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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 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.
A total of two Phase I, two Phase II trials and one Phase III trial 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 studies.
In April 2016, patient recruitment in the first study of PAION’s pivotal U.S. Phase III program in patients undergoing procedural sedation was completed, and in June 2016, PAION announced that the study’s primary efficacy endpoint had been 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 top-up 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 on 18 October 2016 (after the period covered).
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 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.
In addition to the detailed analysis of the primary and secondary endpoints of the Phase III trial (comparison to placebo), Prof. Rex also presented data for the open label midazolam arm. These results will not be part of the label claims. They will however serve as valuable data to plan future studies and perform pharmacoeconomic modelling. 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 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 increased the recruitment rate and PAION therefore confirms the previously communicated timeline for completion of patient recruitment in the second quarter of 2017. Over half of the 420 patients have already been recruited to the study.
A smaller safety trial in high-risk patients (double blind vs. placebo and open label vs. midazolam) undergoing colonoscopies for which patient recruitment is expected to be completed in 2016, and four Phase I trials to further support remimazolam’s safety profile complement the U.S. development program.
In the U.S., PAION is allocating significant resources to achieve the planned completion of the Phase III program, especially on patient enrollment in the Phase III bronchoscopy study. The timing to submit for U.S. market approval following successful completion of the clinical development program is subject to ongoing discussions with Cosmo, who is responsible for all approval activities in the U.S.
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. Specific attention was paid to hemodynamic stability in the clinical program as preclinical data suggested that remimazolam may lead to a hemodynamic stability, which addresses a current need in general anesthesia.
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 anaesthetic 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 the 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 fulfil the requirements for filing in Japan.
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, further confirming the beneficial hemodynamic profile of remimazolam.
In August 2015, the start of the multi-national, multi-center, randomized, single-blind, propofol-controlled, confirmatory EU Phase III study in patients undergoing major cardiac surgery was announced. Due to the complex study design, 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 have been observed.
Currently, PAION is evaluating how to resume the clinical development of remimazolam in the EU.
PAION’s former partner in Japan, Ono, independently initiated a Phase II trial for sedation in intensive care units (ICUs). Ono discontinued this exploratory trial in August 2013. While all patients were sedated successfully and no significant unexpected adverse events were reported, higher than expected plasma concentrations of remimazolam were observed in isolated cases after long-term treatment.
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. As a result, PAION is of the opinion that the maximum dose level has now been defined for ICU sedation. Further development of the program “ICU sedation” is part of the future remimazolam development plan which will 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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