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New Medicines

Ronapreve (UK, EU); REGEN-COV (US) Coronavirus disease 2019 (COVID-19) - treatment in non-hospitalised adults and children, and prevention in close contacts

Information

Ronapreve (UK, EU); REGEN-COV (US)
New molecular entity
Roche
Regeneron

Development and Regulatory status

Approved (Licensed)
Pre-registration (Filed)
Pre-registration (Filed)
Aug 21Approved in the UK for prophylaxis and treatment of acute Covid-19 infection (in patients aged ≥12 years and weighing ≥40kg) [19].
Jul 21FDA revises EUA to include use for post-exposure prophylaxis (prevention) of COVID-19 [17].
Jun 21The EMA has identified five "most promising" COVID-19 therapeutics already in an advanced stage of development that it will prioritise, with the aim of providing more regulatory flexibility with rolling reviews, conditional marketing authorisations and flexible labelling and packaging requirements. At least three of these new products will be authorised by Oct 2021. Casirivimab and imdevimab is one of the 5 products [16].
Jun 21Following positive results from the UK RECOVERY trial for use of REGEN-COV in seronegative hospitalised patients, the company has announced plans to seek an expansion of the EUA in the US to include this patient group and also for use in prevention [15].
Jun 21FDA updated its EUA for Regeneron Pharmaceuticals’ REGEN-COV for a lower dose of 1,200 mg (600mg casirivimab and 600mg imdevimab) based on the positive PIII trial results showing consistent treatment effect between 1,200mg and 2,400mg doses. As part of the updated EUA, REGEN-COV should be administered by intravenous (IV) infusion, but subcutaneous (SC) injections are an alternative when IV infusion is not feasible and would lead to a delay in treatment. The SC administration was authorised based on the totality of scientific evidence, incorporating clinical, viral load reduction and pharmacokinetic data. The Fact Sheet updates remove the previously authorised 2,400 mg IV REGEN-COV dose. Regeneron expects to submit a full Biologics License Application (BLA) for REGEN-COV in non-hospitalized outpatients with COVID-19 in the US later this summer. Regeneron is collaborating with Roche to increase global supply of REGEN-COV. REGEN-COV is also being evaluated in prevention and certain hospitalised COVID-19 patient settings. [12,13].
Mar 21The CHMP positive opinion is intended to support national decision making within EU states on the use of the antibodies before a formal authorisation is granted during a public health emergency. The centralis rolling review continues [10].
Mar 21Following report of positive PIII trial results, the company plan to submit a request to the FDA to update the EUA factsheet for REGEN-COV to include the 1,200mg dose. These PIII data will also form the basis of a full Biologics License Application [9].
Feb 21EMA CHMP begins a rolling review of data for REGN-COV2 antibody combination (casirivimab / imdevimab) for the treatment and prevention of COVID-19. The decision to start is based on preliminary results from a study that indicate a beneficial effect of the medicine in reducing the amount of virus in the nose and throat of non-hospitalised patients with COVID-19. EMA has started evaluating laboratory and animal studies (non-clinical data). The CHMP will evaluate all data, including evidence from a study in hospitalised patients with COVID-19 and other clinical trials as they become available. The rolling review will continue until enough evidence is available to support a formal marketing authorisation application [6].
Feb 21The EMA CHMP issued a positive opinion for casirivimab/ imdevimab (REGN-COV2) to recommend the use to treat confirmed COVID-2019 infection in patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-2019. The CHMP assessed available data in non-hospitalised patients with COVID-2019 as well as supportive data from other settings and from the PI/II/III trial NCT04425629 [10].
Dec 20According to latest pipeline, Roche plans full submission to EU & US in 2021 [4].
Nov 20Emergency use authorisation (EUA) issued in the US for casirivimab and imdevimab to be administered together for treatment of mild to moderate COVID-19 in adults and paediatric patients (12 years and older weighing at least 40kg) with positive COVID-19 test and at high risk for progressing to severe COVID-19. This includes those aged 65 years or older or with certain chronic medical conditions. Casirivimab and imdevimab are not authorised for patients who are hospitalised due to COVID-19 or require oxygen therapy due to COVID-19. An EUA is different to an FDA approval [8].

Category

REGN-COV2 comprises two monoclonal antibodies (REGN10933 and REGN10987) that bind non-competitively with the virus
COVID-19 is an infectious disease caused by coronavirus SARS-CoV-2. Most people infected experience mild to moderate respiratory illness and recover without requiring special treatment. Older people, and those with underlying medical problems are more likely to develop serious illness [1].
Coronavirus disease 2019 (COVID-19) - treatment in non-hospitalised adults and children, and prevention in close contacts
Intravenous infusion

Trial or other data

Apr 21Results reported from the PIII REGN-COV 2069 prevention trial (NCT04452318; n=1,505) comparing SC casirivimab/imdevimab 1,200mg as a single dose vs placebo to reduce COVID-19 infection among household contacts of those with infection. The trial met its primary and key secondary endpoints with 81% reduction in symptomatic infection in those who were not infected when they entered the trial. On average, individuals treated with casirivimab/imdevimab who experienced a symptomatic infection resolved their symptoms in 1 week, compared to 3 weeks with placebo. Infected individuals also cleared the virus faster with casirivimab/imdevimab. Adverse events (AEs) occurred in 20% (n=265 out of 1,311) of REGEN-COV participants and 29% (n=379 out of 1,306) of placebo participants, and serious AEs occurred in 1% (n=10) of REGEN-COV and 1% (n=15) of placebo participants. There were 0 REGEN-COV and 4 placebo participants who were either hospitalised or visited the emergency room because of COVID-19 during the 29-day efficacy assessment period. Injection site reactions, all of which were grades 1-2, occurred in 4% (n=55) of REGEN-COV and 2% (n=19) of placebo participants. No individuals from either group withdrew from the trial due to AEs, and none of the deaths in the trial (2 REGEN-COV, 2 placebo) were attributed to COVID-19 or study drug [11,14].
Mar 21Positive topline results from the PIII trial (NCT04425629) in high-risk non-hospitalised (ambulatory) COVID-19 patients (n=4,567) reported the trial had met its primary endpoint, showing casirivimab with imdevimab (REGEN-COV) significantly reduced the risk of hospitalisation or death by 70% (1,200 mg IV) and 71% (2,400 mg IV) vs placebo. REGEN-COV also met all secondary endpoints including the ability to reduce symptom duration. In addition, a companion PII trial showed that even the lowest doses tested (IV: 300 mg; SC: 600 mg) had significant viral load reductions over the first 7 study days, comparable to the 2,400 mg and 1,200 mg IV doses [9].
Feb 21Independent Data Monitoring Committee (IDMC) finds clear efficacy for REGEN-COV in PIII trial and recommends stopping enrolment into the placebo arm [7].
Dec 20Positive initial results from exploratory analysis of REGEN-COV Phase 3 Prevention Trial. In this, ~ 400 first pple from ongoing PIII trial (recruiting up to 2000 pts). The trial is evaluating REGEN-COV™ (casirivimab and imdevimab antibody cocktail as 1200mg via s.c. inj) vs. placebo in pple at high risk of infection (due to household exposure to a COVID-19 patient). REGEN-COV resulted in 100% prevention of symptomatic infection (8/223 placebo vs. 0/186 REGEN-COV), and approximately 50% lower overall rates of infection (symptomatic and asymptomatic) as well as decreased peak virus levels, viral loads and short duration of viral shedding. Adverse effects were more common with placebo (18% placebo vs. 12% REGEN-COV), driven by the increased rate of SARS-CoV-2 infections in the placebo group. In the placebo group, there was1 death and one COVID-19-hospitalisation; there were no deaths or COVID-19 hospitalisations in the treatment group. Injection site reactions occurred at a rate of ~2% in both groups.[5]
Dec 20PII/III NCT04425629 is ongoing and recruiting patients, including children. The estimated primary completion date is April 2021 [3].
Dec 20In an interim analysis of the PI/II portion of NCT04425629 (n=239), REGN-COV2 antibody cocktail reduced viral load, with greater effect in non-hospitalised patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in combined REGN-COV2 dose groups and placebo group [2].

Evidence based evaluations

REGN-COV2 [EU]; REGEN-COV [US]Coronavirus disease 2019 (COVID-19)- treatment in hospitalised patients

Information

REGN-COV2 [EU]; REGEN-COV [US]
Licence extension / variation
Roche
Regeneron

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Phase III Clinical Trials
Jun 21The EMA has identified five "most promising" COVID-19 therapeutics already in an advanced stage of development that it will prioritise, with the aim of providing more regulatory flexibility with rolling reviews, conditional marketing authorisations and flexible labelling and packaging requirements. At least three of these new products will be authorised by Oct 2021. Casirivimab and imdevimab is one of the 5 products [15].
Jun 21Regeneron plans to take the new data from the RECOVERY trial in hospitalised patients to the FDA to seek expansion of the EUA for use in this patient group, as well as for use in prevention. Currently the EUA only supports use in non-hospitalised patients. The company plans on submitting a full biologics licence application (BLA) later this summer [14].
Feb 21CHMP has issued a scientific opinion supporting the use of the investigational antibody cocktail, casirivimab and imdevimab, as a treatment option for patients with confirmed COVID-19 who do not require oxygen supplementation and who are at high risk of progressing to severe COVID-19 [11].
Feb 21Roche and Regeneron are collaborating on developing and manufacturing REGN-COV2; Roche will be responsible for distribution in Europe and other countries outside the US [11].
Feb 21EMA CHMP begins a rolling review of data for REGN-COV2 antibody combination (casirivimab / imdevimab) for the treatment and prevention of COVID-19. The decision to start is based on preliminary results from a study that indicate a beneficial effect of the medicine in reducing the amount of virus in the nose and throat of non-hospitalised patients with COVID-19. EMA has started evaluating laboratory and animal studies (non-clinical data). The CHMP will evaluate all data, including evidence from a study in hospitalised patients with COVID-19 and other clinical trials as they become available. The rolling review will continue until enough evidence is available to support a formal marketing authorisation application [11].
Dec 20According to latest pipeline, Roche plans full submission to EU & US in 2021 [10].
Nov 20REGEN-COV has received Emergency Use Authorization (EUA) from the US FDA. This is only for treatment in non-hospitalised patients. It does not cover use in hospitalised patients or patients who require oxygen. An EUA is not a full approval [8].
Nov 20Following a safety signal and an unfavourable risk/benefit profile at this time, the independent data monitoring committee (IDMC) of the FDA have paused enrolment of patients requiring high-flow oxygen or mechanical ventilation. The decision has been made pending collection and analysis of further data on patients already enrolled. Enrolment can continue for those on no or low-flow oxygen as the risk/benefit remains acceptable in this cohort. No changes are required to the outpatient trial [7].
Oct 20Regeneron Pharmaceuticals has applied to US FDA for Emergency Use Authorisation (EUA) for REGN-COV2 [4].

Category

REGN-COV2 comprises two monoclonal antibodies (REGN10933 and REGN10987) that bind non-competitively with the virus
COVID-19 is an infectious disease caused by coronavirus SARS-CoV-2. Most people infected experience mild to moderate respiratory illness and recover without requiring special treatment. Older people, and those with underlying medical problems are more likely to develop serious illness [2].
Coronavirus disease 2019 (COVID-19)- treatment in hospitalised patients
Intravenous

Trial or other data

Jun 21New data from the RECOVERY trial (n=9,785) finds treatment with REGEN-COV improves 28 day mortality of the primary analysis population, hospitalised seronegative patients (i.e. without antibodies to COVID-19), at baseline vs usual care. 24% patients in the seronegative REGEN-COV group died vs 30% in the usual care group, rate ratio (RR) 0.80 [95%CI 0.70-0.91]; p=0.001). When combining the larger seropositive group (as well as those with unknown status) with the seronegative patients, there was no longer a significant effect on 28-day mortality (overall 20% of patients in the REGEN-COV group died, vs 21% in the usual care group; RR: 0.96; 95% CI: 0.86-1.03; p=0.17), indicating lack of efficacy in seropositive patients and suggesting that antibody testing would be useful for all hospitalised COVID-19 patients. Additional results reported the median duration of hospital stay was 4 days shorter in the seronegative REGEN-COV group (13 days vs 17 days), and the proportion of patients discharged alive by day 28 was greater (64% vs 58%; RR: 1.19; 95% CI: 1.08-1.30). Among the seronegative patients not on invasive mechanical ventilation at baseline, the risk of progressing to the composite endpoint of invasive mechanical ventilation or death was lower among the REGEN-COV group than the usual care group (30% vs 37%; RR: 0.83; 95% CI: 0.75-0.92) [13,14].
Dec 20Casirivimab/imdevimab (REGN-COV2; REGEN-COV) is an arm of the UK-based RECOVERY trial (NCT04381936). This trial has already enrolled more than 2,000 hospitalised patients in the part of the trial evaluating adding the synthetic neutralising antibodies to standard-of-care compared to standard-of-care alone [12]
Oct 20FDA raised concerns about safety of REGN-COV2 in patients requiring high-flow oxygen or mechanical ventilation. Enrolment of this patient cohort has been paused [7].
Oct 20Regeneron’s REGN-COV2 cocktail meets clinical endpoints in PII/III trial. PIII data (n=799) demonstrates greater reduction in primary endpoint, mean daily change in viral load through day 7 in pts with high viral load treated with REGN-COV2 vs placebo (p<0.0001); with a 57% reduction in COVID-19-related medical visits through day 29 (p=0.024) [5].
Sep 20PI/II/III trial in the US found REGN-COV2 reduced viral load and the time to alleviate symptoms in non-hospitalized patients with COVID-19. The ongoing, randomized, double-blind trial measures the effect of adding REGN-COV2 to usual standard-of-care, compared to adding placebo to standard-of-care [3].
Sep 20PIII open-label trial in patients hospitalized with COVID-19 will compare the effects of adding REGN-COV2 to the usual standard-of-care versus standard-of-care, within the RECOVERY group of trials [1].

Evidence based evaluations