RedHill Biopharma Ltd. (Nasdaq: RDHL) has announced plans to advance its groundbreaking late-stage program for Crohn's disease (CD) with an innovative Phase 2 study of RHB-204. The study, pending FDA Type C discussions expected in Q2/25, will be the first-ever clinical trial specifically targeting Mycobacterium avium subspecies paratuberculosis-positive (MAP+) patients with moderate to severe Crohn's disease.
A Novel Approach Targeting Disease Cause
RHB-204 represents a potential paradigm shift in Crohn's disease treatment by targeting MAP infection, which growing evidence suggests may be a causative factor in the disease rather than merely addressing symptoms as current therapies do. The drug is a proprietary, fixed-dose oral capsule containing a combination of clarithromycin, rifabutin, and clofazimine specifically dosed to treat MAP-related Crohn's disease.
"The role of MAP as a cause of CD, to be tested in this study, supports a paradigm-shifting new therapeutic approach for CD – focused on addressing the actual cause of the disease, not the symptoms," stated RedHill in their announcement.
Patent protected until 2041, RHB-204 is a next-generation formulation of RHB-104, which already demonstrated significant efficacy in a Phase 3 trial. The improved formulation reduces pill burden by 40% while enhancing tolerability, safety, and adherence.
Building on Strong Phase 3 Results
The planned Phase 2 study builds on compelling data from a previous Phase 3 trial of RHB-104, which met both primary and secondary endpoints. In that randomized, double-blind, placebo-controlled study involving 331 patients across 92 global sites, RHB-104 plus standard of care (SoC) demonstrated a statistically significant 64% improvement in efficacy compared to SoC alone.
Key results from the Phase 3 study included:
- 36.7% of RHB-104 patients achieved clinical remission at week 26 versus 22.4% of placebo patients (p = 0.0048)
- Superior remission rates as early as week 16, improving further at week 26 and continuing through week 52
- Meaningful improvement in endoscopic healing despite small sample size
- Statistically significant decline in fecal calprotectin, an inflammatory marker and surrogate for mucosal healing
- Generally safe and well-tolerated profile with adverse events similar to placebo
Dr. David Y. Graham, Professor of Medicine and Molecular Virology and Microbiology at Baylor College of Medicine, highlighted the unmet need: "Up to 40% of patients fail to respond to anti-TNF treatment, and over time up to 50% of responders lose response and have disease flare-ups. In addition to the unmet medical need for alternative therapeutic approaches, most of the existing drugs for CD are both expensive and are intravenously administered, further adding to the treatment cost burden."
Innovative Study Design
The Phase 2 study will incorporate several innovative elements:
- First-ever clinical trial in CD patients who are all MAP-positive
- Primary endpoints including mucosal healing (considered the gold standard in efficacy evaluation), MAP status, and clinical remission
- Correlation of mucosal healing with MAP eradication
- Utilization of novel endpoints and gold standard imaging techniques
- Potential for early efficacy indications at just 16 weeks
Gilead Raday, Chief Operating Officer and Head of R&D at RedHill, explained: "Advances in diagnostic technology have led to increasingly higher identification of MAP in Crohn's diseases patients. Utilizing gold standard imaging technology to provide clear and unambiguous efficacy results, the study is designed to include only MAP positive CD patients and is expected to increase the study's power, potentially allowing to demonstrate the benefits of RHB-204 anti-MAP therapy in a relatively small sample size."
The company expects this focused approach will enable a more efficient study with a clearly defined patient population, precise endpoints, and an expedited timeframe, substantially reducing anticipated program costs. Clinical study material has already been manufactured and is ready for implementation.
Market Potential and Regulatory Strategy
The Crohn's disease market represents a significant commercial opportunity. According to DataMonitor's Disease Analysis report from September 2024, the CD market is expected to grow from $13.6 billion in 2024 to $19.1 billion by 2033 across the United States, Japan, and five major European markets, at a compound annual growth rate of 3.87%.
With approximately 1.6 million diagnosed prevalent cases of CD globally last year and significant numbers of treatment failures with existing therapies, there is a strong need for effective new approaches. The Cleveland Clinic estimates that more than three-quarters of a million Americans and approximately 6-8 million people globally have Crohn's disease.
RedHill intends to explore additional regulatory process designations, such as breakthrough therapy designation and fast track status, which could provide additional exclusivity or potential for priority review vouchers. The company is also actively pursuing partnering and collaborations, including discussions with non-dilutive external funding sources.
About RHB-204
RHB-204 was originally developed for the treatment of pulmonary nontuberculous mycobacteria (NTM) disease caused by Mycobacterium avium complex (MAC). For this indication, it has already received several regulatory designations:
- FDA Fast Track Designation
- FDA Orphan Drug Designation
- Qualified Infectious Disease Product (QIDP) Designation under the Generating Antibiotic Incentives Now Act (GAIN Act), extending U.S. post-approval market exclusivity to a potential total of 12 years
- EU Orphan Designation, providing eligibility for 10 years EU post-approval market exclusivity
The drug contains three antimicrobial agents with potent intracellular, anti-mycobacterial, and anti-inflammatory properties. With its optimized dosing profile, RHB-204 aims to provide enhanced tolerability, safety, and compliance compared to its predecessor RHB-104.
If successful, this approach could represent a significant advancement in Crohn's disease treatment by addressing a potential root cause rather than merely managing symptoms, offering new hope to millions of patients worldwide who struggle with this debilitating condition.
