Redhill Biopharma ($RDHL): Phase 3 Drug candidate RHB-105 likely to succeed, RHB-104 possible

This week I’m hoping to wrap up my two-part series on Redhill Biopharma ($RDHL). Previously I wrote about RDHL’s drug BEKINDA, which I believe is likely to pass its phase 3 trial. RDHL has two other late-stage drugs in the pipeline: RHB-105, which is designed to treat the bacteria which causes stomach ulcers, and RHB-104, which hopes to treat Crohn’s disease.

After doing some research, I believe that RHB-105 is also likely to pass the confirmatory phase 3 trial, which is scheduled to begin later this year. RHB-105 is a combination therapy designed to treat antibiotic-resistant strains of the bacteria that causes ulcers, known as Helicobacter pylori or H.pylori. Essentially, RHB-105 is a single pill containing two antibiotics and a proton pump inhibitor (acid reflux drug). The scientists at Redhill hope that the combination of drugs will be better than the current standard of care – one antibiotic and a proton pump inhibitor. It appears that they may be correct.

$RDHL’s Drug RHB-105: Likely to Pass Confirmatory Phase 3 Trial

Earlier this month, RDHL announced positive data from RHB-105’s initial phase 3 study. Redhill is planning to run a second confirmatory phase 3 study, which will probably begin sometime in June or July of this year. The initial study was well-designed: The placebo was a good match for the active intervention, they used two common methods of diagnosis to confirm the presence of H.pylori and patients who dropped out or did not complete the study were counted as failures.

In the study, RHB-105 eradicated H.pylori infection in 89% of the treated patients. This is significantly better than the standard of care’s success rate, which is roughly 70%. What’s more, at the end of the study they allowed the placebo group to be treated with the standard of care, and only 63% of that group were successfully cured of H.pylori, suggesting that 70% may have been an optimistic estimate.

So, with the first phase 3 trial RHB-105 demonstrated that it is significantly more effective than placebo (unsurprising) and significantly more effective than an estimate of the standard of care (somewhat surprising). As a follow up, the confirmatory trial will be about 4 times larger and will pit RHB-105 directly against the standard of care. There’s some room here for failure. Although I think it’s very unlikely that RHB-105 will perform worse than the standard of care, it’s possible that there won’t be a statistically significant difference between RHB-105 and the standard. I suspect that’s why the researchers are making this trial so much larger – statistically, a large trial is more likely to pick up on small differences between two conditions.

Even with that said, the strong study design and impressive results from the first phase 3 trial make me think that another pass is likely.

Prediction for RHB-105: Confirmatory Phase 3 Approval

Although it will be more than a year before we see any data from the confirmatory phase 3 trial for RHB-105, I believe that the ultimate result will be a success. I’ll update this post if something happens to change my mind.

$RDHL’s Drug RHB-104: Potential to Pass Initial Phase 3 Trial

Unfortunately, there’s not enough data for me to be certain about the third drug candidate, RHB-104. There is a strong theoretical grounding, and I believe it is highly possible that RHB-104 will pass, but I’m not quite confident enough to say “likely.” Part of the issue is the particular nature of Crohn’s disease – although we’ve identified some of the risk factors, nobody has yet proven exactly what causes Crohn’s. And because we don’t know what causes Crohn’s, nearly all of the treatments for the disease treat the symptoms, instead of the cause.

Redhill hopes to be one of the first companies with a treatment for the cause of Crohn’s. RHB-104 is, like -105, a combination therapy. In this case, the combination is of three separate antibiotics. There’s been some very recent research suggesting that combining antibiotics like this may lead to some synergistic effects; that using small doses of multiple antibiotics at the same time is better than using large doses of just one antibiotic. The sum, in effect, is greater than the parts – or at least, that’s what RDHL is hoping.

The three antibiotics in RHB-104 are all aimed at treating a particular strain of bacteria known as MAP. As you’ve probably guessed, the researchers at Redhill Biopharma believe that MAP plays an integral role in causing Crohn’s disease. It’s well-known that MAP causes Johne’s disease in cattle, which is a very similar ailment. Modern research has also conclusively demonstrated that people with Crohn’s have a much higher rate of MAP infection than people without Crohn’s.

Although none of the above is conclusive (or even demonstrates causation), there has been some research suggesting that treating MAP infection may help Crohn’s symptoms:

Effectiveness of RHB-104
Taken from Borody et al (2002), Digest Liver Dis 34:29-38

In addition, a statistical reanalysis of an Australian phase 3 study using anti-MAP therapy to treat Crohn’s disease suggested that anti-MAP therapy may be significantly more effective than placebo. However, there are some inherent issues in reanalysis, and I wasn’t able to find out whether the reanalysis was funded by RDHL.

RHB-104 Phase 3 data
Taken from Behr and Hanley (2008), Lancet Infectious Diseases 8:344

As you can see, there’s some fairly compelling evidence suggesting that MAP might be implicated in Crohn’s. If so, RDHL’s drug will probably be effective, as there’s some separate fairly compelling evidence suggesting that RHB-104 is effective against MAP. I never like to stack assumptions atop assumptions like that, though, which is why I’m ultimately going to say that this is possible, not probable.

Personally, I don’t think that MAP is exclusively responsible for Crohn’s. I suspect that Crohn’s disease is a combination of genetic susceptibility and infection from a handful of possible causes.  Even so, RHB-104 just might work. We should see interim data sometime within the next few months.

Prediction for RHB-104: Possibility for Phase 3 Approval

Unfortunately, I don’t feel comfortable putting the stamp of approval on this one. Even so, with BEKINDA and RHB-105 likely to receive approval, I think $RDHL is a buy.

If you liked this article, please subscribe to the newsletter – in addition to seeing new posts, my subscribers also get updates, news, and advice that isn’t available to people just reading the articles.

Redhill Biopharma ($RDHL)’s Drug BEKINDA will likely pass Phase 3 sometime in 2H2017

Today’s post took me much longer than normal to write. I had a lot of difficulty finding a company that fit my normal criteria – established, but not an industry leader; at least one phase 3 candidate in the pipeline; and so on. I think, however, that the effort was worthwhile. Redhill Biopharma ($RDHL) has a handful of drugs which are very intriguing to me, and I hope to cover their drug for Crohn’s Disease in a future post. Today, though, I’m writing about Redhill Biopharma ($RDHL)’s drug BEKINDA (not an acronym, just an all-caps name for some reason). As always, if you don’t care about the details, feel free to scroll to the end.

BEKINDA, formerly known as RHB-102, is an extended-release formulation of the generic drug ondansetron (commonly known under the brand name Zofran). Ondansetron is an anti-emetic (anti-vomiting) drug, and is used to prevent vomiting in patients undergoing cancer treatment or surgery. Ondansetron is also frequently prescribed off-label for children suffering from acute gastroenteritis (AGE). AGE is something of a catch-all term for “an upset stomach caused by some sort of bug.” When people say “stomach flu,” they’re talking about AGE.

Interestingly, although the use of ondansetron has been studied fairly extensively in children suffering from gastroenteritis, there is almost no data on the use of ondansetron in adults suffering from AGE. And even in children, the use of ondansetron is technically off-label. With all of that background, hopefully it makes sense that RDHL’s formulation of ondansetron, BEKINDA, is intended to be a better method of treating the stomach flu.

While I was evaluating the BEKINDA’s chances in the phase 3 trial, I decided that approval would come down to three things:

  1. Is the drug likely to be effective?
  2. Is the drug likely to be safe?
  3. Did RDHL establish a realistic study protocol?

Is BEKINDA likely to be effective in treating AGE in the phase 3 trial?

In short: yes. As mentioned above, ondansetron is already widely used to treat children with gastroenteritis. A well-designed study found that ondansetron was – in nearly every conceivable measure of effectiveness – statistically superior to both placebo and a European anti-vomiting drug known as Domperidone in treating AGE.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120790/#pone.0165441.ref015
From Marchetti et al., 2016, PLOS one

The success of BEKINDA, which is simply a delayed-release pill containing ondansetron, is probably presaged by these results. Although the data above was for children, there’s no real reason why it wouldn’t hold true for adults, as well. The one caveat here – and I’ll return to this later – is that the data from the table above was taken during the emergency department (ED) visit, meaning it was short-term data.

Is BEKINDA likely to be safe in the phase 3 trial?

To summarize again: yes. There are a few contraindications for ondansetron, but the advantage of reformulating a well-known drug is that all of the kinks have mostly been worked out (or at least discovered). I forsee no significant safety issues in this trial.

Did RDHL establish a realistic study protocol? Will BEKINDA pass phase 3?

This is always the tricky one to answer. Earlier in this article I mentioned that most (if not all) of the data for ondansetron is collected over a very short time period – usually over the course of a few hours – while the study protocol is a bit longer than that. The primary outcome measures of the BEKINDA phase 3 “GUARD study” are the proportion of patients

  • without further vomiting,
  • without rescue medication, and/or
  • who were not given intravenous hydration

from 30 minutes after the first dose until 24 hours later.

The length of time might be a problem, because when the researchers from the study cited above followed up 48 hours after the emergency room visits, they found that there was no longer any difference between the three conditions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120790/#pone.0165441.ref015
From Marchetti et al., 2016, PLOS one

This isn’t really surprising, considering the nature of the drug and the fact that any kids taken to the emergency department for vomiting were likely too sick to get better in one day. The question, though, is whether BEKINDA’s extended release formulation will be enough to overcome this hurdle.

Without phase 2 data to draw on, I turned to the next best thing: a bioavailability study. The only study I could find tested RHB-102 (which became BEKINDA) against the dose of ondansetron used in chemotherapy. Over the course of 5 days, the bioavailability of BEKINDA was either equal to or better than the routine dose. And even better, when researchers tested blood concentrations 24 hours after the initial dose, BEKINDA beat out a non-extended release equivalent dose.

Ultimately, I think that yes, the GUARD study is realistic, and RDHL will likely take home a phase 3 approval.

Conclusion

If BEKINDA posts good data (expected to take place sometime in the second half of this year), it will become the first drug in its class to treat acute gastroenteritis. If the study posts particularly strong results, it may even be possible that just the one study will be sufficient for FDA approval. To summarize, ondansetron (the drug making up BEKINDA) is effective, the study protocol is achievable, and the extended-release formula appears to work.

Based on what I’ve written here, I believe that $RDHL is a buy, for at least until the BEKINDA data is released.

If you liked this article, please subscribe to the newsletter – in addition to seeing new posts, my subscribers also get updates, news, and advice that isn’t available to people just reading the articles.

Prediction: Phase 3 Approval

The drug underlying BEKINDA has already been demonstrated to be effective, and a bioavailability study suggested that the extended-release formulation works.