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39936911000001105

New Medicines

ByfavoProcedural sedation

Information

Byfavo
New molecular entity
PAION
Acacia Pharma

Development and Regulatory status

Launched
Approved (Licensed)
Launched
July 2021
Nov 21In the US, remimazolam was launched by Acacia for procedural sedation in Jan 21. While initial market response was positive, access to clinics and prescribing doctors has been severely limited due to the COVID-19 pandemic. By the end of September, remimazolam had been put on formulary in 95 accounts with a >90% win rate; Acacia expects a total of 150 accounts to put remimazolam on formulary by the end of 2021 [22].
Jul 21Launched in UK [21].
Mar 21Approved in the EU [18].
Jan 21Recommended for EU approval by CHMP - the full indication is "in adults for procedural sedation.” It should be administered by healthcare professionals experienced in sedation [17].
Jul 20Approved in US [15].
Nov 19Paion submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) in procedural sedation and a PIII trial in general anaesthesia is ongoing [14].
Jun 19FDA accepts filing for remimazolam for use in procedural sedation. The US licensee, Cosmo Pharmaceuticals, submitted a new drug application in procedural sedation in the US in Apr 19 and is responsible for any further development activities in the US. In Europe, PAION is currently focused on the development of remimazolam for general anesthesia, but is also evaluating the possibility of submitting a Marketing Authorization Application in procedural sedation based on the US development program [12].
Dec 18PAION and Cosmo Pharmaceuticals announce plans to file for approval to the US FDA for procedural sedation by the end of the Q1 2019 [8].
Mar 17Paion plans to conduct a pre-NDA meeting with the US FDA by end of 2017. A filing for approval of remimazolam for anaesthesia with the EMA is anticipated [7].
Mar 17Paion report that, based on evaluation on how to resume the study, a study design analogous to the successfully completed PIII program in general anaesthesia in Japan would be the best path forward in the EU; i.e. in general surgery [7].
Aug 16PIII study in Germany has been discontinued and EU development suspended due to recruitment challenges because of the complex trial design. Paion is currently evaluating how to resume clinical development in the EU [6].

Category

A benzodiazepine derivative that is a GABA-A receptor agonist; has a rapid offset due to its metabolism to an inactive metabolite by tissue esterase enzymes that are widely distributed throughout the body [6]
A UK survey in 2014 showed that, in a given year, 1 in 20 of the population will require an anaesthetic. Three quarters of patients undergo general anaesthesia whilst the other quarter have their procedure either awake or sedated [13].
Procedural sedation
Intravenous

Further information

Trial or other data

Nov 20NICE Topic Selection Oversight Panel (TSOP) in October 2020. The report included advice and recommendations to aid the decision-making process. TSOP concludes that an appraisal of remimazolam for sedation for people having diagnostic or therapeutic procedures is not appropriate. This means the technology in this indication will not be appraised by NICE [19].
Jun 18PIII randomised, parallel trial (NCT03661489) to assess the efficacy and safety of remimazolam, when compared with propofol, for intravenous anaesthesia during elective surgery is currently recruiting approximately 500 patients in Belgium, Germany and the Netherlands. Based on the Scientific Advice obtained from the EMA in January 2018, if this study produces positive results, it is expected to be the only necessary outstanding trial for filing for market approval in the EU.The primary outcome is to demonstrate non-inferiority of remimazolam compared to propofol by assessing the anaesthetic effect of remimazolam and propofol as percent of time of Narcotrend Index ≤60 during the maintenance phase of general anaesthesia. The study is expected to complete Jun 19 [9,10,11].
Aug 16European PIII study (EudraCT 2014-004565-24) has been discontinued. In the randomised, single-blind, propofol-controlled trial, recruitment of approximately 530 patients was underway in Germany, and was expected to expand to Belgium, France, Poland and Switzerland. The trial aimed to evaluate the efficacy and safety of remimazolam in general anaesthesia in patients undergoing cardiac surgery, including follow-up sedation in the post-anaesthesia care unit or intensive care unit [6].
Jun 16Positive results reported for NCT02290873. The primary outcome measure, success of the procedure, was reached in 91.3% of the patients in the remimazolam arm and in 5.0% in the placebo (including midazolam rescue) arm. In secondary endpoints, the remimazolam arm showed a mean time to start of procedure of 5.1 minutes and a mean time from end of procedure to return to full alertness of the patients of 9.25 minutes [6].
Oct 15Recruitment to trial NCT02290873 continues [5].
Apr 15Paion announced initiation of a U.S. PIII clinical trial of Remimazolam. This is a prospective, double-blind, randomised, placebo and midazolam-controlled, U.S. multicentre study (NCT02290873) in 460 pts undergoing colonoscopies for diagnostic or therapeutic reasons. Pts will be randomised to receive Remimazolam, midazolam or placebo in addition to fentanyl to achieve moderate sedation. The primary objective of this study is to investigate the short-term sedation, and hence the success of a colonoscopy compared to placebo and midazolam. The primary endpoint is the successful completion of the colonoscopy procedure with no requirement for alternative sedative. The completion of recruitment is expected before the end of 2015 [4].
Mar 15Two PIII studies of procedural sedation (in colonoscopy-NCT02290873 and bronchoscopy-NCT02296892) are registered and are expected to start and be completed this year [3].
May 10PII (CNS 7056-004; NCT01145222) trial is recruiting 160 US pts undergoing colonoscopy to evaluate the safety & efficacy of multiple doses of remimazolam. The primary outcome is to assess the success of the procedure, by a composite measurement of sedation level, procedure completion, alternative sedation required & if ventilation is necessary (as in CNS 7056-003). The study is expected to complete Q1 11[1,2].
Apr 09PII (CNS 7056-003; NCT00869440) trial is recruiting 102 US pts undergoing diagnostic upper GI endoscopy to evaluate the safety & pharmacodynamics of remimazolam vs. midazolam. The primary outcomes are MOAA/S scores less than or equal to 4 on three consecutive measurements AND completion of the procedure without need for rescue sedative medication & without requiring manual or mechanical ventilation. The trial is expected to complete Q309 [1,2].

Evidence based evaluations

ByfavoGeneral anaesthesia - induction and maintenance in adults

Information

Byfavo
Licence extension / variation
PAION
Acacia Pharma

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
None
Dec 21Paion files an application for a extension to the marketing authorisation for remimazolam in the indication of general anesthesia in the EU. A decision by the EMA is expected at end 2022 or beginning of 2023 [7].
Nov 21For the indication general anesthesia, the license agreement with Cosmo/Acacia originally provided for an option for the US rights to develop and commercialise remimazolam. As this option was not exercised by the licensee, it has lapsed. An advisory meeting was recently held with the FDA on suitability of the European clinical program for filing of a New Drug Application in the US. As a positive outcome of the Type B meeting, the FDA stated that a submission would be possible with the current data package consisting of European and Asian general anesthesia data. Submission would require a re-analysis of the current data. Alternatively, an additional clinical trial was recommended. PAION will now use the outcome of the meeting to intensify the discussion with interested parties for the general anesthesia licence in the US [8].
Jun 21Paion is planning to submit an extension variation to the marketing authorisation of Byfavo for general anesthesia by end of 2021, based on positive results from an EU-based PIII trial in the procedural sedation indication [6].
Aug 20Remimazolam launched in Japan for use in general anaesthesia [5].

Category

A benzodiazepine derivative that is a GABA-A receptor agonist; has a rapid offset due to its metabolism to an inactive metabolite by tissue esterase enzymes that are widely distributed throughout the body [6].
A UK survey in 2014 showed that, in a given year, 1 in 20 of the population will require an anaesthetic. Three quarters of patients undergo general anaesthesia whilst the other quarter have their procedure either awake or sedated [1].
General anaesthesia - induction and maintenance in adults
Intravenous

Further information

Yes

Trial or other data

Jul 21UK listed as a study site for NCT03661489 [7].
Nov 20PAION reports positive topline data in EU PIII trial in general anaesthesia. Remimazolam demonstrated non-inferiority to propofol for anaesthetic effect [4].
Feb 20The company may submit data from two additional studies in support of a licence application: PII NCT01937767 and a PIII Asian study of ONO-2745 compared with propofol in surgical patients undergoing general anaesthesia that completed in Q1 2013 [3].
Oct 19PIII study (NCT03661489) is recruiting [2].
Jul 18PIII study to evaluate efficacy and safety of remimazolam (CNS7056) compared to propofol for intravenous anesthesia during elective surgery in ASA Class III/IV patients starts (NCT03661489). Remimazolam or propofol, will be administered together with remifentanil as analgesic agent, and with a neuromuscular blocker to facilitate intubation and achieve muscle relaxation. 500 adults will be recruited in Germany. Primary outcome is the anaesthetic effect of remimazolam and propofol assessed as percent (%) of time of narcotrend index (NCI) ≤60 during the maintenance phase of general anesthaesia; collection of these data is due to complete Mar 20 [2].
Aug 17PIII study (NCT02523859) was terminated due to poor recruitment [2].
Jul 15PIII study to investigates the use of remimazolam as a sedative/hypnotic in general anesthesia starts (NCT02523859). Remimazolam or propofol will be administered together with fentanyl/sufentanil/remifentanil as opioid analgesics and a neuromuscular blocker. In total, 530 adults will be recruited in Germany. Primary outcome is success of the procedure during maintenance phase of operation (between arrival at operation theatre and completion of last skin suture, estimated up to 24 hours) (A narcotrend index of 60 or less during at least 85% of the maintenance time and no rescue sedative medication administered). Collection of these data is due to complete Mar 16 [2].

Evidence based evaluations