Clinical Trials

* The Phase III double-blind placebo-controlled MAP Europe study is expected to enroll 360 subjects with moderately active Crohn's disease randomized in up to 60 sites in six European countries.

Similar to the MAP US Phase III study in North America and Israel, the MAP Europe study will be designed to assess the safety and efficacy of fixed-dose combination RHB-104 as well as to initially assess the role of MAP (Mycobacterium avium paratuberculosis) in Crohn's disease. The primary endpoint for the MAP Europe study will be the state of remission at week 26 in subjects randomized to receive RHB-104, as compared to subjects randomized to receive placebo. Secondary and exploratory endpoints will include, among others, state of response at 26 weeks, maintenance of remission through week 52 and efficacy outcome measures in relation to the presence of MAP bacterial infection. The study will be exploratory with respect to the clinical validation of the Company’s proprietary Polymerase Chain Reaction (PCR) assay used to detect MAP. The patent for the diagnostic test was licensed from the University of Central Florida, and initial development was completed by the Company and Quest Diagnostics.

* On December 13, 2016,  RedHill Biopharma reported that, following a pre-planned review of safety data from its ongoing Phase III study with RHB-104 for Crohn’s disease (the MAP US study) by an independent Data and Safety Monitoring Board (DSMB), it has received a unanimous recommendation to continue the study as planned, without any modifications. To date, 242 patients have been enrolled out of a planned total of 410 patients in up to 150 clinical sites in the U.S, Canada, Europe, Israel, Australia and New Zealand.
Two additional independent DSMB meetings are expected to take place in the MAP US study after 50% and after 75% of the 410 patients planned to be enrolled in the study will complete 26 weeks of study participation. The second independent DSMB meeting is expected in the second quarter of 2017 after the first 205 patients are expected to complete 26 weeks of study participation (patient 205 was randomized in August 2016).
The second DSMB meeting will include safety and interim efficacy analysis and could potentially provide the opportunity to expedite the data locking process for the final analysis, once the study is complete. Importantly, this independent DSMB meeting will evaluate the option of an early stop for success for overwhelming efficacy, according to a pre-specified statistical significance threshold for analysis of RHB-104 versus placebo in the primary endpoint. If the pre-specified threshold is met at the second DSMB meeting, the study could be stopped for efficacy or inefficacy. If the pre-specified threshold is not met during the interim analysis, the MAP US study is planned to continue through randomization of all 410 patients and follow-up at week 26.
Taking into account the increase in the total number of patients planned in the MAP US study, and assuming the study is not stopped for success or inefficacy following the DSMB meeting in the second quarter of 2017, completion of recruitment is expected by the end of 2017.
RedHill is advancing its preparation to initiate an open-label extension study for all patients who have completed 26 weeks of treatment in the MAP US study and failed to achieve remission at week 26, the study’s primary endpoint. Patients with a Crohn’s Disease Active Index (CDAI) score of greater than 150 at week 26 will be offered the opportunity to receive treatment with active drug (RHB-104) for a 52-week period. This study is considered separate from the MAP US study and data collected will be supplemental to the MAP US study data.

* On October 6, 2016, RedHill Biopharma provided an update on the RHB-104 Phase III Crohn’s disease development program, planned enhancements to the MAP US first Phase III study and expected milestones,
including an option for early stop for success for overwhelming efficacy.  An option for early stop for success for overwhelming efficacy has been introduced into this Phase III study and analysis is expected in the second quarter of 2017 as part of a second independent data safety and monitoring board (DSMB) interim safety and efficacy review. An independent safety-focused DSMB meeting for the Phase III MAP US study is on track
for the fourth quarter of 2016
Ongoing work on RedHill’s companion MAP diagnostic test has led to the successful identification of MAP DNA in blood samples from Crohn’s disease patients. Further development work on the MAP companion diagnostic is in progress; RedHill has recently entered into a collaboration with Baylor College of Medicine.
In order to enhance the overall robustness of the MAP US Phase III study, provide a more comprehensive assessment of RHB-104’s treatment effect and bolster the likelihood of the study’s success even further, RedHill is implementing several improvements to the study’s protocol and introducing additional enhancements to the overall RHB-104 developmentprogram, including:
- The total number of patients to be enrolled in the MAP US study has been increased from 270 to 410 in order to expand the collection of clinical data, including mucosal healing, and to compensate for early terminations; The increase is in line with historical power assumptions and remission rates of Phase III studies with approved Crohn’s disease drugs
- Overall 90% power has been maintained and sample size calculations have been modified to reduce the detectable effect from 21% to 15%, reflecting a more clinically expected treatment effect; Furthermore, with this modified sample size, more precise estimates of the treatment effect can be ascertained; No changes are planned to the primary endpoint of remission, defined as CDAI (Crohn’s DiseaseActivity Index) of less than 150 at week 26
- With 219 of the targeted 410 patients already enrolled in the MAP US study, the second independent DSMB meeting is expected in the second quarter of 2017, when the first 205 patients will have completed 26 weeks of study participation; This independent DSMB review will include safety and interim efficacy analysis, with
evaluation of an early stop for success under pre-specified efficacy criteria, providing an opportunity to significantly shorten the time to study completion in the event of overwhelming efficacy and potentially expediting the data locking process, once the study is fully completed.
The increase in the number of patients in the MAP US study is also intended to allow for collection of significantly more colonoscopic mucosal healing data, supporting future potential marketing applications and reflecting and adhering to the most recent FDA and EMA guidance.
A third safety-focused independent DSMB meeting is now planned for when 75% of the 410 patients will have completed 26 weeks of study participation.
RedHill is also preparing to initiate an open-label extension study, offering all patients who complete 26 weeks of study drug administration and remain out of remission (CDAI>150) the opportunity to receive treatment with RHB-104 for a 52-week period
To further expedite recruitment and expand data collection in Europe, RedHill is increasing the number of European sites by adding approximately 30 new sites in up to four additional European countries, more than doubling the current number of European sites in the MAP US study
In the coming months, RedHill intends to initiate two additional ex-U.S. small-scale open-label clinical studies with RHB-104, each with up to 20 Crohn’s disease patients, to provide additional supportive clinical data to potential future marketing applications, as well as evaluate RHB-104’s efficacy in newly diagnosed and
treatment-naïve Crohn’s disease patients and as an add-on therapy to current standard of care
RedHill will remain blinded to the interim and ongoing results from the Phase III study; No changes are planned to the MAP US Phase III study’s primary endpoint or 90% power; Assuming enrollment of all 410 planned subjects, completion of patient recruitment is expected by the end of 2017


* On June 23, 2016, RedHill Biopharma announced the publication of an article demonstrating the potential efficacy of RHB-104 for Crohn’s disease associated with Mycobacterium avium subspecies paratuberculosis (MAP) infection. The article was published in the peer-reviewed journal Gut Pathogens and was authored by scientists from the University of Central Florida (UCF) College of Medicine’s Burnett School of Biomedical Sciences.
The article describes a pre-clinical study intended to determine the efficacy of the RHB-104 active components (clarithromycin, clofazimine and rifabutin) against MAP strains isolated from the blood, tissue and milk of Crohn’s disease patients. The researchers determined the minimum inhibitory concentrations of the active components, separately and in dual and triple combinations, against 16 MAP clinical strains and 19 other mycobacteria.
The results of the study demonstrated that the RHB-104 active components, in their individual concentrations or in dual combinations, were not as effective against all microorganisms, compared to the triple combination at minimum inhibitory concentrations level. The authors concluded that lower concentrations of the triple combination of RHB-104 active components provided synergistic anti-MAP growth activity compared to individual or dual combinations of the drugs and, consequently, administration of RHB-104 is considered favorable and should lead to tolerable dosage that is desirable for long-term treatment of Crohn’s disease.
RHB-104 is currently undergoing a first Phase III study for Crohn’s disease in the U.S., Canada, Israel, Australia and additional countries (the MAP US study). Interim analysis of the ongoing randomized, double-blind, placebo-controlled MAP US study is expected in the second half of 2016, after half of the 270 patients planned to be enrolled in the study will have completed 26 weeks of treatment.

* On November 25, 2013, RedHill Biopharma, an emerging Israeli biopharmaceutical company focused primarily on the development and acquisition of late clinical-stage, proprietary formulations and combinations of existing drugs, has announced that the first patient has been recruited and dosed in the MAP US study - a Phase III clinical study designed to evaluate the safety and efficacy of fixed-dose RHB-104 in patients with moderately to severely active Crohn's disease.

The Company is planning to commence a second Phase III study with RHB-104 for Crohn's disease in Europe (the MAP Europe study) following successful Scientific Advice Meetings with the UK and Swedish pharmaceutical regulatory agencies earlier this year. The MAP Europe study is planned to commence in the first half of 2014 and to be conducted in parallel with the ongoing MAP US study.

* On August 20, 2013, RedHill Biopharma has reported that it had recently concluded Scientific Advice Meetings with the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and the Swedish Medical Products Agency (MPA) regarding the regulatory path towards a Phase III clinical study in Europe with RHB-104. In light of the positive feedback received from the UK MHRA and the Swedish MPA, the Company believes there is a clear regulatory path towards a Phase III clinical study in Europe with RHB-104 for the treatment of Crohn's disease (the “MAP Europe” study). The Company intends to file applications to begin the Phase III MAP Europe study in several European countries and, working with a leading international CRO, has already identified potential sites for the study.

RedHill Biopharma plans to commence a first Phase III double-blind placebo-controlled clinical study with RHB-104 for the treatment of Crohn's disease, enrolling 240 subjects in up to 50 sites in North America and Israel (the "MAP US” study) in the coming weeks. The MAP Europe study will commence as soon as possible following the initiation of the MAP US study, in order for the two studies to be conducted in parallel. The Company also intends to complete supplemental clinical and other studies as part of the regulatory plan.