ViiV Healthcare presents three-year switch data for Dovato (dolutegravir/lamivudine) confirming long-term, non-inferior efficacy with no virologic failure versus continuation of TAF-based regimens of at least three drugs

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ViiV Healthcare, the global specialist HIV company majority owned by GlaxoSmithKline plc (“GSK”), with Pfizer Inc. and Shionogi Limited as shareholders, today presented three-year results from the TANGO study at IDWeek 2021, being held virtually 29 September - 3 October. Findings showed that the 2-drug regimen (2DR) Dovato (dolutegravir/lamivudine) continued to demonstrate non-inferior efficacy and a high barrier to resistance compared to continuation of tenofovir alafenamide fumarate (TAF)-based regimens of at least three drugs in virologically suppressed adults living with HIV-1 who had not experienced prior virologic failure.¹ At three years, no participants on dolutegravir/lamivudine (0% [0/369]) met confirmed protocol-defined virologic failure, versus three participants (<1% [3/372]) on the TAF-based regimen. No resistance mutations were reported in either arm.¹

Olayemi Osiyemi, M.D., Founder, CEO, and President of Triple O Medical Services and Triple O Research Institute P.A., United States, lead author and one of the investigators of the TANGO study, said: “These data provide us with further long-term evidence that switching virologically supressed people living with HIV from TAF-based 3-drug regimens to dolutegravir/lamivudine will not only maintain virologic suppression, but offers a treatment option consisting of fewer medicines. As we now consider HIV a long-term condition requiring life-long medication, these results give physicians the data they need to have more confidence in switching their virologically suppressed patients who are taking three or more medicines. Additionally, these data show no confirmed virologic failures, which is important over a long-term study.”

These findings demonstrated the non-inferiority of dolutegravir/lamivudine compared to continuation of TAF-based regimens in the Intention to Treat-Exposed (ITT-E) population (defined as all participants randomised to the study), based on the proportion of participants with plasma HIV-1 RNA ≥50 copies per millilitre (c/mL) at Week 144 (Snapshot virologic failure: 0.3% [1/369] vs 1.3% [5/372]; adjusted difference: -1.1% [95% CI: -2.4%, 0.2%] for the dolutegravir/lamivudine and TAF-based regimen arms, respectively).¹

In the ITT-E population, both treatment arms showed a high proportion of participants with plasma HIV-1 RNA <50 c/mL, with dolutegravir/lamivudine demonstrating non-inferior virologic suppression to the TAF-based regimen (85.9% [317/369] vs 81.7% [304/372], respectively; adjusted difference: 4.2% [95% CI: -1.1%, 9.5%]).¹

Kimberly Smith, M.D., MPH, Head of Research & Development at ViiV Healthcare, said: “The latest results from the TANGO study further reinforce Dovato’s role in the HIV treatment landscape, allowing people living with HIV to maintain virologic suppression over the long-term with fewer medicines.”

Overall adverse event (AE) rates were similar between the study arms, with more drug-related grade 2-5 AEs with dolutegravir/lamivudine versus the TAF-based regimens arm (6% [21/369]) vs 4% [13/371], respectively).¹ Rates of AEs were similar between treatment arms at Weeks 48, 96 and 144. The most common drug-related grade 2-5 AEs in the dolutegravir/lamivudine and TAF-based regimens arms were insomnia (1% [4/369] vs 0% [0/371]), increased weight (<1% [3/369] vs <1% [3/371]), constipation (<1% [2/369] vs <1% [1/371]), depression (<1% [2/369] vs <1% [1/371]), flatulence (<1% [2/369] vs 0% [0/371]) and nausea (0% [0/369] vs <1% [2/371]).¹ As with the findings at Weeks 48 and 96, changes in fasting lipids generally favoured dolutegravir/lamivudine.¹ Decreases in total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides were observed in the dolutegravir/lamivudine arm, compared to increases in the TAF-based regimens arm, while very small changes in TC/HDL ratio were seen across both treatment arms.¹ At Week 144, proximal tubular renal function markers were comparable across the two treatment arms.¹

About TANGO²

TANGO is a phase III, randomised, open-label, active-controlled, multicentre study to assess the antiviral efficacy and safety of switching to a 2-drug regimen (2DR) consisting of dolutegravir/lamivudine in HIV-infected adults who are virologically suppressed and stable on a tenofovir alafenamide fumarate (TAF)-based regimen.

Study participants were HIV-1 infected adults on TAF-based regimens with HIV-1 RNA<50 c/mL for at least six months, without prior virologic failure, no historical nucleoside reverse transcriptase inhibitors (NRTI) or integrase inhibitor (INSTI) major resistance mutation, and no evidence of hepatitis B infection. Participants were randomised to switch to dolutegravir/lamivudine or continue on the TAF-based regimens through Week 148. The primary endpoint was the proportion of participants with a viral load of >50 c/mL at Week 48 (FDA Snapshot algorithm) for the Intention to Treat-Exposed (ITT-E) population. Secondary endpoints included efficacy at Weeks 96 and 144 in the ITT-E and Per Protocol (PP) populations.

About Dovato (dolutegravir/lamivudine)^3,4

Dovato is a once-daily, single-pill, 2-drug regimen (2DR) that combines the integrase strand transfer inhibitor (INSTI) dolutegravir (Tivicay, 50 mg) with the nucleoside reverse transcriptase inhibitor (NRTI) lamivudine (Epivir, 300 mg).

Dovato (dolutegravir 50 mg/lamivudine 300 mg tablets) is authorised in the EU for the treatment of HIV-1 infection in adults and adolescents above 12 years of age weighing at least 40 kg, with no known or suspected resistance to the INSTI class, or lamivudine. In the US, Dovato is indicated as a complete regimen to treat HIV-1 infection in adults with no antiretroviral (ARV) treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ARV regimen with no history of treatment failure and no known resistance to any component of Dovato.

Dovato uses two medicines, instead of the traditional three, to inhibit the viral life cycle at two different sites. INSTIs, like dolutegravir, 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. Lamivudine is an NRTI that works by interfering with the conversion of viral ribonucleic acid (RNA) into deoxyribonucleic acid (DNA) which in turn stops the virus from multiplying.

Dovato is approved in the US, Europe, Japan, Australia and other countries worldwide.

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

Important Safety Information for Dovato (50mg dolutegravir/300mg lamivudine) Tablets

INDICATION

DOVATO is indicated as a complete regimen to treat HIV-1 infection in adults with no antiretroviral (ARV) treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ARV regimen with no history of treatment failure and no known resistance to any component of DOVATO.

IMPORTANT SAFETY INFORMATION

BOXED WARNING: PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV-1: EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBV

All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If DOVATO is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.

Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment.

Contraindications

· Do not use DOVATO in patients with previous hypersensitivity reaction to dolutegravir or lamivudine

· Do not use DOVATO in patients receiving dofetilide

Warnings and precautions

Hypersensitivity Reactions:

· Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury

· Discontinue DOVATO immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated

Hepatotoxicity:

· Hepatic adverse events have been reported, including cases of hepatic toxicity (elevated serum liver biochemistries, hepatitis, and acute liver failure), in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors

· Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of DOVATO. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn

· Monitoring for hepatotoxicity is recommended

Embryo Fetal Toxicity:

· Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy due to the risk of neural tube defects

· Pregnancy testing is recommended before initiation of DOVATO. Individuals of childbearing potential should be counseled on the consistent use of effective contraception

Lactic Acidosis and Severe Hepatomegaly with Steatosis:

Fatal cases have been reported with the use of nucleoside analogs, including lamivudine. Discontinue DOVATO if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations.

Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of DOVATO and other drugs may occur (see Contraindications and Drug interactions).

Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of DOVATO.

Adverse reactions

The most common adverse reactions (incidence ≥2%, all grades) with DOVATO were headache (3%), nausea (2%), diarrhea (2%), insomnia (2%), fatigue (2%), and anxiety (2%).

Drug interactions

· Consult full Prescribing Information for DOVATO for more information on potentially significant drug interactions

· DOVATO is a complete regimen. Coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended

· Drugs that induce or inhibit CYP3A or UGT1A1 may affect the plasma concentrations of dolutegravir

· Administer DOVATO 2 hours before or 6 hours after taking polyvalent cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, DOVATO and supplements containing calcium or iron can be taken with food

Use in specific populations

· Pregnancy: There are insufficient human data on the use of DOVATO during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established. Advise individuals of childbearing potential of the potential risk of neural tube defects. Assess the risks and benefits of DOVATO and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester

· Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant

· Females and Males of Reproductive Potential: Pregnancy testing is recommended before initiation of DOVATO. Counsel individuals of childbearing potential taking DOVATO on the consistent use of effective contraception

· Renal Impairment: DOVATO is not recommended for patients with creatinine clearance <30 mL/min. Patients with a sustained creatinine clearance between 30 and 49 mL/min should be monitored for hematologic toxicities, which may require a dosage adjustment of lamivudine as an individual component

· Hepatic Impairment: DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C)

Please refer to the full European Summary of Product Characteristics for Dovato for full prescribing information, including contraindications, special warnings and precautions for use. For the US, please refer to the US Prescribing Information, including Boxed Warning.

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 aims are to take a deeper and broader interest in HIV and 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. 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 in the Company's Annual Report on Form 20-F for 2020, GSK’s Q2 Results and any impacts of the COVID-19 pandemic.

Registered in England & Wales:

GSK PLC	ViiV Healthcare Limited
No. 3888792	No. 06876960

Registered Office:
980 Great West Road
Brentford, Middlesex
TW8 9GS

References

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¹ Osiyemi O, Ajana F, Bisshop F, et al. Switching to DTG/3TC Fixed-Dose Combination (FDC) Is Non-inferior to Continuing a TAF-Based Regimen (TBR) in Maintaining Virologic Suppression through 144 Weeks (TANGO Study). Presented at IDWeek 2021.

² ClinicalTrials.gov. Switch Study to Evaluate Dolutegravir Plus Lamivudine in Virologically Suppressed Human Immunodeficiency Virus Type 1 Positive Adults (TANGO). Available at: https://clinicaltrials.gov/ct2/show/NCT03446573. Accessed September 2021.

³ Dovato EU Summary of Product Characteristics. March 2021. Available at: https://www.medicines.org.uk/emc/product/10446/smpc. Accessed September 2021.

⁴ Dovato US Prescribing Information. Available at: https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Dovato/pdf/DOVATO-PI-PIL.PDF. Accessed September 2021.

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