ViiV Healthcare announces Juluca (dolutegravir/rilpivirine) maintains HIV viral suppression at 148-weeks

Issued: London, UK

ViiV Healthcare today presented three year results from the SWORD 1 & 2 studies, demonstrating that 84% (432/513) of participants who switched from their current three- or four-drug antiretroviral regimen to a 2-drug regimen of dolutegravir (ViiV Healthcare) and rilpivirine (Janssen Sciences Ireland UC, part of the Janssen Pharmaceutical Companies of Johnson & Johnson) maintained viral suppression (viral load ≤50 copies/mL).¹ These results were presented at the 25th Annual Conference of the British HIV Association (BHIVA) taking place from 2-5 April in Bournemouth, UK.

Professor Chloe Orkin, Consultant Physician and Clinical Professor at Queen Mary University of London and SWORD investigator, said, “With the SWORD data we now have three year data showing the excellent effectiveness and tolerability of Juluca, the first approved dolutegravir-based 2-drug regimen. Importantly, the improvements in bone markers seen at earlier timepoints in the study are maintained over three years. Combined with the potential benefits of lowering the number of antiretroviral agents patients take, these data support the strategy of switching virologically-suppressed, stable patients to the 2-drug regimen of dolutegravir and rilpivirine.”

Findings in the ‘late switch’ arm (n=477), where participants continued on their current antiretroviral regimen until week 52 before switching to the 2-drug regimen of dolutegravir and rilpivirine, showed comparable virologic suppression, tolerability and resistance to that seen in the early switch group at week 100.¹

Through 148 weeks of the study, there was a low number of confirmed virologic withdrawals (CVWs) across study populations who received dolutegravir + rilpivirine (1%; 11/990). Drug-related grade 2-4 adverse events occurred in 5% (47/990) of patients, with adverse events leading to discontinuation reported in 6% (61/990) of patients.¹ Improvements in bone biomarkers were reported across the study groups through week 148 (bone-specific alkaline phosphate change from baseline of -3.4μg/mmol (n=432) in early switch, -3.5μg/mmol (n=433) in late switch; osteocalcin change from baseline of -4.9μg/mmol (n=431) in early switch, -4.8μg/mmol (n=433) in late switch; procollagen 1 N-terminal propeptide change from baseline of -4.2μg/mmol (n=431) in early switch, -7.3μg/mmol (n=431) in late switch; type I collagen C-telopeptides change from baseline of -0.1μg/mmol (n=433) in early switch, -0.1μg/mmol (n=431) in late switch).1 There were also improvements in the renal biomarkers for patients switching away from a TDF containing regimen to dolutegravir + rilpivirine (retinol-binding protein/creatinine ratio change of -28.8μg/mmol (n=285) in early switch, -22.3μg/mmol (n=294) in late switch from a TDF baseline, and -2.3μg/mmol (n=114) in early switch, 0.4μg/mmol (n=125) in late switch from a no-TDF baseline).1 Across both early and late switch arms, no patients developed resistance to dolutegravir and few (n=6) to rilpivirine.¹

John C. Pottage, Jr, M. D. Chief Scientific Medical Officer at ViiV Healthcare, said, “The SWORD 1+2 studies are the first phase III HIV studies to show long-term data for switching from three-drug combination to an oral 2-drug regimen , and the efficacy, tolerability and barrier to resistance out to three years demonstrated in the study provides further reassurance of the suitability of Juluca for many virologically supressed adults living with HIV.”

Juluca has been approved in the EU², the US³ and other countries, with further regulatory marketing applications submitted worldwide.

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 pill in order to expand the treatment options available to people living with HIV.

About Juluca (dolutegravir/rilpivirine)
Juluca has been approved in the US, the EU and other countries 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.^3,4

Juluca is a 2-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.⁴

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 2-drug, daily oral regimen of dolutegravir plus rilpivirine compared with current antiretroviral therapy. In the SWORD studies, dolutegravir and rilpivirine are provided as individual pills.^5,6

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 secondary measures to assess change in health-related quality of life.^5,6

For more information on the study please visit: www.clinicaltrials.gov

Juluca trademark is owned by the ViiV Healthcare group of companies.

IMPORTANT SAFETY INFORMATION

Important Safety Information for Juluca in the European Union:⁴
Juluca (dolutegravir 50mg, rilpivirine 25mg) is contraindicated in any patient with hypersensitivity to the active substances dolutegravir or rilpivirine or to any of the excipients.

Juluca is contraindicated in patients taking:

• Dofetilide
• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• the antimycobacterials rifampicin, rifapentine
• proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole
• the systemic glucocorticoid dexamethasone, except as a single dose treatment
• St John's wort (Hypericum perforatum)

Factors that decrease the exposure of the components of Juluca should be avoided. Juluca should not be taken with any other medicinal products containing dolutegravir or rilpivirine or antiretroviral medicinal products used for the treatment of HIV.

The safety and efficacy of Juluca has not yet been established in patients <18 years and/or in women who are pregnant. Use of Juluca in these patient populations is not recommended.

No dosage adjustment is required in patients with mild or moderate renal impairment. In patients with severe or end stage renal disease, the combination of Juluca with a strong CYP3A inhibitor should only be used if the benefit outweighs the risk. No data are available in subjects receiving dialysis although differences in pharmacokinetics are not expected in this population.

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score A or B). Juluca should be used with caution in patients with moderate hepatic impairment. No data are available in patients with severe hepatic impairment (Child-Pugh score C); therefore Juluca is not recommended in these patients.

Hypersensitivity reactions have been reported with dolutegravir and were characterised by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Juluca should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with Juluca after the onset of hypersensitivity may result in a life-threatening allergic reaction.

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves’ disease) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

Monitoring of liver function is recommended in patients with hepatitis B and/or C co-infection. No clinical data are available in patients with hepatitis B co-infection. Physicians should refer to current treatment guidelines for the management of HIV infection in patients co-infected with hepatitis B virus. Limited data is available in patients with hepatitis C co-infection. A higher incidence of liver chemistry elevations (Grade 1) were observed in patients treated with dolutegravir and rilpivirine co-infected with hepatitis C compared to those who were not co-infected.

Patients should be advised that Juluca does not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.

Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

At supra-therapeutic doses (75 and 300 mg once daily), rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG). Rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Juluca should be used with caution when co-administered with medicinal products with a known risk of Torsade de Pointes.

Please refer to the full European Summary of Product Characteristics for full prescribing information, including contraindications, special warnings and precautions for use.⁴

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 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.

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 'Principal risks and uncertainties' in the company's Annual Report on Form 20-F for 2018.

References

1. van Wyk J, Orkin C, Rubio R et al. Durable suppression and low rate of virologic failures 3 years after switch to DTG+RPV 2-Drug Regimen: SWORD 1&2 Studies. Presented at BHIVA, April 2019.
2. European Medicines Agency. Juluca. Available at: https://www.ema.europa.eu/documents/overview/juluca-epar-medicine-overview_en.pdf. Last accessed February 2019
3. 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 February 2019.
4. Juluca EU Summary of product characteristics. Available at: www.medicines.org.uk/emc/product/9246. Last accessed February 2019
5. 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. Last accessed February 2019.
6. 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. Last accessed February 2019