• ViiV Healthcare’s Vocabria (cabotegravir injection) used in combination with Janssen Pharmaceutical Companies of Johnson & Johnson’s Rekambys (rilpivirine injection) reduces treatment dosing days from 365 to 12 or 6 per year
• Long-acting regimen is based on co-administration of cabotegravir and rilpivirine injections once-monthly or once every 2-months to treat HIV-1
• Vocabria (cabotegravir) tablets for use as an oral lead-in therapy with Edurant (rilpivirine tablets) prior to starting the long-acting regimen also receives positive CHMP opinion

LONDON–(BUSINESS WIRE)–ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer Inc. and Shionogi Limited as shareholders, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending marketing authorisation for Vocabria (cabotegravir injection and tablets) in combination with Rekambys (rilpivirine injection) and Edurant (rilpivirine tablets), for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the non-nucleoside reverse transcriptase inhibitor (NNRTI) and integrase inhibitor (INI) class.¹

Deborah Waterhouse, CEO, ViiV Healthcare, said “Today’s positive CHMP opinion marks an important step in providing a new option that changes the treatment experience for people living with HIV across Europe. Vocabria injection used in combination with Rekambys has the potential to ease the day-to-day burden of HIV by offering significantly less frequent dosing from 365 days with oral regimens to 12 or 6 treatments per year. Through our innovative R&D, we are now one step closer to offering an HIV medicine in Europe with a novel route of administration and dosing schedule compared to other therapies. We’re proud to be providing different treatment options that meet the diverse needs of the HIV community.”

If approved, cabotegravir injection used in combination with rilpivirine injection will be the first complete long-acting regimen, dosed once-monthly or once every 2-months, for virologically suppressed people living with HIV-1 across Europe. This treatment will offer people living with HIV an option with significantly less frequent dosing and comparable efficacy to daily oral regimens. Cabotegravir and rilpivirine injections are administered as two intramuscular (IM) injections in the buttocks during the same visit at a specialist clinic by a healthcare professional. Prior to the initiation of the injections, cabotegravir and rilpivirine oral tablets are taken for approximately one month (at least 28 days) to assess tolerability to the medicines.

The Marketing Authorisation Application (MAA) for cabotegravir injection and tablets is based on the pivotal phase III ATLAS (Antiretroviral Therapy as Long-Acting Suppression), FLAIR (First Long-Acting Injectable Regimen) and ATLAS-2M studies.

The ATLAS and FLAIR studies included more than 1,100 participants from 16 countries.^2,3 The studies demonstrated that cabotegravir and rilpivirine when injected intramuscularly in the buttocks, once-monthly, was as effective as continuing their daily, oral, antiretroviral regimens in maintaining viral suppression throughout the 48-week study period. (Read more…) The long-acting regimen was preferred by approximately 9 out of 10 patients who switched to cabotegravir and rilpivirine long-acting in the ATLAS and FLAIR studies over their previous daily oral therapy.*

In both studies, the most common adverse reactions (Grades 1 to 4) observed in ≥ 2% of participants receiving cabotegravir and rilpivirine were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, rash, and diarrhoea. Over the 48-week study period, a total of 4% of participants discontinued cabotegravir and rilpivirine due to adverse events.⁴

48-week data from the pivotal ATLAS-2M study were also included in the MAA to support the use of cabotegravir and rilpivirine once every 2-months. Results from the study showed the antiviral activity and safety of long-acting cabotegravir and rilpivirine injections administered once every 2-months was non-inferior to long-acting cabotegravir and rilpivirine injections administered once-monthly in virologically suppressed adults living with HIV-1 infection over a 48-week period. In the ATLAS-2M study rates of serious adverse events (SAEs) (27/522 [5.2%]) and withdrawals due to adverse events (AEs) (12/522 [2.3%]) at 48 weeks were low and were similar to those experienced in the one month arm (SAEs: 19/523 [3.6%], withdrawals due to AEs 13/523 [2.5%]).⁵

The Patient Reported Outcomes data from the ATLAS-2M study showed high levels of treatment satisfaction and acceptance,^** with 98% (n=300/306) of participants who were randomised to receive an oral lead-in followed by once every 2-months dosing preferring treatment once every 2-months compared to daily oral treatment (oral lead-in). Results indicate that administration frequency and convenience were the most common reasons for preferring treatment every 2-months.

ViiV Healthcare’s mission is to ensure that no one living with HIV is left behind. As the only pharmaceutical company solely focused on HIV and AIDS, ViiV Healthcare is working to deliver a broad range of treatments that meet the needs of a wide variety of people living with HIV (PLHIV). The company invest in R&D programmes that continuously push the boundaries to provide a portfolio of innovative treatment options that will help make a difference to the lives of PLHIV. Cabotegravir and rilpivirine has been co-developed as part of a collaboration with Janssen Pharmaceutical Companies of Johnson & Johnson and builds on ViiV Healthcare’s industry leading portfolio, centred on delivering innovative medicines for the HIV community.

The CHMP positive opinion is one of the final steps before marketing authorisation is granted by the European Commission, which has the authority to approve medicines for use throughout the European Union. If approved, cabotegravir injection and tablets will be marketed as Vocabria to be used with Janssen’s Rekambys (rilpivirine injection) and Edurant (rilpivirine tablets).

Once-monthly dosing of cabotegravir and rilpivirine has been approved by Health Canada as a co-pack with two injectable medicines under the brand name Cabenuva, for the treatment of HIV-1 infection in adults who are virologically stable and suppressed. Vocabria (cabotegravir) oral tablets have also been approved by Health Canada. In July, ViiV Healthcare resubmitted the New Drug Application (NDA) for once-monthly dosing of cabotegravir and rilpivirine to the US Food and Drug Administration (FDA), and further regulatory applications have been submitted and are being reviewed by other regulatory bodies worldwide.

-END-

Notes to editor

About cabotegravir

Cabotegravir is an INI developed by ViiV Healthcare for the treatment of HIV-1 in virologically suppressed adults. It is being evaluated in combination with injectable rilpivirine as a long-acting formulation.

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.

About rilpivirine and rilpivirine long-acting

The oral formulation of rilpivirine is also approved for the treatment of HIV-1 infection 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.

Rilpivirine long-acting (brand name Rekambys) is a prolonged-release suspension for IM injection being developed by Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Rilpivirine is an NNRTI that works by interfering with an enzyme called reverse transcriptase, which in turn stops the virus from multiplying.

Important Safety Information (ISI)

The following Important Safety Information is based on the Summary of Product Characteristics for Vocabria. Please consult the full Summary of Product Characteristics for all the safety information.

Vocabria (cabotegravir) injection is indicated, in combination with rilpivirine injection, for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the NNRTI and INI class

Vocabria injection is indicated for the treatment of HIV-1 in combination with rilpivirine injection, therefore, the prescribing information for rilpivirine injection should be consulted for recommended dosing.

Vocabria tablets are indicated in combination with rilpivirine tablets for the short-term treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the NNRTI and INI class for:

• oral lead in to assess tolerability of Vocabria and rilpivirine prior to administration of long acting Vocabria injection plus long acting rilpivirine injection.
• oral therapy for adults who will miss planned dosing with Vocabria injection plus rilpivirine injection.

Vocabria tablets are only indicated for treatment of HIV-1 in combination with rilpivirine tablets, therefore, the prescribing information for Edurant tablets should also be consulted for recommended dosing.

Prior to starting Vocabria injection, healthcare professionals should have carefully selected patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses.

Following discontinuation of Vocabria and rilpivirine injection, it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the final injection of Vocabria when dosed monthly and no later than two months after the final injection of Vocabria when dosed every 2 months.

Elderly (≥65 years of age): No dose adjustment is required in elderly patients. There are limited data available on the use of cabotegravir in patients aged 65 years and over.

Paediatrics (<18 years of age): The safety and efficacy of Vocabria in children and adolescents aged under 18 years have not been established. No data are available.

Contraindications

Hypersensitivity to cabotegravir or rilpivirine or to any of the excipients.

Concomitant use with: rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or phenobarbital.

Special Warnings and Precautions for Use

Vocabria injection

Residual concentrations of cabotegravir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer), therefore, physicians should take the prolonged release characteristics of Vocabria injection into consideration when the medicinal product is discontinued.

If virologic failure is suspected, an alternative regimen should be adopted as soon as possible.

Baseline factors associated with virological failure

Before starting the regimen, it should be taken into account that multivariable analyses indicate that a combination of at least 2 of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI ≥30 kg/m². In patients with an incomplete or uncertain treatment history without pre-treatment resistance analyses, caution is warranted in the presence of either BMI ≥30 kg/m² or HIV-1 A6/A1 subtype.

Hypersensitivity reactions

Hypersensitivity reactions have been reported in association with other integrase inhibitors. These reactions were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. While no such reactions have been observed to date in association with Vocabria, physicians should remain vigilant and should discontinue Vocabria and other suspected medicinal products immediately, should signs or symptoms of hypersensitivity develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia or angioedema). Clinical status, including liver aminotransferases should be monitored and appropriate therapy initiated. Administration of oral lead-in is recommended to help identify patients who may be at risk of a hypersensitivity reaction.

Hepatoxicity

Hepatotoxicity has been reported in a limited number of patients receiving Vocabria with or without known pre-existing hepatic disease.

Monitoring of liver chemistries is recommended and treatment with Vocabria should be discontinued if hepatotoxicity is suspected.

HBV/HCV co-infection

Patients with hepatitis B co-infection were excluded from studies with Vocabria. It is not recommended to initiate Vocabria 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. Monitoring of liver function is recommended in patients with hepatitis C co-infection.

Interactions with medicinal products

Caution should be given to prescribing Vocabria injection and tablets with medicinal products that may reduce its exposure.

Concomitant use of Vocabria injection with rifabutin is not recommended.

Polyvalent cation containing antacids are recommended to be taken at least 2 hours before and 4 hours after taking Vocabria tablets.

Effect of other medicinal products on the pharmacokinetics of cabotegravir

Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1 and to a lesser extent by UGT1A9. Medicinal products which are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations leading to lack of efficacy.

Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions (ARs) from monthly dosing studies were injection site reactions (up to 84%), headache (up to 12%) and pyrexia^* (10%).

The most frequently reported ARs from ATLAS-2M every 2-month dosing were injection site reactions (76%), headache (7%) and pyrexia^* (7%).

^*Pyrexia includes the following: feeling hot, body temperature increased.

Description of selected adverse reactions

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.

Weight increased

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.

Pregnancy

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

Breast-feeding

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.

Rekambys (rilpivirine injection) ISI

The following Important Safety Information is based on the Summary of Product Characteristics for REKAMBYS (rilpivirine injection). Please consult the full Summary of Product Characteristics for all the safety information.

REKAMBYS is indicated, in combination with cabotegravir injection, for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection in adults who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with, agents of the NNRTI and INI class

REKAMBYS should always be co-administered with a cabotegravir injection. The prescribing information for cabotegravir injection should be consulted for recommended dosing.

Prior to the initiation of REKAMBYS, rilpivirine oral tablets, together with cabotegravir oral tablets, should be taken for approximately 1 month (at least 28 days) to assess tolerability to rilpivirine and cabotegravir. One rilpivirine 25‑mg tablet should be taken with a meal with one cabotegravir 30‑mg tablet once daily.

Prior to starting REKAMBYS, the healthcare professional should carefully select patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance associated with missed doses.

Following discontinuation of REKAMBYS in combination with cabotegravir injection, it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the last every 1 month injection of REKAMBYS or two months after the last every 2 months injection of REKAMBYS.

Elderly: There is limited information regarding the use of REKAMBYS in patients > 65 years of age. No dose adjustment of REKAMBYS is required in older patients.

Paediatric Patients: The safety and efficacy of REKAMBYS in children and adolescents aged < 18 years have not been established. No data are available.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

REKAMBYS must not be co‑administered with the following medicinal products, which may result in loss of therapeutic effect of REKAMBYS:

• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• the antimycobacterials rifabutin, rifampicin, rifapentine
• the systemic glucocorticoid dexamethasone, except as a single dose treatment
• St John’s wort (Hypericum perforatum).

Special Warnings and Precautions for Use

Risk of resistance following treatment discontinuation

To minimise the risk of developing viral resistance it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the last every 1 month injection of REKAMBYS or two months after the last every 2 months injection of REKAMBYS.

Long-acting properties of rilpivirine injection

Residual concentrations of rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 4 years in some patients) and should be considered upon discontinuation of REKAMBYS.

Baseline factors associated with virological failure

Before starting the regimen, it should be taken into account that multivariable analyses indicate that a combination of at least 2 of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI ≥30 kg/m². In patients with an incomplete or uncertain treatment history without pre-treatment resistance analyses, caution is warranted in the presence of BMI ≥30 kg/m² and/or HIV‑1 subtype A6/A1.

Post-injection reactions

Partial intravenous administration may result in AEs due to temporarily high plasma concentrations. In clinical studies, serious post-injection reactions were reported within minutes after the injection of rilpivirine, including dyspnoea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events were very rare and began to resolve within a few minutes after the injection.

Carefully follow the Instructions for Use when preparing and administering REKAMBYS to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated.

Cardiovascular

REKAMBYS should be used with caution when co‑administered with a medicinal product with a known risk of Torsade de Pointes. At supra‑therapeutic doses (75 and 300 mg once daily), oral rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG). Oral rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Plasma rilpivirine concentrations after REKAMBYS injections are comparable to those during such oral rilpivirine therapy.

HBV/HCV co-infection

Patients with hepatitis B co-infection were excluded from studies with REKAMBYS. It is not recommended to initiate REKAMBYS in patients with hepatitis B co-infection. In patients co‑infected with hepatitis B receiving oral rilpivirine, the incidence of hepatic enzyme elevation was higher than in patients receiving oral rilpivirine who were not hepatitis B co‑infected. 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. In patients co‑infected with hepatitis C receiving oral rilpivirine, the incidence of hepatic enzyme elevation was higher than in patients receiving oral rilpivirine who were not hepatitis C co‑infected. The pharmacokinetic exposure of oral and injectable rilpivirine in co‑infected patients was comparable to that in patients without hepatitis C co‑infection.

Contacts

ViiV Healthcare media enquires:
Patricia O’Connor (Global)

+44 (0) 7469 375019 (London)

Audrey Abernathy

+1 916054521 (US)

Read full story here

• ViiV Healthcare’s Vocabria (cabotegravir injection) used in combination with Janssen Pharmaceutical Companies of Johnson & Johnson’s Rekambys (rilpivirine injection) reduces treatment dosing days from 365 to 12 or 6 per year
• Long-acting regimen is based on co-administration of cabotegravir and rilpivirine injections once-monthly or once every 2-months to treat HIV-1
• Vocabria (cabotegravir) tablets for use as an oral lead-in therapy with Edurant (rilpivirine tablets) prior to starting the long-acting regimen also receives positive CHMP opinion

LONDON–(BUSINESS WIRE)–ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer Inc. and Shionogi Limited as shareholders, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending marketing authorisation for Vocabria (cabotegravir injection and tablets) in combination with Rekambys (rilpivirine injection) and Edurant (rilpivirine tablets), for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the non-nucleoside reverse transcriptase inhibitor (NNRTI) and integrase inhibitor (INI) class.¹

Deborah Waterhouse, CEO, ViiV Healthcare, said “Today’s positive CHMP opinion marks an important step in providing a new option that changes the treatment experience for people living with HIV across Europe. Vocabria injection used in combination with Rekambys has the potential to ease the day-to-day burden of HIV by offering significantly less frequent dosing from 365 days with oral regimens to 12 or 6 treatments per year. Through our innovative R&D, we are now one step closer to offering an HIV medicine in Europe with a novel route of administration and dosing schedule compared to other therapies. We’re proud to be providing different treatment options that meet the diverse needs of the HIV community.”

If approved, cabotegravir injection used in combination with rilpivirine injection will be the first complete long-acting regimen, dosed once-monthly or once every 2-months, for virologically suppressed people living with HIV-1 across Europe. This treatment will offer people living with HIV an option with significantly less frequent dosing and comparable efficacy to daily oral regimens. Cabotegravir and rilpivirine injections are administered as two intramuscular (IM) injections in the buttocks during the same visit at a specialist clinic by a healthcare professional. Prior to the initiation of the injections, cabotegravir and rilpivirine oral tablets are taken for approximately one month (at least 28 days) to assess tolerability to the medicines.

The Marketing Authorisation Application (MAA) for cabotegravir injection and tablets is based on the pivotal phase III ATLAS (Antiretroviral Therapy as Long-Acting Suppression), FLAIR (First Long-Acting Injectable Regimen) and ATLAS-2M studies.

The ATLAS and FLAIR studies included more than 1,100 participants from 16 countries.^2,3 The studies demonstrated that cabotegravir and rilpivirine when injected intramuscularly in the buttocks, once-monthly, was as effective as continuing their daily, oral, antiretroviral regimens in maintaining viral suppression throughout the 48-week study period. (Read more…) The long-acting regimen was preferred by approximately 9 out of 10 patients who switched to cabotegravir and rilpivirine long-acting in the ATLAS and FLAIR studies over their previous daily oral therapy.*

In both studies, the most common adverse reactions (Grades 1 to 4) observed in ≥ 2% of participants receiving cabotegravir and rilpivirine were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, rash, and diarrhoea. Over the 48-week study period, a total of 4% of participants discontinued cabotegravir and rilpivirine due to adverse events.⁴

48-week data from the pivotal ATLAS-2M study were also included in the MAA to support the use of cabotegravir and rilpivirine once every 2-months. Results from the study showed the antiviral activity and safety of long-acting cabotegravir and rilpivirine injections administered once every 2-months was non-inferior to long-acting cabotegravir and rilpivirine injections administered once-monthly in virologically suppressed adults living with HIV-1 infection over a 48-week period. In the ATLAS-2M study rates of serious adverse events (SAEs) (27/522 [5.2%]) and withdrawals due to adverse events (AEs) (12/522 [2.3%]) at 48 weeks were low and were similar to those experienced in the one month arm (SAEs: 19/523 [3.6%], withdrawals due to AEs 13/523 [2.5%]).⁵

The Patient Reported Outcomes data from the ATLAS-2M study showed high levels of treatment satisfaction and acceptance,^** with 98% (n=300/306) of participants who were randomised to receive an oral lead-in followed by once every 2-months dosing preferring treatment once every 2-months compared to daily oral treatment (oral lead-in). Results indicate that administration frequency and convenience were the most common reasons for preferring treatment every 2-months.

ViiV Healthcare’s mission is to ensure that no one living with HIV is left behind. As the only pharmaceutical company solely focused on HIV and AIDS, ViiV Healthcare is working to deliver a broad range of treatments that meet the needs of a wide variety of people living with HIV (PLHIV). The company invest in R&D programmes that continuously push the boundaries to provide a portfolio of innovative treatment options that will help make a difference to the lives of PLHIV. Cabotegravir and rilpivirine has been co-developed as part of a collaboration with Janssen Pharmaceutical Companies of Johnson & Johnson and builds on ViiV Healthcare’s industry leading portfolio, centred on delivering innovative medicines for the HIV community.

The CHMP positive opinion is one of the final steps before marketing authorisation is granted by the European Commission, which has the authority to approve medicines for use throughout the European Union. If approved, cabotegravir injection and tablets will be marketed as Vocabria to be used with Janssen’s Rekambys (rilpivirine injection) and Edurant (rilpivirine tablets).

Once-monthly dosing of cabotegravir and rilpivirine has been approved by Health Canada as a co-pack with two injectable medicines under the brand name Cabenuva, for the treatment of HIV-1 infection in adults who are virologically stable and suppressed. Vocabria (cabotegravir) oral tablets have also been approved by Health Canada. In July, ViiV Healthcare resubmitted the New Drug Application (NDA) for once-monthly dosing of cabotegravir and rilpivirine to the US Food and Drug Administration (FDA), and further regulatory applications have been submitted and are being reviewed by other regulatory bodies worldwide.

-END-

Notes to editor

About cabotegravir

Cabotegravir is an INI developed by ViiV Healthcare for the treatment of HIV-1 in virologically suppressed adults. It is being evaluated in combination with injectable rilpivirine as a long-acting formulation.

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.

About rilpivirine and rilpivirine long-acting

The oral formulation of rilpivirine is also approved for the treatment of HIV-1 infection 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.

Rilpivirine long-acting (brand name Rekambys) is a prolonged-release suspension for IM injection being developed by Janssen Sciences Ireland UC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson.

Rilpivirine is an NNRTI that works by interfering with an enzyme called reverse transcriptase, which in turn stops the virus from multiplying.

Important Safety Information (ISI)

The following Important Safety Information is based on the Summary of Product Characteristics for Vocabria. Please consult the full Summary of Product Characteristics for all the safety information.

Vocabria (cabotegravir) injection is indicated, in combination with rilpivirine injection, for the treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the NNRTI and INI class

Vocabria injection is indicated for the treatment of HIV-1 in combination with rilpivirine injection, therefore, the prescribing information for rilpivirine injection should be consulted for recommended dosing.

Vocabria tablets are indicated in combination with rilpivirine tablets for the short-term treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection in adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with agents of the NNRTI and INI class for:

• oral lead in to assess tolerability of Vocabria and rilpivirine prior to administration of long acting Vocabria injection plus long acting rilpivirine injection.
• oral therapy for adults who will miss planned dosing with Vocabria injection plus rilpivirine injection.

Vocabria tablets are only indicated for treatment of HIV-1 in combination with rilpivirine tablets, therefore, the prescribing information for Edurant tablets should also be consulted for recommended dosing.

Prior to starting Vocabria injection, healthcare professionals should have carefully selected patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance with missed doses.

Following discontinuation of Vocabria and rilpivirine injection, it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the final injection of Vocabria when dosed monthly and no later than two months after the final injection of Vocabria when dosed every 2 months.

Elderly (≥65 years of age): No dose adjustment is required in elderly patients. There are limited data available on the use of cabotegravir in patients aged 65 years and over.

Paediatrics (<18 years of age): The safety and efficacy of Vocabria in children and adolescents aged under 18 years have not been established. No data are available.

Contraindications

Hypersensitivity to cabotegravir or rilpivirine or to any of the excipients.

Concomitant use with: rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or phenobarbital.

Special Warnings and Precautions for Use

Vocabria injection

Residual concentrations of cabotegravir may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer), therefore, physicians should take the prolonged release characteristics of Vocabria injection into consideration when the medicinal product is discontinued.

If virologic failure is suspected, an alternative regimen should be adopted as soon as possible.

Baseline factors associated with virological failure

Before starting the regimen, it should be taken into account that multivariable analyses indicate that a combination of at least 2 of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI ≥30 kg/m². In patients with an incomplete or uncertain treatment history without pre-treatment resistance analyses, caution is warranted in the presence of either BMI ≥30 kg/m² or HIV-1 A6/A1 subtype.

Hypersensitivity reactions

Hypersensitivity reactions have been reported in association with other integrase inhibitors. These reactions were characterised by rash, constitutional findings and sometimes organ dysfunction, including liver injury. While no such reactions have been observed to date in association with Vocabria, physicians should remain vigilant and should discontinue Vocabria and other suspected medicinal products immediately, should signs or symptoms of hypersensitivity develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia or angioedema). Clinical status, including liver aminotransferases should be monitored and appropriate therapy initiated. Administration of oral lead-in is recommended to help identify patients who may be at risk of a hypersensitivity reaction.

Hepatoxicity

Hepatotoxicity has been reported in a limited number of patients receiving Vocabria with or without known pre-existing hepatic disease.

Monitoring of liver chemistries is recommended and treatment with Vocabria should be discontinued if hepatotoxicity is suspected.

HBV/HCV co-infection

Patients with hepatitis B co-infection were excluded from studies with Vocabria. It is not recommended to initiate Vocabria 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. Monitoring of liver function is recommended in patients with hepatitis C co-infection.

Interactions with medicinal products

Caution should be given to prescribing Vocabria injection and tablets with medicinal products that may reduce its exposure.

Concomitant use of Vocabria injection with rifabutin is not recommended.

Polyvalent cation containing antacids are recommended to be taken at least 2 hours before and 4 hours after taking Vocabria tablets.

Effect of other medicinal products on the pharmacokinetics of cabotegravir

Cabotegravir is primarily metabolised by uridine diphosphate glucuronosyl transferase (UGT) 1A1 and to a lesser extent by UGT1A9. Medicinal products which are strong inducers of UGT1A1 or UGT1A9 are expected to decrease cabotegravir plasma concentrations leading to lack of efficacy.

Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions (ARs) from monthly dosing studies were injection site reactions (up to 84%), headache (up to 12%) and pyrexia^* (10%).

The most frequently reported ARs from ATLAS-2M every 2-month dosing were injection site reactions (76%), headache (7%) and pyrexia^* (7%).

^*Pyrexia includes the following: feeling hot, body temperature increased.

Description of selected adverse reactions

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.

Weight increased

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.

Pregnancy

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

Breast-feeding

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.

Rekambys (rilpivirine injection) ISI

The following Important Safety Information is based on the Summary of Product Characteristics for REKAMBYS (rilpivirine injection). Please consult the full Summary of Product Characteristics for all the safety information.

REKAMBYS is indicated, in combination with cabotegravir injection, for the treatment of human immunodeficiency virus type 1 (HIV‑1) infection in adults who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with, agents of the NNRTI and INI class

REKAMBYS should always be co-administered with a cabotegravir injection. The prescribing information for cabotegravir injection should be consulted for recommended dosing.

Prior to the initiation of REKAMBYS, rilpivirine oral tablets, together with cabotegravir oral tablets, should be taken for approximately 1 month (at least 28 days) to assess tolerability to rilpivirine and cabotegravir. One rilpivirine 25‑mg tablet should be taken with a meal with one cabotegravir 30‑mg tablet once daily.

Prior to starting REKAMBYS, the healthcare professional should carefully select patients who agree to the required injection schedule and counsel patients about the importance of adherence to scheduled dosing visits to help maintain viral suppression and reduce the risk of viral rebound and potential development of resistance associated with missed doses.

Following discontinuation of REKAMBYS in combination with cabotegravir injection, it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the last every 1 month injection of REKAMBYS or two months after the last every 2 months injection of REKAMBYS.

Elderly: There is limited information regarding the use of REKAMBYS in patients > 65 years of age. No dose adjustment of REKAMBYS is required in older patients.

Paediatric Patients: The safety and efficacy of REKAMBYS in children and adolescents aged < 18 years have not been established. No data are available.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

REKAMBYS must not be co‑administered with the following medicinal products, which may result in loss of therapeutic effect of REKAMBYS:

• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• the antimycobacterials rifabutin, rifampicin, rifapentine
• the systemic glucocorticoid dexamethasone, except as a single dose treatment
• St John’s wort (Hypericum perforatum).

Special Warnings and Precautions for Use

Risk of resistance following treatment discontinuation

To minimise the risk of developing viral resistance it is essential to adopt an alternative, fully suppressive antiretroviral regimen no later than one month after the last every 1 month injection of REKAMBYS or two months after the last every 2 months injection of REKAMBYS.

Long-acting properties of rilpivirine injection

Residual concentrations of rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 4 years in some patients) and should be considered upon discontinuation of REKAMBYS.

Baseline factors associated with virological failure

Before starting the regimen, it should be taken into account that multivariable analyses indicate that a combination of at least 2 of the following baseline factors may be associated with an increased risk of virological failure: archived rilpivirine resistance mutations, HIV-1 subtype A6/A1, or BMI ≥30 kg/m². In patients with an incomplete or uncertain treatment history without pre-treatment resistance analyses, caution is warranted in the presence of BMI ≥30 kg/m² and/or HIV‑1 subtype A6/A1.

Post-injection reactions

Partial intravenous administration may result in AEs due to temporarily high plasma concentrations. In clinical studies, serious post-injection reactions were reported within minutes after the injection of rilpivirine, including dyspnoea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events were very rare and began to resolve within a few minutes after the injection.

Carefully follow the Instructions for Use when preparing and administering REKAMBYS to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated.

Cardiovascular

REKAMBYS should be used with caution when co‑administered with a medicinal product with a known risk of Torsade de Pointes. At supra‑therapeutic doses (75 and 300 mg once daily), oral rilpivirine has been associated with prolongation of the QTc interval of the electrocardiogram (ECG). Oral rilpivirine at the recommended dose of 25 mg once daily is not associated with a clinically relevant effect on QTc. Plasma rilpivirine concentrations after REKAMBYS injections are comparable to those during such oral rilpivirine therapy.

HBV/HCV co-infection

Patients with hepatitis B co-infection were excluded from studies with REKAMBYS. It is not recommended to initiate REKAMBYS in patients with hepatitis B co-infection. In patients co‑infected with hepatitis B receiving oral rilpivirine, the incidence of hepatic enzyme elevation was higher than in patients receiving oral rilpivirine who were not hepatitis B co‑infected. 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. In patients co‑infected with hepatitis C receiving oral rilpivirine, the incidence of hepatic enzyme elevation was higher than in patients receiving oral rilpivirine who were not hepatitis C co‑infected. The pharmacokinetic exposure of oral and injectable rilpivirine in co‑infected patients was comparable to that in patients without hepatitis C co‑infection.

Contacts

ViiV Healthcare media enquires:
Patricia O’Connor (Global)

+44 (0) 7469 375019 (London)

Audrey Abernathy

+1 916054521 (US)

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