Overview

To date, Remimazolam has been studied in more than 1,000 patients 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 (Lead indication U.S.)

A total of six Phase I, two Phase II and two Phase III trials have been completed in procedural sedation. The first in-human trial explored a broad range of doses from no effect to loss of consciousness (not wanted for procedural sedation but indicative for induction of general anesthesia). Based on this trial, the next set of trials covered a colonoscopy study in healthy volunteers and a Phase IIa study in upper GI endoscopy. These studies confirmed the need for an approximately 50 % dose reduction in combination with opioids (colonoscopy) and were the basis for the Phase IIb study in colonoscopy patients. In this study, a fixed dose regime consisting of starting dose and top-ups was tested with the lowest of the starting doses being selected for use in the ongoing Phase III program.

 

In March 2015, the first U.S. Phase III study was started, the patient recruitment was completed in April 2016, and in June 2016, PAION announced, that remimazolam met its primary efficacy endpoint. 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.

The primary outcome measure was a composite endpoint defined as: no need for rescue medication, completion of the procedure and no more than 5 doses within any 15-minute window. The primary endpoint was reached in 91.3% of the patients in the remimazolam arm and 1.7% in the placebo (including midazolam rescue) arm.

 

Further data on the clinical results of remimazolam’s U.S. Phase III colonoscopy trial were presented at the 2016 American College of Gastroenterology (ACG) Annual Scientific Meeting in Las Vegas in October 2016:

 

Remimazolam

Placebo

Midazolam
(Open Label) *

Success of procedure

91.3%

1.7%

25.2%

Use of rescue sedation

3.4%

95.0%

64.7%

Average fentanyl dose

88.6 mcg

121.3 mcg

106.9 mcg

Time from start of medication to start of procedure (median)

4.0 minutes

19.5 minutes

19.0 minutes

Time from end of procedure to fully alert (mean)

7.2 minutes

21.3 minutes

15.7 minutes

Time to back to normal

331 minutes

572 minutes

553 minutes

* not part of label claim

Patient satisfaction was similar in all arms of the study.

 

In addition to the above study, the U.S. Phase III program includes a second confirmatory, prospective, double-blind placebo-controlled, randomized, multi-center open label vs. midazolam trial in 420 patients undergoing bronchoscopies. Patient recruitment was initially moderate. However, continuous measures to accelerate patient recruitment, such as improvements in the feasibility of the study protocol, opening additional study centers and intensified support of existing study centers have significantly increased the recruitment rate and completion of patient recruitment is expected shortly.

 

As part of the U.S. development program, also a safety study in ASA III/IV patients undergoing colonoscopy (American Society of Anesthesiologists classification) was performed. In December 2016, successful completion of patient recruitment was announced, and headline data are planned to be presented in the first half of 2017. This prospective, double-blind, randomized, placebo- and active controlled, multicenter, parallel group study enrolled 79 high-risk patients (i.e. ASA III/IV) undergoing a colonoscopy into a remimazolam, midazolam or placebo (including midazolam ‘rescue’ sedation) treatment group.

 

Four Phase I studies were performed in the course of the U.S. Phase III development program. Based on the results of preclinical and Phase I studies and in consultation with the FDA, PAION will now start additional Phase I studies to further assess the abuse potential of remimazolam. One aspect is if remimazolam could inappropriately be used as a knock-out cocktail in combination with alcohol and another aspect is if it could be abused intranasally. 

General anesthesia (Lead indication in Europe + Japan)

A total of three Phase I (Japan), two Phase II (Japan and EU) and two Phase III (Japan) trials in general anesthesia have been completed. In the clinical program, specific attention was paid to hemodynamic stability, which addresses a current need in general anesthesia. Preclinical data had suggested that remimazolam may lead to a hemodynamic stability; this has been clinically confirmed.

 

The Japanese program started with a comparative Phase I study building on PAION’s first human trial and showed an identical pharmacokinetic and pharmacodynamic profile. The next step was a continuous infusion Phase I study to define induction and maintenance doses for anesthesia. The doses for induction and maintenance identified as safe and effective in the Phase II study subsequently conducted were then used in the Japanese Phase III studies, which confirmed remimazolam’s efficacy and safety as a general anesthetic and its favorable hemodynamic profile compared to propofol.

 

Based upon the successful completion of Phase III in Japan, a pre-NDA meeting (NDA = New Drug Application) with the Japanese Pharmaceuticals and Medical Devices Agency (“PMDA”) took place in January 2016. During the meeting, all open questions raised for discussion following the preliminary assessment of the PMDA were clarified. The PMDA stated that the non-clinical and clinical data package were regarded as complete for filing in the indication "Induction and maintenance of general anesthesia”. The clinical development program fully carried out in Japan by PAION’s former partner Ono in general anesthesia was complemented by PAION's growing data sets in all aspects from CMC (chemistry, manufacturing, control) to clinical and pre-clinical data generated outside of Japan. In October 2015, PAION already reported that the PMDA had confirmed that both the raw materials produced by PAION in Europe as well as the finished formulation of remimazolam fulfill the requirements for filing in Japan. PAION now plans the preparation and submission of an application for market approval of remimazolam in Japan. This includes, among other things, the necessary validation of commercial-scale production for the Japanese market. The required approval dossier will be prepared by an experienced contract research organization (CRO) in close consultation with PAION. Such a dossier could serve as a reference dossier in certain other markets. This would significantly reduce the necessary additional investment for partners in the respective markets depending on the specific regulatory environment.

In order to allow using the Japanese data for filing in the EU, the same induction and maintenance doses were used in the European Phase II trial performed in 2014, delivering further evidence for a potentially beneficial hemodynamic profile of remimazolam.

 

Based on these positive data, a multi-national, multi-center, randomized, single-blind, propofol-controlled, confirmatory Phase III study in patients undergoing major cardiac surgery was started in the EU in August 2015. Due to the complex study design in cardiac surgery, the trial faced recruitment challenges. Despite intensive efforts to enhance patient recruitment, the trial proved to be difficult to implement in practice. Therefore, in February 2016, PAION decided to discontinue the trial in order to avoid a long and expensive study with the existing design. No drug-related serious adverse events were observed.

 

In the meantime, PAION evaluated how to resume the clinical development of remimazolam in the EU. Based on the findings, PAION considers a study design analogous to the successfully completed Phase III program in general anesthesia in Japan to be useful. Such a Phase III study would thus be conducted with procedures in general surgery. Therefore and based on consultation with key opinion leaders in general anesthesia, a Phase I study is currently being prepared aiming at determining required patient numbers for the new Phase III study with a different patient population as precisely as possible. In this Phase I study it is planned to measure the depth of sedation of remimazolam particularly accurately on the basis of the subjects’ brain activity, since sedation depth needs to be measured objectively in addition to the subjective measurement by an anesthetist as an approval prerequisite in the EU. In particular, it is supposed to be demonstrated that patients are sufficiently narcotized during the surgery compared to the reference medication.

 

For a Phase III program in the EU, PAION currently expects funding needs of approx. EUR 20 million to EUR 25 million until filing for market approval subject to further coordination with the regulatory authority. Secured funding, the conduct of the preparatory Phase I study and the necessary scientific consultations with the relevant European regulatory authority EMA to specify the new European Phase III program are a prerequisite for a study start in 2018.

ICU sedation

PAION’s former partner in Japan, Ono, independently initiated a Phase II trial for sedation in intensive care units (ICUs). Higher than expected plasma concentrations of remimazolam were observed in isolated cases after long-term treatment 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 the patient presenting on the ICU. Further development of the program “ICU sedation” is part of the future remimazolam development plan which could be addressed after availability of required funds. 

 

Disclaimer

PAION’s product candidate (Remimazolam) is still in the development phase and is not approved for treating any disease in any country in the world currently. It can neither be prescribed nor acquired for therapeutic use.

 

PAION’s website may contain information about PAION’s product candidates and about clinical trials. This is provided solely with the aim of increasing transparency regarding the clinical trials performed on behalf of PAION. The information on this website is not intended to replace the advice of medical professionals and should not be understood to constitute medical recommendations. Patients should always obtain comprehensive medical advice before making decisions about their course of treatment.

 

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