New Huntington Disease Drug Is Safe, but Is It Effective?

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Prana Biotechnology's (NASDAQ: PRAN  ) Huntington disease drug, PBT2, is safe, but whether it helps patients enough to get approved remains to be seen.

The press release headline "Prana Announces Successful Phase 2 Results in Huntington Disease Trial" sounds good, but the primary endpoint of the phase 2 trial was safety, not efficacy, so it wasn't that high of a hurdle to jump over.

"There were no substantial differences in adverse events across the two PBT2 dose groups and the placebo group," the press release said. Yee-haw.

Moving on
Because let's face it, the Food and Drug Administration isn't going to approve a drug just because it's safe. It has to do something to help patients.

Prana ran a bunch of efficacy tests on the patients, measuring cognition, motor skills, function, and behavior. Only one test of cognition was statistically significant.

I've heard many people argue that's data mining. And on some level, it is; the more measurements you make, the more likely it is that something will come back as statistically significant, even if it's just an artifact.

But I think investors should give Prana Biotechnology the benefit of the doubt, here. The hypothesis is that PBT2's mechanism of action -- reducing metal mediated toxicity -- can improve cognitive function. It appears the other tests were performed to be thorough rather than because anyone expected an actual improvement. For motor function, for instance, PBT2 doesn't act on dopamine levels, so it's unlikely it would improve motor function.

The trial results would have had a lot more weight if Prana had listed cognitive function as a co-primary endpoint with safety and left the other tests as secondary endpoints. Of course, if they had, and the cognitive test wasn't statistically significant, the company would have had a hard time justifying moving PBT2 into a phase 3 trial.

Alternating numbers and letters
The Trail Making Test Part B, which showed a statistically significant improvement, requires patients to draw a line from points alternating numbers and letters: 1-A-2-B-3-C, and so on.

Here's how the patients in the different dosing groups did after taking the drug for 26 weeks.

Source: Prana Biotechnology.

I'd feel a lot more confident if the 100 mg dose was closer to half way between the 250 mg dose and the placebo group. While a dose-dependent efficacy would be a good sign, it isn't necessarily a sign that the improvement at 250 mg is an artifact; some drugs have a threshold that needs to be reached before they start working.

More importantly, while the difference was statistically significant, it isn't clear to me if the FDA will see the difference as clinically meaningful. The Trail Making Test Part B is designed to test executive cogitation, the ability to problem solve and be flexible in situations that demand it. The FDA will need to be convinced that the difference translates into a meaningful improvement in Huntington disease patients' lives.

Prana plans to meet with the agency to work out details for a larger phase 3 trial.

A sign of things to come?
Prana is also testing PBT2 in a phase 2 trial in Alzheimer's disease, which is scheduled to read out in March. The hypothesis is that metals, which PBT2 binds up, may be leading to cognitive decline in both diseases. Like the Huntington disease trial, it's a phase 2 proof-of-concept trial, making it hard to handicap.

The good news is, the trial's primary endpoint is a measurement of efficacy rather than just safety, like the Huntington disease trial. The bad news is, the primary endpoint is the level of amyloid plaques in patients' brains, which is a rather indirect measure of efficacy, and it's still hotly debated whether amyloid plaques are a cause or an effect of Alzheimer's disease. Investors should pay more attention to the cognition tests, which will be run as a secondary endpoint.

Good buy?
For the most part, investing in neurodegenerative diseases is a crapshoot.

Not that it stops companies from trying. Merck (NYSE: MRK  ) recently moved MK-8931 into a phase 2/3 study last year. Eli Lilly (NYSE: LLY  ) is testing solanezumab in a large phase 3 trial despite previous failures of the drug.

I can't really blame companies for proceeding. The potential market is so large, it's not hard to justify paying for the clinical trials even if the chance at success is less than 50%.

The obvious difference between investing in Merck or Eli Lilly and investing in Prana is that the failure of trials by the large pharmas won't kill the company. If you're going to invest in Prana, make sure it's money you can afford to lose. At a market cap under $400 million, there's a lot of upside if PBT2 works in Huntington or Alzheimer's disease, but it doesn't come without a lot of risk.

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Read/Post Comments (3) | Recommend This Article (10)

Comments from our Foolish Readers

Help us keep this a respectfully Foolish area! This is a place for our readers to discuss, debate, and learn more about the Foolish investing topic you read about above. Help us keep it clean and safe. If you believe a comment is abusive or otherwise violates our Fool's Rules, please report it via the Report this Comment Report this Comment icon found on every comment.

  • Report this Comment On February 19, 2014, at 7:46 PM, GroverNeuse wrote:

    Happy to see a balanced story regarding Prana.

    I was wondering if you can comment on the significance of the open label extension of the IMAGINE trial for Alzheimer's.

    Also a small point: if you listened to the conference call, it was clear the only reason Prana called the trial a success was because of safety. Period. Dr. Tanzi was clear on that; he said he was encouraged by the secondary endpoints, but stated that because of the profiles of patients chosen and the protocol used, he really didn't expect statistically significant findings.

    I bring this up because it is being implied that somehow Prana is "spinning" the findings.

    If you listen to the call, you know that is just not correct.



  • Report this Comment On February 19, 2014, at 8:09 PM, sajmal wrote:

    Clear explanation. Thanks. Couple of points:

    1) No telling if increasing dosage to 500mg results in exponential improvement.

    2) These are pure-plays. If successful, the upside is a lot more than at big pharma.

    3) Their progress on cognition coupled with others' progress on motor skills etc. will/could result in a drug cocktail. Think about how we overcame AIDS.

    4) Encourage these small companies to keep going. They bring fresh thinking, are not handicapped by big company quarterly results and R&D priorities, and are nimble and driven.

    5) Statistical significance is not a fluke. You get a z score within your p (probability) and q (quality) ranges and you can begin to get confident about future outcomes.

    So, not disagreeing with you. Just adding my 2 cents. Thanks for your note. Full disclosure: I am invested emotionally and financially.

  • Report this Comment On February 20, 2014, at 1:56 AM, cmarystewart wrote:

    Thank you Brian for a clear article. It outlines both the upside and the risks though I agree with sajmal that the upside from a successful drug is much higher for a pure play than it is for big pharma so you if you are going to discuss the relative risk, you also need to discuss potential returns.

    It is good to see Motley Fool has decided to put someone with the appropriate experience to write on Prana.

    I did however think Prana deserved apology after the previous article by Leo Sun when he used the profile of the trial participants pre-trial (which was shared to show each group was evenly weighted) to assert that there was no meaningful impact from the trial. That was one of the sloppiest pieces of journalism I have ever seen. I note it has now been pulled.

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Brian Orelli

Dr. Orelli is a Senior Biotech Specialist. He has written about biotech, pharmaceutical, and medical device companies for The Motley Fool since 2007.

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