Overview

To date, Remimazolam has been studied in various trials undergoing conscious sedation or general anesthesia.

Further details of trials with Remimazolam can be found on the websites operated by the National Institutes of Health at www.clinicaltrials.gov and other platforms such as the EU Clinical Trials Register at https://www.clinicaltrialsregister.eu or the Japanese clinical trials information site at www.clinicaltrials.jp.

 

Dose finding

Dose finding followed a rational development plan as all mammalian species use tissue esterases to metabolize remimazolam. Thus animal data could be predictive for human dosage. It is known that the tissue esterase system is highly conserved amongst all mammalian species including the human race. Thus remimazolam was a suitable candidate for a translational approach that had the potential to predict the doses that lead to sedation and loss of consciousness. 

Procedural sedation

The first U.S. Phase III trial was successfully completed in 2016, and the primary efficacy endpoint was achieved. The Phase III trial enrolled 461 patients at 13 U.S. sites and was designed to evaluate the efficacy and safety of remimazolam compared to placebo (with midazolam rescue) in patients undergoing proceduralist-administered sedation for colonoscopy. In addition, the trial had an open-label midazolam arm.

In addition to the above trial, the U.S. Phase III program included a second confirmatory, prospective, double-blind, randomized, placebo-controlled multi-center trial with an open-label midazolam arm in 446 patients undergoing bronchoscopies. The trial was successfully completed in 2017, and the primary efficacy endpoint was achieved. The Phase III trial was conducted at 15 U.S. sites and was designed to evaluate the efficacy and safety of remimazolam compared to placebo (with midazolam rescue medication) in patients undergoing bronchoscopy.

As part of the U.S. development program, also a safety trial in ASA III/IV (American Society of Anesthesiologists classification) patients undergoing colonoscopy (American Society of Anesthesiologists classification) was performed which was successfully completed in 2017. The trial enrolled 79 patients and was designed to evaluate the safety and efficacy of remimazolam compared to placebo (with midazolam rescue sedation) in patients undergoing proceduralist-supervised sedation for colonoscopy.

 

Summary of key results from the three Phase III trials:

 

 

 
 

Remimazolam

 
 

Placebo

 
 

Midazolam
(Open Label) *

 
 

Primary endpoint achieved (ITT)

 
 

80.6–91.3%

 
 

0.0–4.8%

 
 

12.9–32.9%

 
 

Time from start of medication to start of procedure

 
 

4.0–5.0 min

 
 

17–19.5 min

 
 

15.5–19.0 min

 
 

Time from end of procedure to fully alert

 
 

3.0–6.0 min

 
 

5.3–15.0 min

 
 

7.0–13.0 min

 
 

Time to back to normal

 
 

192–402 min

 
 

348–936 min

 
 

366–444 min

 

 * Only partially relevant for the label claim

General anesthesia

In the clinical program, specific attention was paid to hemodynamic stability, which addresses a current need in general anesthesia. Preclinical data had suggested and clinical data confirmed that a better hemodynamic stability can be reached with remimazolam than with propofol.

The clinical development program completed in Europe and Japan demonstrated safety and efficacy as an anesthetic as well as an improved hemodynamic profile compared to propofol.

In Europe, a randomized, single-blind, propofol-controlled, confirmatory Phase III trial enrolled 424 ASA III/IV patients (American Society of Anesthesiologists classification III to IV) undergoing planned surgery at more than 20 European sites. The primary objective of the trial was to demonstrate non-inferiority of remimazolam compared to propofol for the induction and maintenance of general anesthesia during elective surgery. The key secondary objective was to show improved hemodynamic stability compared to propofol. In the trial, remimazolam met both the primary and key secondary endpoints.

ICU sedation

PAION’s former licensee in Japan, Ono, independently initiated a Phase II trial for sedation in intensive care units (ICUs). Higher than expected plasma concentrations by pure calculation of remimazolam were observed in isolated cases after long-term treatment as is known from similar substances, and Ono discontinued this exploratory trial in 2013. Patients were sedated successfully and no significant unexpected adverse events were reported.

The observed phenomenon of elevated remimazolam plasma concentrations was subsequently thoroughly investigated using a series of preclinical tests and pharmacokinetic models. None of these experiments was able to reproduce the findings or provide a mechanistic explanation for the elevated plasma concentrations. Further analysis has revealed that such pharmacokinetic deviations are common for utilization of sedatives like midazolam and propofol on the ICU and the most likely explanation is the underlying serious condition of patients presenting on the ICU. Further development of this indication is currently not being conducted.

 

Disclaimer

PAION's product candidate (Remimazolam) is at the end of the development phase and  is approved in the U.S. and China for procedural sedation and in Japan and South Korea for general anesthesia. It can currently neither be prescribed nor acquired for therapeutic use in Europe.

 

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