ViiV Healthcare Submits Supplemental New Drug Application to US FDA for Expanded Use of Cabenuva (cabotegravir, rilpivirine) as an HIV Treatment for Use Every 2-Months

ViiV Healthcare, the global specialist HIV company majority owned by GlaxoSmithKline plc ("GSK"), with Pfizer Inc. and Shionogi Limited as shareholders, announced today the submission of a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) for the expanded use of Cabenuva (cabotegravir, rilpivirine). The sNDA seeks to expand Cabenuva's label to include every 2-months dosing for the treatment of HIV-1 infection in virologically suppressed adults (HIV-1 RNA less than 50 copies per milliliter [mL]) on a stable regimen, with no history of treatment failure, and with no known or suspected resistance to either cabotegravir or rilpivirine. Cabenuva is a complete long-acting regimen with two separate injectable medicines, ViiV Healthcare's cabotegravir and rilpivirine, a product of Janssen Sciences Ireland UC. The medication was approved by the FDA in January 2021 as a once monthly treatment for HIV-1 infection in virologically suppressed adults. Prior to initiating treatment of Cabenuva, oral dosing of cabotegravir and rilpivirine should be administered for approximately one month to assess the tolerability of each therapy.¹

Kimberly Smith, M.D., MPH, Head of Research & Development at ViiV Healthcare, said: "Today's submission of Cabenuva dosed every 2-months marks another meaningful step forward in our ongoing commitment to bring innovative HIV treatments to the community. This first-of-its-kind regimen reflects the evolving needs of people living with HIV, and, if this expanded use is approved, could allow adults living with HIV to maintain virologic suppression with six dosing days per year. At ViiV Healthcare, we will continue to advance new approaches to care as part of our mission of leaving no person living with HIV behind."

The sNDA is based on results from the global phase IIIb ATLAS-2M study, which showed the antiviral activity and safety of Cabenuva administered every 2-months was non-inferior when compared to once monthly administration.² Non-inferiority was determined by comparing the proportion of participants with plasma HIV-1 RNA ? 50 copies per milliliter (c/mL) using the FDA Snapshot algorithm at Week 48 (Intent-to-Treat Exposed [ITTE] population), which showed that the every 2-months arm (9/522 [1.7%]) and once monthly arm (5/523 [1.0%]) were similarly effective (adjusted difference: 0.8%, 95% confidence interval [CI]: -0.6, 2.2). The study also found that rates of virologic suppression (HIV-1 RNA <50 c/mL), a key secondary endpoint, were similar, whether Cabenuva was administered every 2-months (492/522 [94.3%]) or once monthly (489/523 [93.5%]) (adjusted difference: 0.8%, 95% CI: -2.1, 3.7). Treatment with Cabenuva was generally well-tolerated across both study arms. In the every 2-months arm, rates of serious adverse events (SAEs: 27/522[5.2%]) and withdrawals due to adverse events (AEs: 12/522 [2.3%]) were low and similar to those experienced in the once monthly arm (SAEs: 19/523 [3.6%], withdrawals due to AEs 13/523 [2.5%]).²

About ATLAS-2M (NCT03299049)

The ATLAS-2M study is an ongoing phase IIIb, randomized, open-label, active-controlled, multicenter, parallel-group, non-inferiority study designed to assess the non-inferior antiviral activity and safety of long-acting cabotegravir and rilpivirine administered every eight weeks (2-months, 3mL dose of each medicine) compared to every four weeks (once monthly, 2mL dose of each medicine) over a 48-week treatment period in 1,045 adults living with HIV-1.² Subjects were required to be virologically suppressed for six months or greater, on first or second antiretroviral regimen, with no prior virologic failure. The primary outcome measure for the study was the proportion of participants with HIV-1 RNA ? 50 c/mL at Week 48 using the FDA Snapshot algorithm (Intent-to-Treat Exposed [ITT-E] population).

ATLAS-2M is part of ViiV Healthcare's extensive and innovative clinical trial program and is being conducted at research centers in Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden and the United States.

For further information please see https://clinicaltrials.gov/ct2/show/NCT03299049.

About Cabenuva (cabotegravir, rilpivirine)

Cabenuva is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are virologically suppressed (HIV-1 RNA less than 50 copies per milliliter [mL]) on a stable regimen, with no history of treatment failure, and with no known or suspected resistance to either cabotegravir or rilpivirine. Cabenuva is administered as two intramuscular injections (cabotegravir, rilpivirine) in the buttocks during the same visit by a healthcare professional.

The complete regimen combines the integrase strand transfer inhibitor (INSTI) cabotegravir, developed by ViiV Healthcare, with rilpivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Janssen. Rilpivirine is approved in the US as a 25mg tablet taken once-a-day for the treatment of HIV-1 in combination with other antiretroviral agents in antiretroviral treatment-naïve patients 12 years of age and older and weighing at least 35-kg with a viral load ? 100,000 HIV RNA copies/mL.

INSTIs 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.

Trademarks are owned by or licensed to the ViiV Healthcare group of companies.

Important Safety Information for Cabenuva (cabotegravir 200mg/mL; rilpivirine 300 mg/mL) extended-release injectable suspensions

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.

About ViiV Healthcare

ViiV Healthcare is a global specialist HIV company established in November 2009 by GlaxoSmithKline (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV and for people who are at risk of becoming infected with HIV. Shionogi joined in October 2012. The company's aim is to take a deeper and broader interest in HIV/AIDS than any company has done before and take a new approach to deliver effective and innovative medicines for HIV treatment and prevention, as well as support communities affected by HIV. For more information on the company, its management, portfolio, pipeline and commitment, please visit www.viivhealthcare.com.

About GSK

GSK is a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. For further information please visit www.gsk.com/about-us/.

Cautionary statement regarding forward-looking statements

GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D "Risk Factors" in the company's Annual Report on Form 20-F for 2019 and as set out in GSK's "Principal risks and uncertainties" section of the Q4 Results and any impacts of the COVID-19 pandemic.

__________________________

¹ Cabenuva (cabotegravir, rilpivirine) Prescribing Information. US Approval January 2021.
² Overton E et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. The Lancet. 2020;396(10267):1994-2005.