access to health care
through far-reaching policies, programs and partnerships. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer’s disease and
infectious diseases including HIV and Ebola. 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 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 2018
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 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
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
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