ViiV Healthcare announces the European Commission Decision for Vocabria (Cabotegravir) and Rekambys (Rilpivirine) injections to be initiated with or without an oral lead-in period for the long-acting treatment of HIV. Healthcare professionals and people living with HIV now have the choice of starting long-acting treatment with the oral initiation phase or starting injections directly.
ViiV Healthcare, the global specialist HIV company majority owned by GlaxoSmithKline plc (“GSK”), with Pfizer Inc. and Shionogi Limited as shareholders, announced that the European Commission has granted a decision to update the Summary of Product Characteristics (SmPC) for Vocabria (Cabotegravir injections and tablets) and The Janssen Pharmaceutical Companies of Johnson & Johnson’s Rekambys (Rilpivirine long-acting injectable suspension) giving healthcare professionals and people living with HIV the option to start with injections, without the need for an oral lead-in of Cabotegravir and rilpivirine. Oral Cabotegravir and Rilpivirine can be taken for a month to assess tolerability to the medicines, which is now optional with the SmPC update. The data showed that both initiation routes have similar safety and efficacy profiles.1,2
Harmony P. Garges, M.D., MPH, Chief Medical Officer at ViiV Healthcare said: “Being able to initiate cabotegravir and rilpivirine injections without an oral lead-in simplifies the initiation experience for both healthcare professionals and people living with HIV, meaning that they can start long-acting therapy sooner. People living with HIV can experience a range of challenges with daily oral antiretroviral therapy, including daily reminders of HIV and the fear of disclosing their HIV status. We are pleased that with this decision, they now have a choice of switching from their current oral therapy to a long-acting injectable therapy without having to transition through an oral lead-in. At ViiV Healthcare, we are proud to be able to offer innovative choices that meet the changing needs of people living with HIV.”
The decision from the European Commission was based on the phase III FLAIR clinical trial Week 124 results, and supported by extensive safety and tolerability data from Phase II and Phase III studies of oral cabotegravir and rilpivirine, prior to intramuscular injections, where no safety signals that would require the use of an oral lead-in were identified.3 Administration of cabotegravir and rilpivirine injections without the oral lead-in was investigated as part of an extension to the Phase III FLAIR clinical trial, with results showing that there were no meaningful differences in outcomes regarding maintenance of virologic suppression, safety, tolerability and pharmacokinetics in people starting cabotegravir and rilpivirine injections with or without the oral lead-in.2
ViiV Healthcare’s Cabotegravir in combination with Janssen Pharmaceutical Companies of Johnson & Johnson’s rilpivirine was co-developed as part of a collaboration with Janssen and builds on ViiV Healthcare’s industry-leading portfolio that is centred on delivering innovative medicines for the HIV community.
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 Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson.
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 Vocabria (Cabotegravir):
Cabotegravir, sold under the brand name Vocabria, is a antiretroviral medication used for the treatment of HIV/AIDS. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination with rilpivirine It is an integrase inhibitor with a carbamoyl pyridone structure similar to that of dolutegravir.
Cabotegravir in combination with rilpivirine is indicated for the treatment of human immunodeficiency virus type-1 (HIV-1) in adults. The combination injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/mL) with their current antiretroviral treatment, and when the virus has not developed resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors. The tablets are used to check whether a person tolerates the treatment before the injection therapy is started.
The two medicines are the first antiretroviral drugs that come in a long-acting injectable formulation.This means that instead of daily pills, people receive intramuscular injections monthly or every two months.
Mechanism of action (MOA):
Cabotegravir is an integrase strand transfer inhibitor. This means it blocks the HIV’s enzyme integrase, thereby preventing its genome from being integrated into the human cells’ DNA. As this is a necessary step for the virus to replicate, its further spread is hampered.
Cabotegravir glucuronide, the main metabolite in human bile and urine
When taken by mouth, Cabotegravir reaches highest blood plasma levels after three hours. Taking the drug together with food slightly increases its concentrations in the blood, but this is not clinically relevant. After injection into the muscle, cabotegravir is slowly absorbed into the bloodstream, reaching its highest blood plasma levels after about seven days.
Over 99% of the substance are bound to plasma proteins. The drug is inactivated in the body by glucuronidation, mainly by the enzyme UGT1A1, and to a much lesser extent by UGT1A9. More than 90% of the circulating substance are the unchanged cabotegravir, however. The biological half-life is 41 hours for the tablets and 5.6 to 11.5 weeks for the injection.
Elimination has only been studied for oral administration: Most of the drug is eliminated via the faeces in unchanged form (47%). It is not known how much of this amount comes from the bile, and how much was not absorbed in the first place. (The bile actually contains the glucuronide, but this could be broken up again in the gut lumen to give the parent substance that is observed in the faeces.) To a lesser extent it is excreted via the urine (27%), almost exclusively as the glucuronide.
UGT1A1 poor metabolizers have 1.3- to 1.5-fold increased cabotegravir concentrations in the body. This is not considered clinically significant
Local injection site reactions (ISRs)
Up to 1% of subjects discontinued treatment with Vocabria plus rilpivirine because of ISRs. When dosing monthly, up to 84% of subjects reported injection site reactions; out of 30393 injections, 6815 ISRs were reported. When dosing every 2 months, 76% of patients reported injection site reactions; out of 8470 injections, 2507 ISRs were reported.
The severity of reactions was generally mild (Grade 1, 70%-75% of subjects) or moderate (Grade 2, 27%-36% of subjects). 3-4% of subjects experienced severe (Grade 3) ISRs. The median duration of overall ISR events was 3 days. The percentage of subjects reporting ISRs decreased over time.
At the Week 48 time point, subjects in studies FLAIR and ATLAS, who received Vocabria plus rilpivirine gained a median of 1.5 kg in weight subjects continuing on their current antiretroviral therapy (CAR) gained a median of 1.0 kg (pooled analysis). In the individual studies FLAIR and ATLAS, the median weight gains in the Vocabria plus rilpivirine arms were 1.3 kg and 1.8 kg respectively, compared to 1.5 kg and 0.3 kg in the CAR arms.
At the 48 week timepoint, in ATLAS-2M the median weight gain in both the monthly and 2-monthly CAB+RPV dosing arms was 1.0 kg.
There are a limited amount of data from the use of cabotegravir in pregnant women. The effect of Vocabria on human pregnancy is unknown.
Cabotegravir was not teratogenic when studied in pregnant rats and rabbits but, exposures higher than the therapeutic dose showed reproductive toxicity in animals. The relevance to human pregnancy is unknown.
Vocabria injection is not recommended during pregnancy unless the expected benefit justifies the potential risk to the foetus. Cabotegravir has been detected in systemic circulation for up to 12 months or longer after an injection
It is expected that cabotegravir will be secreted into human milk based on animal data, although this has not been confirmed in humans. Cabotegravir may be present in human milk for up to 12 months or longer after the last cabotegravir injection.
It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
About Rekambys ( Rilpivirine)
Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs such as efavirenz
In the US, rilpivirine is approved for treatment-naive patients with a viral load of 100,000 copies/mL or less at therapy initiation. It has to be combined with other drugs against HIV.
In the European Union, rilpivirine is approved in combination with cabotegravir for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/ml) with their current antiretroviral treatment, and when the virus has not developed resistance to certain class of anti-HIV medicines called non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (INIs).
Mechanism of action (MOA):
Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI).
When taken by mouth, rilpivirine reaches highest levels in the blood plasma after about four to five hours. Taking the drug without food lowers its plasma levels by 40% as compared to taking it with food, which is considered to be clinically relevant. Therefore, patients are advised to take the medication together with a meal. After injection into the muscle, the substance reaches highest plasma levels after three to four days.
Independently of the mode of application, rilpivirine is almost completely bound to plasma proteins (99.7%), mostly to albumin. It is metabolised mainly by the liver enzyme CYP3A4. Metabolites include several oxidation products, glucuronides, and glucuronides of oxidized metabolites. The biological half-life is approximately 45 hours for the tablets and 13 to 28 weeks for the injection.
Elimination has only been studied for oral administration: Most of the drug is excreted via the faeces (85%), partly in unchanged form (25%), partly in form of its metabolites (60%). A minor amount is excreted via the urine (6%), almost exclusively as metabolites.
Interactions with other medicinal products:
REKAMBYS should not be administered with other antiretroviral medicinal products, except for cabotegravir injection for the treatment of HIV-1 infection.
There are limited data of REKAMBYS in pregnant women. REKAMBYS is not recommended during pregnancy unless the expected benefit justifies the potential risk. Lower exposures of oral rilpivirine were observed when rilpivirine 25mg once daily was taken during pregnancy. In the Phase 3 studies with oral rilpivirine, lower rilpivirine exposure, similar to that seen during pregnancy, has been associated with an increased risk of virological failure, therefore viral load should be monitored closely. Alternatively, switching to another ART regimen could be considered.
Immune reactivation syndrome
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 and autoimmune hepatitis) 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.
Transmission of HIV
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Patients should be advised that REKAMBYS or any other antiretroviral therapy 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.
What is Summary of product characteristics?
A document describing the properties and the officially approved conditions of use of a medicine. Summaries of product characteristics form the basis of information for healthcare professionals on how to use the medicine safely and effectively. Abbreviated as SmPC.
About ViiV Healthcare:
ViiV Healthcare is a pharmaceutical company specializing in the development of therapies for HIV infection that was created as a joint venture by Pfizer and GlaxoSmithKline in November 2009 with both companies transferring their HIV assets to the new company. In 2012 Shionogi joined the company. 76.5% of the company is now owned by GlaxoSmithKline, 13.5% by Pfizer and 10% by Shionogi. This ownership structure may change depending upon the achievement of certain milestones.
About Janssen Pharmaceutical:
Janssen Pharmaceuticals is a pharmaceutical company headquartered in Beerse, Belgium, and wholly-owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen.
In 1961, Janssen Pharmaceuticals was purchased by New Jersey-based American corporation Johnson & Johnson, and became part of Johnson & Johnson Pharmaceutical Research and Development (J&J PRD), now renamed to Janssen Research and Development (JRD), which conducts research and development activities related to a wide range of human medical disorders, including mental illness, neurological disorders, anaesthesia and analgesia, gastrointestinal disorders, fungal infection, HIV/AIDS, allergies and cancer. Janssen and Ortho-McNeil Pharmaceutical have been placed in the Ortho-McNeil-Janssen group within Johnson & Johnson Company
About GlaxoSmithKline plc:
GlaxoSmithKline PLC is a global healthcare company. The Company operates through two segments: Pharmaceuticals and Vaccines. The Company focuses on its research across six areas: Respiratory diseases, human immunodeficiency virus (HIV)/infectious diseases, Vaccines, Immuno-inflammation, Oncology and Rare diseases. The Company makes a range of prescription medicines and vaccines products. The Pharmaceuticals business discovers, develops and commercializes medicines to treat a range of acute and chronic diseases. The Vaccines business provides vaccines for people of all ages from babies and adolescents to adults and older people. It has a portfolio of medicines in respiratory and HIV. Its Pharmaceuticals business includes Respiratory, HIV, Specialty products, and Classic and Established products. Its Vaccines business has a portfolio of over 40 pediatric, adolescent, adult, older people and travel vaccines.
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