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To date, Remimazolam has been studied in more than 1,700 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 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.
Remimazolam is currently in the final stage of clinical development for procedural sedation in the U.S. A total of seven Phase I, two Phase II and three 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 shortly completed 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 the primary efficacy endpoint was met. 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.
Important secondary endpoints in the remimazolam arm showed a median time from start of medication to start of procedure of 4.0 minutes (placebo 19.5 minutes) and a mean time from end of procedure to return to full alertness of 7.2 minutes (placebo 21.3 minutes). Additionally, time from last dose to “back to normal” as reported by patients on remimazolam was 331 minutes (placebo 572 minutes).
There were no treatment-emergent serious adverse events in the trial. Hypotension was 44.3% with remimazolam and 47.5% with placebo and accounted for most of the adverse events in all study arms. Hypoxia occurred in 1.0% of patients given remimazolam, 3.4% in the placebo arm.
On the Hopkins Verbal Learning Test administered five minutes after reaching the fully alert status, the total raw score, delayed recall, memory retention, and recognition discrimination scores were all better with remimazolam compared to placebo.
Patient satisfaction was similar in all arms of the study.
The open label midazolam patients showed a median time from start of medication to start of procedure of 19.0 minutes and a mean time from end of procedure to return to full alertness of 15.7 minutes. Midazolam patients took 553 minutes to be back to normal. Hypotension was 67.3% with midazolam and hypoxia occurred in 1.0% of patients given midazolam.
In addition to the above study, the U.S. Phase III program includes a second confirmatory, prospective, double-blind, randomized, placebo-controlled multi-center trial with an open label midazolam arm in 446 patients undergoing bronchoscopies.
In June 2015, the study was started, the patient recruitment was completed in March 2017, and in June 2017, PAION announced that the primary efficacy endpoint was met. The Phase III trial enrolled 446 patients at 15 U.S. sites and was designed to evaluate the efficacy and safety of remimazolam compared to placebo (with midazolam rescue medication) in procedural sedation in patients undergoing bronchoscopy.
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 for remimazolam/placebo and no more than 3 doses within any 12-minute window for midazolam. The primary endpoint was reached in 82.5% of the patients treated in the remimazolam arm and 3.4% in the placebo arm (p-value of <0.0001). Important secondary endpoints included median time from start of medication to start of procedure (5.0 minutes in the remimazolam arm versus 17.0 minutes for placebo) and median time from end of procedure to return to full alertness (remimazolam 6.0 minutes versus placebo 14.0 minutes). Additionally, the patients’ subjective impression of time from last dose to “back to normal” was a median of 404 minutes for remimazolam versus 935 minutes for placebo.
In the open label midazolam arm, procedural success was achieved in 34.8% of patients. Midazolam patients showed a median time from start of medication to start of procedure of 16.0 minutes and a median time from end of procedure to return to full alertness of 12.0 minutes. Additionally, time from last dose to “back to normal” as reported by patients on midazolam was a median of 478.5 minutes.
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 in March 2017, PAION announced positive headline data from the U.S. clinical safety trial of remimazolam in ASA III/IV patients (American Society of Anesthesiologists classification) undergoing colonoscopy. The trial enrolled 79 patients and was designed to evaluate the efficacy and safety of remimazolam compared to placebo (with midazolam ‘rescue’ sedation) in patients undergoing proceduralist-supervised sedation for colonoscopy. This study also included an open label arm in which midazolam was dosed according to U.S. label. The trial confirmed remimazolam’s safety profile and tolerability shown in all previous studies in a more vulnerable patient population. Overall, remimazolam demonstrated good respiratory and cardiovascular stability as compared to placebo with midazolam rescue. No adverse events of concern were observed in either group. In addition, the efficacy and efficiency improvements were comparable to the two positive pivotal U.S. Phase III trials in colonoscopy and bronchoscopy patients. Success of the procedure (including no requirement for rescue medication and the application of not more than five doses in any 15-minute interval) was achieved in 84.4% of patients in the remimazolam arm and 0% in the placebo arm. Other relevant endpoints showed a median time from start of medication to start of procedure of 5.0 minutes for remimazolam (placebo: 18.5 minutes) and a median time from end of procedure to return to full alertness of 3.0 minutes (placebo: 5.0 minutes). By comparison, procedural success was achieved in 12.9% of the midazolam patients. Midazolam patients showed a median time from start of medication to start of procedure of 19.0 minutes and a median time from end of procedure to return to full alertness of 7.0 minutes.
Summary of headline data of the three Phase III studies:
Primary endpoint achieved
Time from start of medication to start of procedure
Time from end of procedure to fully alert
Time to back to normal
* not part of label Claim
Based on the results of preclinical and Phase I studies and in consultation with the Food and Drug Administration (FDA), PAION has started additional Phase I studies to further assess the abuse potential of remimazolam. Two aspects are being studied: if remimazolam could inappropriately be used as a knock-out cocktail in combination with alcohol and if it could be abused intranasally.
Recruitment of a trial evaluating the oral administration of remimazolam with alcohol has been completed in the third quarter of 2017. Recruitment of the first of two planned trials evaluating the intranasal administration of remimazolam has been completed in the second quarter of 2017. PAION plans to discuss further details of the human abuse liability program with the FDA in the fourth quarter of 2017, prior to initiating the second intranasal study.
Conditional on successful study results and dependent on discussions with the FDA, PAION currently expects to complete the human abuse liability program in the first half of 2018.
The FDA publishes drug classification schedules under the Controlled Substance Act (CSA). The drug classification schedule classifies drugs into groups based on risk of abuse. Midazolam, for example, is included in Schedule IV. Substances in this schedule have a lower potential for abuse relative to substances in Schedule III. PAION expects that remimazolam will receive the same classification as midazolam.
PAION is allocating significant resources to achieve the completion of the U.S. clinical development program. The company has regular interactions with the FDA to ensure that all relevant data for the NDA submission have been collected. This will be followed by an integrated “overall” analysis of all clinical studies with remimazolam. Subject to the successful completion of the clinical development program, including the completion of all analyses and reports, filing for approval in the U.S. could take place subsequently after finalization of a market approval dossier. Before filing, usually a pre-NDA meeting with the U.S. regulatory authority FDA is held, which Cosmo currently plans shortly before filing for approval. The necessary coordination and preparatory work are currently being conducted together with Cosmo, U.S. key opinion leaders and regulatory experts. Filing for market approval is Cosmo’s responsibility. Cosmo currently expects filing for approval in the second half of 2018.
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 with the 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 Pharmaceutical Co., Ltd. (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 is now working on the preparation of a filing dossier for remimazolam in Japan. The required approval dossier is being prepared by an experienced 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.
In consultation with key opinion leaders in general anesthesia, PAION has successfully conducted a Phase I trial to serve as a means to define key elements and sample size calculation for the planned Phase III trial. Based on the results of this study and subsequent simulations, PAION currently assumes that approximately 500 patients will be required for the EU Phase III study in general anesthesia.
PAION plans to continue the EU clinical development program for remimazolam with a study design close to the successfully completed Phase III program in general anesthesia in Japan but in sicker patients, where the medical need to reduce hypotensive events is greater. Prior to initiating the Phase III program, which is planned for 2018, PAION will obtain Scientific Advice from the European Medicines Agency (EMA), the relevant European regulatory authority.
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.
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.
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