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Thursday, October 6, 2016

RedHill's Phase 3 Crohn's Disease Program Just Got More Interesting

On October 6, 2016, RedHill Biopharma Ltd. (NASDAQ: RDHL) announced a number of changes and protocol enhancements to the ongoing Phase 3 Crohn's Disease (CD) program with RHB-104, dubbed MAP-U.S. The changes are designed to enhance the overall robustness of the study and provide a more comprehensive assessment of RHB-104’s treatment effect. These changes will allow RedHill to increase the pace of enrollment, as well as better evaluate all patients enrolled in the study and bolster the likelihood of success.

RedHill has both increased the size of the trial and the amount of data they plan to collect as part of the trials key endpoints. Importantly, an independent data safety monitoring board (DSMB) review of the trial will take place in the second quarter of 2017. This review will include both a safety and interim efficacy analysis, and could potentially provide the opportunity to expedite the data locking process for the final analysis. Furthermore, this DSMB review will also evaluate the option of an early stop for success, according to a pre-specified statistical significance threshold for analysis requiring overwhelming efficacy of RHB-104 versus placebo in the primary endpoint.

A Little Background Info

RHB-104 is a proprietary and potentially groundbreaking oral antibiotic combination therapy with potent intracellular, anti-mycobacterial, and anti-inflammatory properties. Development programs with RHB-104 include the Phase 3 MAP U.S. study for CD and a Phase 2a exploratory study for multiple sclerosis. The development of RHB-104 is based on increasing evidence supporting the hypothesis that Crohn’s disease is caused by Mycobacterium avium paratuberculosis (MAP) infection in susceptible patients.

For a detailed look at RHB-104, see my article from July 2016:
→ RedHill's Phase 3 Crohn's Drug Is A Potential Game-Changer

RedHill is currently enrolling patients in a Phase 3 clinical study called MAP U.S. at up to 150 clinical sites in the U.S, Canada, Europe, Israel, Australia and New Zealand. Target enrollment for the study is 410 patients. This is the first Phase 3 study conducted by the company with RHB-104. Additional studies will likely be required to support a U.S. approval of RHB-104 in CD.

The MAP U.S. study is a randomized, double-blind, placebo-controlled study intended to evaluate the safety and efficacy of RHB-104 in patients with moderately to severely active Crohn’s Disease, defined as Crohn’s Disease Activity Index (CDAI) from 220 to 450. Subjects enrolled in the study are randomized in a 1:1 fashion to receive RHB-104 or a placebo, with a primary endpoint of disease remission, defined as a reduction in CDAI to less than 150 at week 26. Secondary and exploratory endpoints include state of response at 26 weeks, maintenance of remission through week 52, and efficacy outcome measures in relation to the presence of Mycobacterium avium paratuberculosis (MAP) bacterial infection. Exploratory endpoints include endoscopic evaluation of mucosal healing.

Important Changes To The Study

As noted above, RedHill has made several important changes to the MAP U.S. study designed to enhance the overall robustness of the study and provide a more comprehensive assessment of the drug's treatment effect.

Size & Scope: Planned enrollment in the study has been increased from 270 patients to 410 patients. Management has increased the size of the study to expand the collection of clinical data including colonoscopic mucosal healing and compensate for early terminations. While expanding the enrollment may push back the final data analysis, management believes the costs associated with increasing the size of the study are manageable. Management also plans to add up to 30 new clinical sites in Europe, including sites in four new countries, which will bring the total number of sites actively recruiting patients to 150. This should help speed enrollment to 410 patients.

Increasing both the size and scope of the trial will allow RedHill to provide more data to the U.S. FDA ahead of discussions around the second Phase 3 program. The number of sites in Europe has been doubled, which should facilitate conversations with the EU EMA around approval of RHB-104 in Europe as well. Importantly, the primary endpoint of the study has not been changed; however, because the sample sizes have been increased, the detectable effect has been reduced from 21% to 15% to show statistically significant separation between RHB-104 and the placebo. This means the trial has a better chance of success.

Increased Review: An interim safety review by the independent DSMB is scheduled to take place here in the fourth quarter 2016. Subsequent reviews will take place when 50% and 75% of the patients complete 26 weeks of treatment. Management believes 50% completion will take place in the second quarter 2017. Importantly, this interim review will now include both a safety and efficacy analysis. The modifications to the design allow for sequential tests to be made. If the pre-specified statistical significance threshold for overwhelming efficacy (i.e. p-value < 0.003) is met at the interim analysis in the second quarter of 2017, the study could be stopped for early success. Should the pre-specified threshold not be met in the interim analysis, the study is planned to proceed through completion of randomization of the 410 patients and follow-up at 26 weeks, with final efficacy testing performed using a two-sided p-value of 0.049.

The introduction of the potential for early termination of the study is very interesting. This presents a clear major catalyst for the shares coming in the next 6-9 months. In my "RDHL Valuation" article published in September 2016, I noted that I believe RHB-104 is RedHill's most valuable asset, with a current net present value of $200 million. This exceeds the total current market value of the company at only $175 million.

Increased Retention: To improve patient retention and further expedite recruitment, RedHill is 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. This not only helps RHB-104 provide additional data to the FDA and EMA on RHB-104's long-term safety profile but also assures that any patient that responds to the drug will have access for a full year. This has been heavily requested by principle investigators.

Additional Studies: RedHill has also reported that it plans to initiate two additional open-label, ex-U.S. clinical studies in up to 20 Crohn’s disease patients each to further evaluate the safety of efficacy of RHB-104, including generation of additional efficacy data in newly diagnosed and treatment-na├»ve Crohn’s disease patients and as an add-on therapy to current standard-of-care. Also, an extensive pharmacokinetic (PK) program is ongoing, including a population PK study which is being conducted as part of the MAP U.S. study along with previously completed food effect and drug-drug interaction studies. This additional data will help support the future potential marketing applications in both the U.S. and EU.

Separately, the company plans to present top-line data from the Phase 2a CEASE-MS study with RHB-104 for the treatment of relapsing-remitting multiple sclerosis (RRMS) in the fourth quarter of 2016. Back in April 2016, RedHill provided an interim look at the trial. The data showed patients on RHB-104 achieved an annualized relapse rate (ARR) at 24 weeks of only 0.288 in the mITT population and 0.0 in the PP population. The 0.288 ARR number in the mITT group compares favorably with previously reported pivotal studies of interferon beta-1a therapies Avonex® (0.67)(1) and Rebif® (0.87-0.91)(2). The data also compares well to other first-line therapies referenced in Nature in 2011 (3).

RHB-104 Companion Diagnostic

Many researchers have noted the high correlation between MAP infection and incidence of CD. For example, MAP can be cultured from the peripheral mononuclear cells from 50–100% of patients with Crohn’s disease, and less frequently from healthy individuals (45). Obviously, the association does not prove causation, but MAP would not be the first pathogenic bacteria known to cause gastrointestinal inflammatory conditions. The obligate pathogen H. pylori are the proven instigator of gastric and peptic ulcer disease (6).

Independent work conducted by a number of institutions has confirmed the link between CD and MAP infection. For example, a systemic review and meta-analysis published in Lancet Infectious Disease in 2007 noted a greater than 7x increase in odds for MAP infection (via PCR in tissue samples) and 1.7x increase in odds (via ELISA in serum) for patients with CD versus healthy controls (7). The authors, having looked at 28 case-controlled studies, concluded that, "The association of MAP and Crohn's disease seems to be specific, but its role in the aetiology of Crohn's disease remains to be defined."

In this regard, RedHill and Q2 Solutions (formerly Quest Diagnostics) continue to advance the development program for a commercial companion diagnostic for the detection of MAP bacteria in Crohn’s disease patients.

The collaboration with Q2 Solutions has led to successful results, including initial validation of RedHill’s platform PCR detection methodology licensed from the University of Central Florida (UCF) and developed by Professor Saleh A. Naser, a leading investigator in the field of MAP and its association with Crohn’s. Further testing of the technology at three different U.S. laboratories has successfully identified MAP DNA in blood samples drawn from patients with CD outside of the MAP U.S. study. Optimization of the processes for rapid detection of MAP is currently in progress.

Critical to the successful development of a companion diagnostic will be ensuring that any future commercial test is accurate and reproducible. RedHill believes that PCR (polymerase chain reaction) technology is the most promising approach currently available and is focusing its efforts in that direction. RedHill has recently initiated a collaboration with Baylor College of Medicine intended to advance further the efforts to develop a companion diagnostic for MAP. This collaboration is on top of the previous collaborations with UCF and the University of Minnesota. 

Conclusion

I think things just got more interesting for investors in RedHill Biopharma around RHB-104. As noted above, this is the flagship asset in my opinion. I'm confident that RHB-105, which is about to start a second Phase 3 program for the treatment of H. pylori infection, has tremendous value. I'm also incredibly intrigued by Yeliva®, currently in Phase 2 studies for multiple solid tumor indications.

That being said, given the flurry of deals we have seen in the UC/CD space over the past few years, RHB-104 is the drug that will make RedHill a major player in specialty pharma. So far, 219 of the 410 patients have been enrolled. Full enrollment of the Phase 3 MAP U.S. study is expected by the end of 2017, which puts top-line data likely in the third quarter of 2018. This is admittedly a long way off; however, the interim analysis that will take place in the second quarter 2017 is now meaningful. Positive data has the potential to end the trial, after which RedHill will likely start entertaining partnership talks. It's a major catalyst for the shares only six months away.

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Related: Read my update on RDHL following the company's semi-annual R&D update in August 2016 → LINK

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Please see additional important information about BioNap, Inc. in our Disclaimer.
We hold no position in shares of RDHL as of this article.

9 comments:

  1. What do you guys think of these changes?

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    1. I think its good news. Happy to see a nice catalyst.

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  2. The statistical significance for overwhelming results, was that .005? What would it take to receive that kind of statistical significance? I am not very well educated in this subject but know that a smaller p number means the higher the statistical significance that the drug performed much better than placebo.

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    1. It's p<0.003. So with 205 patients enrolled at 1:1, with 90% power assuming the placebo group comes in around 20% at 26 weeks, the remission rate for RHB-104 would need to be > 47% to achieve P<0.003. This equates to an effect size of 27%. However, once the trial fully enrolls to 410 patients at 1:1, the final p-value must only be less than 0.049. Assuming the same 20% for the placebo, this means RHB-104 must show 35% remission, which is an effect size of only 15%. Hope this is helpful.

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    2. Is it possible for RHB-104 to reach p<0.003 taking into account the inclusion criteria for the clinical trial? Professor Borody´s second study in 54 patients in 2005 shows a remission rate of 60%, especially in the subgroup with a CDAI of >200.

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    3. Yes, but it all depends on what the placebo group does. If the placebo group does 20%, then 60% is a home run. If it does 40%, then 60% falls short.

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    4. If you look at the Pfizer study in Australia, the remission rate in the placebo group was 50% at weeks 16 and 22% at weeks 52. It could be very hard for RHB-104 to achieve statistical significance of p<0.0003 at weeks 26. Hopefully the "new" dose in comparison to the Pfizer dose and the inclusian criteria lead to higher remission rates in the RHB-104 group.

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    5. Keep in mind the PFE study was a little different design. The patients were given steroids to drive them into remission and then the endpoint was looking at relapse rate. In the MAP US study, the patients must be on stable doses of other medication and still have a CDAI > 220 to 450, so I think we will see a meaningfully lower placebo result at 26 weeks than what Pfizer saw.

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  3. Tom Br alias CloefkapperOctober 9, 2016 at 8:16 AM

    Regarding Crohne: Tigenix (Belgian based biotech) has an approved cell product Cx601;besides Takeda has licensed it for the Japanese market.

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