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Juluca, the first single pill, 2-drug regimen, for the maintenance treatment of HIV, granted marketing approval by Japan Ministry of Health, Labour and Welfare

Japan, London, 26 November 2018 – ViiV Healthcare today announced that the Ministry of Health, Labour and Welfare (MHLW) has approved Juluca Combination Tablets (containing dolutegravir 50mg/rilpivirine 25mg) for the maintenance treatment of human immunodeficiency virus type 1 (HIV-1) infection.1

Juluca is a two-drug regimen of dolutegravir (ViiV Healthcare), the most widely prescribed integrase inhibitor worldwide 2, and rilpivirine (Janssen Sciences Ireland UC, part of the Janssen Pharmaceutical Companies of Johnson & Johnson).3 The distribution and sales operations of the once-daily single-pill regimen will be conducted by GlaxoSmithKline K.K. Tokyo, in the same way as for existing products of ViiV Healthcare in Japan.

Dustin Haines, President, ViiV Healthcare, Japan said, “This regulatory approval demonstrates our commitment to bringing new medicines for people living with HIV, as they now have the opportunity to maintain their viral suppression with only two drugs within a single-pill.”

The drug was filed for approval in Japan on 1 August 2018.1 Juluca received approval for the treatment of HIV infection in November 2017 4 in the US and in May 2018 in Europe.5

Dr. Ichiro Koga, MD, Director Medical Affairs, ViiV Healthcare, Japan said, “We have found a way to reduce the number of antiretrovirals whilst maintaining the efficacy of the traditional three-drug regimen, for people living with HIV. This innovative advancement supports our commitment to making HIV treatment a smaller part of people’s lives and demonstrates the potential of our robust clinical research programme.”

The approval of Juluca was based on the SWORD studies that included more than one thousand patients who previously achieved viral suppression on a three- or four-drug (integrase inhibitor, non-nucleoside reverse transcriptase inhibitor, or protease inhibitor-based) antiretroviral regimen. The 48 week results were presented at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) and published in The Lancet in 2018.6

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Notes to editors
In June 2014, ViiV Healthcare and Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, announced a collaboration to investigate the potential of combining dolutegravir and rilpivirine in a single tablet in order to expand the treatment options available to people living with HIV.

About Juluca (dolutegravir/rilpivirine)
Juluca was approved by the US Food and Drug Administration (FDA) on 21st November 2017, 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 mL) on a stable antiretroviral regimen for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of Juluca.4

Juluca is a two-drug regimen, single pill that combines the integrase inhibitor dolutegravir (50mg), with the non-nucleoside reverse transcriptase inhibitor rilpivirine (25mg), taken once-daily as a complete HIV regimen for people living with HIV who are virologically suppressed.

Two essential steps in the HIV life cycle include reverse transcription – when the virus turns its RNA (ribonucleic acid) copy into DNA (deoxyribonucleic acid) – and integration – the moment when viral DNA becomes part of the host cell’s DNA. These processes require two enzymes called nucleoside reverse transcriptase and integrase. Non-nucleoside reverse transcriptase inhibitors and integrase inhibitors interfere with the action of these two enzymes to prevent the virus from replicating. This decrease in replication can lead to less virus being available to cause subsequent infection of uninfected cells.

About the SWORD phase III programme for dolutegravir and rilpivirine
The SWORD phase III programme evaluates the efficacy, safety, and tolerability of switching to dolutegravir plus rilpivirine from current integrase inhibitor-, non-nucleoside reverse transcriptase inhibitor-, or boosted protease inhibitor-based antiretroviral regimen in HIV-1-infected adults who are virologically suppressed with a three or four-drug regimen. SWORD-1 (NCT02429791) and SWORD-2 (NCT02422797) are replicate 148-week, randomised, open-label, non-inferiority studies to assess the antiviral activity and safety of a two-drug, daily oral regimen of dolutegravir plus rilpivirine compared with current antiretroviral therapy. In the SWORD clinical trials, dolutegravir and rilpivirine are provided as individual tablets.

The primary endpoint is the proportion of patients with plasma HIV-1 RNA <50 copies per millilitre (c/mL) at week 48. Key secondary endpoints include evaluation of the development of viral resistance, measurements of safety and tolerability, and changes in renal, bone and cardiovascular biomarkers. The studies also include exploratory measures to assess change in health-related quality of life, willingness to switch and adherence to treatment regimens.7,8

For more information on the trials please visit: www.clinicaltrials.gov
Juluca and Tivicay are trademarks owned by the ViiV Healthcare group of companies.
Edurant (rilpivirine) is a registered trademark of Janssen Sciences Ireland UC.

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use JULUCA safely and effectively. See full prescribing information for JULUCA at http://glaxosmithkline.co.jp/viiv/medical/medicine.html.

JULUCA (dolutegravir and rilpivirine) tablets, for oral use

INDICATIONS AND USAGE
HIV-1 infection
(1) Juluca Combination Tablets are indicated for patients receiving anti-HIV therapy that have no history of virological failure, virologically suppressed (HIV-1 RNA < 50 copies/mL) at least 6 months prior to switching, no resistance mutation to either antiretroviral component and are judged appropriate to switch to Juluca Combination Tablets. [See “CLINICAL STUDIES”]
(2) When treating patients with Juluca Combination Tablets, treatment history and, if possible, drug resistance test result (genetic analysis or phenotypic analysis) should be referred. 
DOSAGE AND ADMINISTRATION
The usual initial adult dose is one tablet (50 mg of dolutegravir and 25 mg of rilpivirine) once daily taken orally with a meal or immediately after a meal.
(1) Treatment with Juluca Combination Tablets should be initiated under supervision of a physician with sufficient experience in anti-HIV therapy.
(2) Do not use with other medical product containing dolutegravir. When Juluca Combination Tablets is used in combination with rifabutin, 25 mg of rilpivirine product once daily should be administered concomitantly. When combination use of rifabutin is discontinued, administration of rilpivirine alone should also be discontinued. Do not use any products containing rilpivirine except using Juluca Combination Tablets in combination with rifabutin.

DOSAGE FORMS AND STRENGTHS
Each tablet contains: 50 mg of dolutegravir and 25 mg of rilpivirine

CONTRAINDICATIONS
- Patients with known hypersensitivity to dolutegravir sodium or rilpivirine hydrochloride or to any of the excipients.
- Patients taking rifampicin, carbamazepine, phenytoin, fosphenytoin, phenobarbital, foods containing St. John's Wort, systemic administration of dexamethasone (except as a single dose treatment) and proton pump inhibitors (omeprazole, lansoprazole, rabeprazole, esomeprazole, vonoprazan fumarate)

PRECAUTIONS
Juluca Combination tablets should be administered with care in the following patients:
- Patients who are likely to develop arrhythmia (e.g., hypokalaemia, marked bradycardia, acute myocardial ischaemia, cardiac failure congestive, congenital long QT syndrome) or who are taking drugs known to cause QT prolongation [QT prolongation has been observed with administration of rilpivirine 75 mg and 300 mg, and QT prolongation may cause arrhythmia in these patients.
- Patients co-infected with hepatitis B or C virus, hepatic function may worsen.
- Immune reconstitution syndrome has been reported in patients who are treated with multi-drug therapy.
- As hepatic function disorder and/ or jaundice may occur, close monitoring including routine liver function test should be conducted.
DRUG INTERACTIONS
- Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.
- Refer to the full prescribing information for important drug interactions with JULUCA.
- Drugs that induce or inhibit CYP3A4 or UGT1A1 may affect the plasma concentrations of the components of JULUCA.
- Drugs that increase gastric pH or containing polyvalent cations may decrease plasma concentrations of the components of JULUCA
- Consider alternatives to prescribing JULUCA with drugs with a known risk of Torsade de Pointes.

ADVERSE REACTIONS
- The most common adverse reactions (all Grades) observed in at least 2% of subjects were diarrhoea and headache.
Clinically significant adverse reactions
- 1) Drug-induced hypersensitivity syndrome (incidence unknown: Rash and pyrexia are observed as initial symptoms, and may be followed by serious delayed hypersensitive symptoms accompanied by hepatic impairment, lymphadenopathy and eosinophili, etc. Patients should be carefully monitored, and in the event of such symptoms, Juluca Combination Tablets must be discontinued and appropriate measures should be taken. Symptoms including rash, pyrexia and hepatic impairment may relapse or be prolonged even after administration is discontinued, and thus, caution should be exercised.
- 2) Hepatic function disorder (< 1%) and/ or jaundice (incidence unknown) : Hepatic function disorder and/ or jaundice accompanied by increased AST, ALT, and/or bilirubin may occur, so in case abnormality is observed, administration should be discontinued, or other appropriate therapeutic measures should be taken.

To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872

Use during pregnancy, Delivery or Lactation
1) Juluca Combination Tablets should be used only if the expected benefit justifies the potential risk in pregnant women or women who may be pregnant, but it is recommended to be avoided in the early stage of pregnancy due to the risk of neural tube defects. Women of childbearing potential (WOCBP) should undergo pregnancy testing and/ or clinical examination before initiation of Juluca Combination Tablets to confirm not to be pregnant. WOCBP who are taking Juluca Combination Tablets should use effective contraception throughout and for a certain period after treatment. Safety on administration during pregnancy has not been established.

2) Nursing should be discontinued during the administration of Juluca Combination Tablets. [It is not known whether dolutegravir and rilpivirine are excreted into human breast milk. Dolutegravir and rilpivirine have been reported to be excreted into breast milk in the animal studies (rats). Also, in general, women infected with HIV should not breastfeed under any circumstances for the prevention of infants from becoming infected with HIV].

For further information on Juluca uses affects and indication please refer to product information - http://glaxosmithkline.co.jp/viiv/medical/medicine.html.

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.

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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 Principal risks and uncertainties in the company's Annual Report on Form 20-F for 2017.

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References
1. Ministry of Health, Labor and Welfare AIDS Surveillance Committee) / http://api-net.jfap.or.jp/status/2017/17nenpo/h29gaiyo.pdf Last accessed November 2018.
2. IMS data. Number of Patients on Dolutegravir, Worldwide. August 2017.
3. Juluca EU Summary of product characteristics. Available at: https://www.medicines.org.uk/emc/product/9246 Last accessed November 2018.
4. U.S. Food and Drug Administration. Juluca (dolutegravir and rilpivirine) Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/210192s000lbl.pdf Last accessed November 2018.
5. European Medicines Agency. Juluca. Available at: https://www.ema.europa.eu/documents/overview/juluca-epar-medicine-overview_en.pdfLast accessed November 2018.
6. Llibre JM, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. The Lancet. 2018 Mar 3;391(10123):839-849.
7. Clinical trials.gov. SWORD-1 - Regimen Switch to Dolutegravir + Rilpivirine From Current Antiretroviral Regimen in Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults (SWORD-1). Available at: https://clinicaltrials.gov/ct2/show/NCT02429791?term=dolutegravir+AND+sword&cond=HIV&rank=3 Last accessed November 2018.
8. Clinical trials.gov. SWORD-2 - Regimen Switch to Dolutegravir + Rilpivirine From Current Antiretroviral Regimen in Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults (SWORD-2). Available at: https://clinicaltrials.gov/ct2/show/NCT02422797?term=dolutegravir+AND+sword&cond=HIV&rank=1 Last accessed November 2018.