With a PDUFA target date of Feb. 3, 2014 for its migraine drug, RHB-103, and NDA filing planned for the first quarter of 2014 for the anti-emetic drug, RHB-102, RedHill Biopharma (NASDAQ:RDHL) is now focusing its efforts on its flagship programs: RHB-104 for Crohn's disease and RHB-105 for Helicobacter pylori (H. pylori).
RedHill is preparing to begin a potential groundbreaking Phase III study in the current quarter in North America and Israel (the MAP U.S. Study) of Crohn's disease, using a novel patent-protected formulation that combines three antibiotic ingredients in a single capsule, and is planning and preparing a parallel Phase III study in Europe (the MAP Europe Study).
"Following the discovery of the link between H. pylori bacterium and peptic ulcers, there is a growing body of evidence supporting the proposition that Crohn's disease and other so-called autoimmune diseases, such as multiple sclerosis, are linked to infections," chief business officer Guy Goldberg says in an interview with BioTuesdays.com, referring to emerging scientific evidence that the microbiome, or the trillions of intestinal microbes, plays a major role in health and disease.
"There's a paradigm shift of viewing the body not as a single organism but as a collection of organisms, with the microbiome as the habitat within the body," he adds.
In 2005, researchers in Australia won the Nobel Prize for identifying H. pylori bacterium and the role it plays in causing peptic ulcers. Stress and lifestyle were long believed to be the primary cause of intestinal ulcers. Fellow Australian, Prof. Thomas Borody, who is now a member of RedHill's advisory board, developed the first antibiotic treatment for ulcers.
RedHill's two lead drug candidates - RHB-104, for Crohn's disease and multiple sclerosis (MS), and RHB-105, forH. pylori - were built on the success of Prof. Borody's approaches to gastrointestinal tract diseases and infections.
"RHB-104 is the biggest program in our pipeline," Mr. Goldberg says. "To the best of our knowledge, we are the only company with a Phase III combination antibiotic approach for treating Crohn's disease, even though there is a lot of academic research connecting Crohn's to a bacterial infection."
RedHill is currently advancing six clinical programs; two of which are expected to be reviewed by the FDA during 2014, and three that are entering pivotal clinical studies.
In a research report last month, Bioassociate Innovative Consulting reiterated its "buy" rating and price target of $14.91 per RedHill American Depositary Share, "given the multiple milestones approaching and the company being on-track with the clinical programs' timelines."
Crohn's is a severe inflammatory disease in the GI tract. Existing drugs, such as Remicade, treat the inflammatory symptoms of the disease by suppressing the immune system. However, they are widely considered to have a poor safety profile and limited long-term efficacy. "There clearly is a strong unmet medical need for a better alternative for Crohn's patients," Mr. Goldberg contends. The global market to treat Crohn's exceeded $3.5-billion in 2012.
Phase II Study Pictures in Crohn's Patients (Borody et al (2002), Digest Liver Dis 34:29-38)
He explains that RHB-104 is a novel and proprietary combination of three approved antibiotic ingredients - clarithromycin, clofazimine and rifabutin - targeting Mycobacterium Avium Paratuberculosis (MAP). Crohn's patients are believed to have seven times greater likelihood of being MAP-positive than non-Crohn's patients.
The MAP U.S. Study will enroll 240 moderately-to-severely active Crohn's patients at 50 sites in North America and Israel. The primary endpoint is the state of remission at week 26. The study will also examine safety, the maintenance of remission through week 52, efficacy outcome measures in relation to the presence of MAP infection and other secondary endpoints.
If the study is successful, RedHill may submit a new drug application to the FDA in 2015. RHB-104 previously received orphan drug status from the FDA for pediatric use. Mr. Goldberg says discussions are underway with European regulators to begin a second Phase III study with RBH-104 in Europe - the MAP Europe Study.
RedHill also is developing RHB-104 to treat patients with relapsing remitting MS. In June, the company commenced a Phase IIa proof-of-concept trial in Israel. "This is the first time that this type of antibiotic therapy will be tested on MS patients in a Phase II clinical trial," Mr. Goldberg contends.
RedHill's second lead program is RHB-105 in development to treat H. pylori bacteria, which plays an important role in gastritis, peptic ulcers and gastric cancer. Mr. Goldberg points out that H. pylori is increasingly developing resistance to treatment with clarithromycin and metronidazole, and that standard therapy fails in up to 30% to 40% of patients who continue to remain H. pylori-positive.
A Phase IIa study in 2005 by Prof. Borody in Australia demonstrated over 90% eradication of the bacteria in 130 patients who had previously failed standard therapy with clarithromycin. Approximately three million H. pylori-infected patients are treated annually in the U.S. market, resulting in a potential market estimated at $1-billion to $1.5-billion.
Mr. Goldberg explains that RHB-105 is a novel all-in-one combination of two antibiotics - rifabutin and amoxicillin - and a proton pump inhibitor, omeprazole. RedHill plans to begin a Phase II/3 clinical trial with RHB-105 during the quarter, he says, adding that a successful study could lead to an NDA filing in 2014.
In addition to RHB-104 and RHB-105, RedHill has four other late-stage drug candidates in its pipeline of new formulations and combinations of existing drugs. As of June 30, 2013, the company had $14.7-million of cash and no debt.
In March, the FDA accepted an NDA filing for RHB-103 and gave the company a PDUFA date of Feb. 3, 2014. RHB-103 is a proprietary, oral, thin film formulation of the migraine drug, rizatriptan, which dissolves on the tongue, is pleasant-tasting and, in Mr. Goldberg's words, "offers an attractive alternative for migraine sufferers." The NDA filing followed a successful study that found RHB-103 to be bioequivalent to the active ingredient in Merck's migraine drug, Maxalt MLT.
RedHill also is planning an NDA filing in the first quarter next year for RHB-102, a once-daily controlled-release formulation of ondansetron, the active drug in GlaxoSmithKline's Zofran, for the treatment of chemotherapy and radiotherapy-induced nausea and vomiting in cancer patients.
In April 2012, RedHill announced positive results in a pivotal bioequivalence clinical trial, comparing RHB-102 against ondansetron. After a successful meeting with the FDA in February 2013, the company announced plans to conduct additional pharmacokinetic studies to support its planned NDA filing in the first quarter of 2014.
RHB-101 is RedHill's once-daily, controlled-release formulation of carvedilol, the active ingredient in Glaxo's Coreg, to treat congestive heart failure and hypertension. While Coreg is on the market in the U.S., Mr. Goldberg says no once-daily version exists in Europe and RHB-101 has several potential advantages over the once-daily version approved in the U.S.
In May 2013, the company met with the FDA and plans to conduct additional chemistry, manufacturing and controls (CMC) and pharmacokinetic work prior to submitting an NDA.
The company also met with European regulators in March 2013 and plans to conduct additional CMC work prior to submitting an application for marketing approval of RHB-101 by the end of 2014, with Denmark as the reference member state in the EU. "We think we have developed a path forward in Europe without having to conduct additional clinical studies," Mr. Goldberg suggests.
RedHill is also developing RHB-106 as an oral bowel preparation capsule for GI tract procedures such as colonoscopy. It would allow patients to avoid the often unpleasant taste of liquid products and improve patient compliance. A completed Phase IIa study with 62 patients in Australia found significantly improved patient response and equal bowel cleansing. RedHill is moving forward with a development plan for the RHB-106.