Janssen Announces U.S. FDA Approval of CABENUVA (rilpivirine and cabotegravir), the First Long-Acting Regimen for the Treatment of HIV
TITUSVILLE, N.J., Jan. 21, 2021 /PRNewswire/ -- The Janssen Pharmaceutical Companies of Johnson & Johnson today announced the U.S. Food and Drug Administration (FDA) has approved CABENUVA (consisting of Janssen's rilpivirine and ViiV Healthcare's cabotegravir), the first and only once-monthly, long-acting regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults. The novel regimen was co-developed as part of a collaboration with ViiV Healthcare and builds on Janssen's 25-year commitment to make HIV history. In the U.S., ViiV Healthcare is the marketing authorization holder for CABENUVA.
CABENUVA is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those 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 with no known or suspected resistance to either cabotegravir or rilpivirine. Prior to initiating treatment with CABENUVA, oral cabotegravir (VOCABRIA) and oral rilpivirine (EDURANT(®)) should be administered for approximately one month to assess the tolerability of each therapy.
CABENUVA, a co-packaged kit with two injectable medicines, offers people living with HIV a new approach for maintaining viral suppression.(1 )
Click to Tweet: #BREAKING: The #FDA has approved another treatment option for people living with #HIV. Read full announcement here: http://bit.ly/38rPgFi
"With the approval of CABENUVA, we're proud to bring a new treatment option to people living with HIV that removes the burden of taking a daily pill," said Paul Stoffels, M.D., Vice Chairman of the Executive Committee and Chief Scientific Officer, Johnson & Johnson. "While much more remains to be done to make HIV history, today's milestone reminds us how far medical innovation has come since the first reported cases of the virus almost 40 years ago."
The approval of CABENUVA is based on the pivotal Phase 3 ATLAS (Antiretroviral Therapy as Long-Acting Suppression) and FLAIR (First Long-Acting Injectable Regimen) studies that included more than 1,100 patients from 16 countries, including the U.S. The studies demonstrated that CABENUVA was as effective as continuing a daily, oral, three-drug regimen in maintaining viral suppression throughout the 48-week study period.
In the ATLAS study, CABENUVA met the primary endpoint for noninferiority (the proportion of participants with plasma HIV-1 RNA >=50 copies per milliliter [c/mL] at Week 48), with a comparable number of patients receiving either CABENUVA or their daily current antiretroviral regimen (CAR) having an HIV-1 RNA level >=50 c/mL. Two percent of patients receiving the long-acting injectable and 1% of patients receiving CAR had an HIV-1 RNA level >=50 c/mL at Week 48 (Treatment Difference 0.7%; 95% CI: -1.2%, 2.5%).
In the FLAIR study, at Week 48, a comparable number of patients receiving either CABENUVA or daily oral dolutegravir/abacavir/lamivudine therapy had an HIV-1 RNA count >=50 c/mL, meeting noninferiority criteria. Two percent of patients in both treatment arms had an HIV-1 RNA count >=50 c/mL at Week 48 (Treatment Difference -0.4%; 95% CI: -2.8%, 2.1%).
Adverse reactions of at least Grade 2 severity in patients who were receiving CABENUVA or CAR were, respectively: injection site reactions (37%, 0), pyrexia (2%, 0), fatigue (1%, <1%), headache (<1%, <1%), musculoskeletal pain (1%, 0), nausea (<1%, 0), sleep disorders (<1%, 0), dizziness (<1%, 0) and rash (<1%, 0).
Results from these trials were presented at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI).
"This is an exciting new option for patients and providers, as it provides an alternative strategy for effective HIV treatment," said Susan Swindells, MBBS, Professor, Department of Internal Medicine, University of Nebraska Medical Center. "CABENUVA once-monthly injections showed comparable efficacy to daily oral antiretroviral treatment in maintaining viral suppression - a first in the treatment paradigm."
"For more than 25 years, we have been committed to changing the course of the HIV epidemic through the pursuit of innovative treatments and effective prevention," said Mathai Mammen, M.D., Ph.D., Global Head, Janssen Research & Development, Johnson & Johnson. "This new treatment option for people living with HIV brings us one step closer toward alleviating this global health threat."?
The once-monthly rilpivirine and cabotegravir injectable treatment was approved by Health Canada on March 20, 2020, and the European Commission approved a once-monthly and once every two-month version of the injectable treatment on December 21, 2020. Regulatory reviews continue in Australia and Switzerland, and several additional submissions are planned throughout 2021.
About CABENUVA (rilpivirine and cabotegravir)
CABENUVA is approved as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those 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 with no known or suspected resistance to either cabotegravir or rilpivirine. CABENUVA is administered by a healthcare provider once-monthly as two individual intramuscular injections in the buttocks.
The complete regimen combines rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Janssen Sciences Ireland UC, with the integrase strand transfer inhibitor (INSTI) cabotegravir, developed by ViiV Healthcare.
INSTIs, like cabotegravir, inhibit HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection.
Rilpivirine is an NNRTI that works by interfering with an enzyme called reverse transcriptase, which in turn stops the virus from multiplying.
About EDURANT(®) (rilpivirine)
EDURANT(®) (rilpivirine), in combination with other antiretroviral agents, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients 12 years of age and older and weighing at least 35 kg with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy.
Limitations of Use:
-- More EDURANT(®)-treated subjects with HIV-1 RNA greater than 100,000
copies/mL at the start of therapy experienced virologic failure (HIV-1
RNA >=50 copies/mL) compared to EDURANT(®)-treated subjects with
HIV-1 RNA less than or equal to 100,000 copies/mL
EDURANT(®) is also indicated in combination with VOCABRIA (oral cabotegravir) for short-term treatment of HIV-1 infection in adults who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as:
-- Oral lead-in to assess the tolerability of rilpivirine prior to
administration of rilpivirine extended-release injectable suspension, a
component of CABENUVA (cabotegravir, rilpivirine) extended-release
injectable suspensions
-- Oral therapy for patients who will miss planned injection dosing with
CABENUVA (cabotegravir; rilpivirine) extended-release injectable
suspensions
Janssen is the marketing authorization holder for EDURANT(®) in the U.S.
Trademarks are owned by or licensed to Janssen and the ViiV Healthcare group of companies.
About ATLAS and FLAIR
ATLAS (NCT02951052) is a Phase 3, open-label, active-controlled, multicenter, parallel-group, noninferiority study designed to assess the antiviral activity, safety and tolerability of a two-drug regimen of long-acting, injectable rilpivirine and cabotegravir dosed every four weeks compared to continuation of current oral antiretroviral therapy (ART) of two nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (INSTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or protease inhibitor (PI) among virally suppressed individuals. Participants were required to be virally suppressed for six months or longer, on a first or second regimen, with no prior failure. The primary endpoint for ATLAS is the proportion of participants with plasma HIV-1 RNA >=50 c/mL per the FDA Snapshot algorithm at Week 48 (Missing, Switch, or Discontinuation = Failure, Intent-to-Treat Exposed [ITT-E] population).
FLAIR (NCT02938520) is a Phase 3, randomized, open-label, multicenter, parallel-group, noninferiority study designed to assess the antiviral activity, safety and tolerability of a two-drug regimen of intramuscular, long-acting, injectable rilpivirine and cabotegravir in adults living with HIV who were virologically suppressed following 20 weeks of induction therapy with either dolutegravir/abacavir/lamivudine or dolutegravir plus 2 other NRTIs if subjects were HLA-B*5701 positive. Participants who were virologically suppressed (HIV-1 RNA less than 50 copies/mL) were then randomized (1:1) to receive either a cabotegravir plus rilpivirine regimen or remain on the current antiretroviral regimen. The primary endpoint for FLAIR is the proportion of participants with plasma HIV-1 RNA >=50 c/mL per the FDA Snapshot algorithm at Week 48 (Missing, Switch, or Discontinuation = Failure, Intent-to-Treat Exposed [ITT-E] population).
Important Safety Information for CABENUVA
CABENUVA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those 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 with no known or suspected resistance to either cabotegravir or rilpivirine.
CONTRAINDICATIONS
-- Do not use CABENUVA in patients with previous hypersensitivity reaction
to cabotegravir or rilpivirine.
-- Do not use CABENUVA in patients receiving carbamazepine, oxcarbazepine,
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic
dexamethasone (>1 dose), and St John's wort.
WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions:
-- Hypersensitivity reactions, including cases of Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS), have been reported during
postmarketing experience with rilpivirine-containing regimens. While
some skin reactions were accompanied by constitutional symptoms such as
fever, other skin reactions were associated with organ dysfunctions,
including elevations in hepatic serum biochemistries.
-- Serious or severe hypersensitivity reactions have been reported in
association with other integrase inhibitors and could occur with
CABENUVA.
-- Discontinue CABENUVA immediately if signs or symptoms of
hypersensitivity reactions develop. Clinical status, including liver
transaminases, should be monitored and appropriate therapy initiated.
Prescribe the oral lead-in prior to administration of CABENUVA to help
identify patients who may be at risk of a hypersensitivity reaction.
Post-Injection Reactions:
-- Serious post-injection reactions (reported in less than 1% of subjects)
were reported within minutes after the injection of rilpivirine,
including dyspnea, agitation, abdominal cramping, flushing, sweating,
oral numbness, and changes in blood pressure. These events may have been
associated with inadvertent (partial) intravenous administration and
began to resolve within a few minutes after the injection.
-- Carefully follow the Instructions for Use when preparing and
administering CABENUVA to avoid accidental intravenous administration.
Observe patients briefly (approximately 10 minutes) after the injection.
If a post-injection reaction occurs, monitor and treat as clinically
indicated.
Hepatotoxicity:
-- Hepatotoxicity has been reported in patients receiving cabotegravir or
rilpivirine with or without known pre-existing hepatic disease or
identifiable risk factors.
-- Patients with underlying liver disease or marked elevations in
transaminases prior to treatment may be at increased risk for worsening
or development of transaminase elevations.
-- Monitoring of liver chemistries is recommended and treatment with
CABENUVA should be discontinued if hepatotoxicity is suspected.
Depressive Disorders:
-- Depressive disorders (including depressed mood, depression, major
depression, mood altered, mood swings, dysphoria, negative thoughts,
suicidal ideation or attempt) have been reported with CABENUVA or the
individual products.
-- Promptly evaluate patients with depressive symptoms.
Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions:
-- The concomitant use of CABENUVA and other drugs may result in known or
potentially significant drug interactions (see Contraindications and
Drug Interactions).
-- Rilpivirine doses 3 and 12 times higher than the recommended oral dosage
can prolong the QTc interval. CABENUVA should be used with caution in
combination with drugs with a known risk of Torsade de Pointes.
Long-Acting Properties and Potential Associated Risks with CABENUVA:
-- Residual concentrations of cabotegravir and rilpivirine may remain in
the systemic circulation of patients for prolonged periods (up to 12
months or longer). Select appropriate patients who agree to the required
monthly injection dosing schedule because non-adherence to monthly
injections or missed doses could lead to loss of virologic response and
development of resistance.
-- To minimize the potential risk of developing viral resistance, it is
essential to initiate an alternative, fully suppressive antiretroviral
regimen no later than 1 month after the final injection doses of
CABENUVA. If virologic failure is suspected, switch the patient to an
alternative regimen as soon as possible.
ADVERSE REACTIONS
The most common adverse reactions (incidence >=2%, all grades) with CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.
DRUG INTERACTIONS
-- Refer to the applicable full Prescribing Information for important drug
interactions with CABENUVA, Vocabria, or rilpivirine.
-- Because CABENUVA is a complete regimen, coadministration with other
antiretroviral medications for the treatment of HIV-1 infection is not
recommended.
-- Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease
the plasma concentrations of cabotegravir. Drugs that induce or inhibit
CYP3A may affect the plasma concentrations of rilpivirine.
-- CABENUVA should be used with caution in combination with drugs with a
known risk of Torsade de Pointes.
USE IN SPECIFIC POPULATIONS
-- Pregnancy: There are insufficient human data on the use of CABENUVA
during pregnancy to adequately assess a drug-associated risk for birth
defects and miscarriage. Discuss the benefit-risk of using CABENUVA
during pregnancy and conception and consider that cabotegravir and
rilpivirine are detected in systemic circulation for up to 12 months or
longer after discontinuing injections of CABENUVA. An Antiretroviral
Pregnancy Registry has been established.
-- Lactation: The CDC recommends that HIV?1-infected mothers in the United
States not breastfeed their infants to avoid risking postnatal
transmission of HIV-1 infection. Breastfeeding is also not recommended
due to the potential for developing viral resistance in HIV-positive
infants, adverse reactions in a breastfed infant, and detectable
cabotegravir and rilpivirine concentrations in systemic circulation for
up to 12 months or longer after discontinuing injections of CABENUVA.
Please see full Prescribing Information.
EDURANT(®) Important Safety Information
Contraindications
-- Coadministration of EDURANT(®) with the following drugs is
contraindicated because significant decreases in rilpivirine plasma
concentrations may occur due to CYP3A enzyme induction or gastric pH
increase, which may result in loss of virologic response and possible
resistance and cross-resistance: carbamazepine, oxcarbazepine,
phenobarbital, phenytoin, rifampin, rifapentine, proton pump inhibitors
such as esomeprazole, lansoprazole, omeprazole, pantoprazole, and
rabeprazole, systemic dexamethasone (more than single dose), and
products containing St. John's wort (Hypericum perforatum)
Warnings and Precautions
-- Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity
reactions have been reported during the postmarketing experience,
including cases of Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS), with rilpivirine-containing regimens. While some skin reactions
were accompanied by constitutional symptoms such as fever, other skin
reactions were associated with organ dysfunctions, including elevations
in hepatic serum biochemistries. EDURANT(®) should be discontinued
immediately if signs or symptoms of severe skin or hypersensitivity
reactions develop, including but not limited to, severe rash or rash
accompanied by fever, blisters, mucosal involvement, conjunctivitis,
facial edema, angioedema, hepatitis or eosinophilia. Clinical status
including laboratory parameters should be monitored and appropriate
therapy should be initiated
-- Hepatotoxicity: Hepatic adverse events were reported. Patients with
underlying hepatic disease, including hepatitis B or C, or marked
elevations in transaminases before treatment may be at increased risk
for worsening or development of transaminase elevations. Monitor liver
function tests (LFTs) before and during treatment. A few hepatotoxicity
cases occurred in patients with no pre-existing hepatic disease or other
identifiable risk factors; therefore, monitoring of LFTs should be
considered in all patients
-- Depressive Disorders: Severe depressive disorders, defined as depressed
mood, depression, dysphoria, major depression, mood altered, negative
thoughts, suicide attempt, and suicidal ideation, have been reported
with EDURANT(®). Immediate medical evaluation is recommended for severe
depressive symptoms
-- Fat Redistribution: Redistribution and/or accumulation of body fat have
been observed in patients receiving antiretroviral (ARV) therapy. The
causal relationship, mechanism, and long-term consequences of these
events have not been established
-- Immune Reconstitution Syndrome has been reported in patients treated
with combination ARV therapy, including EDURANT(®). Autoimmune
disorders (such as Graves disease, polymyositis, Guillain-Barré
syndrome and autoimmune hepatitis) have also been reported to occur in
the setting of immune reconstitution; however, the time to onset is more
variable and can occur many months after initiation of treatment
Drug Interactions
-- EDURANT(®) should be used with caution when coadministered with drugs
that may reduce the exposure of rilpivirine, such as antacids and
H2-receptor antagonists. If EDURANT(®) is used with CABENUVA
(cabotegravir, rilpivirine injections), use with rifampin is
contraindicated
-- Concomitant use of EDURANT(®) with rifabutin may cause a decrease in
the plasma concentrations of rilpivirine. Please read the Dosage and
Administration Section of the Prescribing Information for more details
regarding the concomitant use of EDURANT(®) and rifabutin
-- EDURANT(®) should be used with caution when coadministered with a drug
with a known risk of Torsade de Pointes
-- EDURANT(®) should not be used in combination with NNRTIs
This is not a complete list of potential drug interactions.
Please see full Prescribing Information for more details.
Use in Specific Populations
-- Hepatic Impairment: EDURANT(®) should be used with caution in patients
with severe hepatic impairment (Child-Pugh Class C) as pharmacokinetics
of EDURANT(®) have not been evaluated in these patients
-- Pregnancy: In a clinical trial, total rilpivirine exposures were
generally lower during pregnancy compared to the postpartum period
-- Lactation: Women infected with HIV should be instructed not to
breastfeed due to the potential for HIV transmission
This list of uses in specific populations is not complete.
Please refer to the EDURANT(®) Prescribing Information for additional information.
Adverse Reactions
-- The most common adverse drug reactions reported (incidence >2%) of at
least moderate intensity (>= Grade 2) in patients taking EDURANT(®)
through 96 weeks were depressive disorders (5%), headache (3%), insomnia
(3%), and rash (3%)
This is not a complete list of all adverse drug reactions reported with the use of EDURANT(®).
Please read the full Prescribing Information for a complete list of adverse drug reactions.
cp-51575v4
About the Janssen Pharmaceutical Companies of Johnson & Johnson
At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension.
Learn more at www.janssen.com and follow us at www.twitter.com/JanssenGlobal and www.twitter.com/JanssenUS. Janssen Research & Development and Janssen Sciences Ireland Unlimited Company are members of the Janssen Pharmaceutical Companies of Johnson & Johnson.
To learn more about Janssen's commitment to the prevention and treatment of HIV, please visit jnj.com/HIV.
Cautions Concerning Forward-Looking Statements
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding rilpivirine and development of potential preventive and treatment regimens for HIV. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Sciences Ireland UC, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 29, 2019, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in the company's most recently filed Quarterly Report on Form 10-Q, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.
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REFERENCES
1. CABENUVA (cabotegravir, rilpivirine) Prescribing Information. US Approval January 2021.
© Janssen Therapeutics, Division of Janssen Products, LP 2021 1/21 cp-203584v1
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