ACOR’s Phase 3 Drug CVT-301

Today we’re going to be doing some due diligence on Acorda Therapeutics’ [$ACOR] Phase 3 drug CVT-301. $ACOR actually has two drugs in third phase clinical trials, but we’ll cover the other one later. ACOR’s phase 3 data for CVT-301 is scheduled to be released sometime in Q1 of 2017.

Summary

The Phase 2 data for CVT-301 looked great. However, the Phase 3 trials are scheduled to be a lot longer, which will provide a lot more opportunities for safety issues and for the drug to stop working as well. I’m more concerned about safety issues than I am about the drug not working anymore; it’s not uncommon for patients to be on levodopa (what CVT-301 is) for a decade or more.

Ultimately, I’m going to go cautiously call this one a Phase 3 pass, but I wouldn’t bet the pharm on it (get it?).

Background

CVT-301 is a powdered, inhalable form of the common drug levodopa, which is currently the most effective oral treatment for the symptoms of Parkinson’s disease.  Even while using the oral form of levodopa, however, people afflicted with Parkinson’s often suffer what are called “OFF periods,” which are periods when the symptoms (shakiness, etc.) flare up . These OFF periods become more and more common with age and time spent using levodopa, with about 70% of patients suffering OFF periods by the time they’ve been on treatment for 9 years. CVT-301 is designed to be used when one of these OFF periods begins, with the goal of controlling the symptoms. Think of CVT-301 like an inhaler, but for the symptoms of Parkinson’s disease.

Research

The research behind CVT-301 looks pretty good, for the most part. The placebo was excellent (they used a lactose compound which had no effect but still had the subjects get a sensation in the lungs like the real drug did).

The design of the Phase 2 trial was relatively simple. The researchers gave the study group and the placebo group the drug inhaler, and told them to use it up to 3x daily when their symptoms flared up. At the end of each week, the researchers brought the subjects into the clinic, had a doctor confirm that they were in an OFF state, and then had them use the drug (or placebo) while recording the results for the next hour.

The effects of the drug were quite clear, which is a really good sign. In the first week of treatment, there was a significant difference between the real drug and the placebo at 10 minutes all the way through 60 minutes after use (when they stopped recording the results). In the fourth week of treatment, they used a bit more drug and the gap between the real drug and the placebo had actually widened, which is great. The treatment effect was really quite large, and the Phase 3 trial is testing the same measures, so a pass looks likely from that standpoint.

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Statistical power and the p-values both looked good. Safety data looked identical between the placebo and the real drug; a few people developed a cough from the drug but it wasn’t enough for anybody to stop taking the drug.

There was one major problem which hasn’t been resolved to my satisfaction. For some reason there was a significant difference in pre-trial levodopa usage between the study group and the placebo group. The study group was on a lower dosage of levodopa than the placebo group was. I have no idea why this happened.  It may have been intentionally designed by the researchers to try to get a strong effect, or it may have just been a quirk of the randomization. The fact that it wasn’t even discussed by the researchers suggests that it was probably intentional. Like I said, not great.

Upcoming Research

The Phase 3 studies are going to be a lot longer. Each of those studies is scheduled to last a year. In addition, the doses are being upped from a maximum of 3x daily to a maximum of 5x daily. As good as the Phase 2 data looked, the long duration and increased doses in the Phase 3 trial are making the risks of safety issues or efficacy issues much higher. As I mentioned above, I’m more worried about safety issues than I am about the drug not working anymore.

Fundamentals

There’s been quite a lot of insider selling over the last year — 157,000 shares worth, to be exact. There are always a lot of potential explanations for insiders selling their shares, but it can suggest that the people close to the company don’t expect the value of their shares to skyrocket in the near term. In this case it appears that most (if not all) of the selling is automatic selling, so that isn’t as much of a concern.

The balance statements for the company look fine. Unlike most of the biopharma companies we do due diligence on, ACOR actually has a profit stream coming in! This means that the success or failure of this drug won’t be as much of a binary event as it usually is. In other words, if CVT-301 fails it won’t kill the company, and if it succeeds their stock won’t triple overnight.

Conclusion

As good as the Phase 2 data looked, there’s still something that feels a little off to me about CVT-301’s chances for a Phase 3 pass. I’m going to tentatively mark this one as pass predicted, but I can really see it going either way. If something comes up to change my mind, I’ll update this post.

Prediction: Possibly Phase 3 Approval

Genocea Biosciences

Genocea Biosciences [$GNCA, market cap $131M] is a company that researches immunotherapies, focusing on the T-Cell component of the immune system. They claim to use a proprietary research platform called ATLAS, but there’s not a lot of info available on how ATLAS works or compares to other platforms.

Their chief candidate (in phase 2b trials) right now is a drug called GEN-003, a vaccine aimed at decreasing the severity and viral transmission rate of genital herpes. They are working on some cancer stuff as well, but it’s all smoke at the moment. Two things are exciting about GEN-003, should it be a viable therapy:

1) Their drug has so far shown comparable results to daily oral medication (i.e. valtrex), but GEN-003 is an annual injection.

2) If GEN-003 is successful, it will be one of the first-ever T-cell vaccines for an infectious disease. Some T-cell therapies are used to treat leukemia/lymphoma, but as far as I know, this would be one of the first commercially available T-Cell therapies for something other than cancer.

The latter point especially makes GNCA a prime buyout target if GEN-003 is successful. Remember the ATLAS thing? If they’ve successfully used it to create a widely-applicable T-cell vaccine, a large company will want that technology.

Gen-003

Here’s where we’re at so far.

In 2012, Phase 1 trials established that the concept would probably work and was safe.

In 2014 they started the first part of Phase 2 trials, using 6 different formulations of the vaccine to see which one worked the best.

In 2015 they started Phase 2b, a closer look at the 2 best-performing formulations.

The Good

In March this year, GNCA announced that they had positive 12-month efficacy results for their drug. The presentation is here. This is big, though — positive 12-month efficacy will probably be their phase 3 endpoint and determinant of drug approval. Hitting it here means that the NDA is pretty likely to be approved.

The next step for Gen-003 is the phase 2b trial (ongoing), which is comparing the two most promising formulations of the drug. GNCA estimates that they will meet with the FDA in Q1 of 2017 to discuss the end of the phase 2 period. Given the strong results in Phase 2, if the drug passes phase 2, a phase 3 go seems extremely likely.

The Bad

Their research seems pretty solid, on the whole, but there are two problems so far. First, they rolled the placebo group into a testing group after the drug administration and first datapoint (on day 28 of the trial). Basically they confirmed that there was a significant difference with the drug and no change for the placebo group, then rolled the placebo group. Given that the rest of the trial was just following up to make sure the results stuck around, this isn’tterrible, but it’s not great. I don’t know why they rolled the placebo group. Potential explanations include a need for more test participants and a desire to give the patients access to the real thing after the first datapoints showed a statistically significant difference between the drug and the placebo.

Second, in every trial far, GEN-003 has outperformed the placebo in viral shedding, but matched the placebo in actual lesion outbreak [results album] Potential explanations: a) viral shedding is determined in a lab, but lesion outbreak is patient-reported. It’s possible that there are some reporting issues there. b) placebo effect can decrease lesion outbreak (external symptom and immune mediated) but not viral shedding (asymptomatic, less immune mediated).

Summary

Although I’m not thrilled about the lesion thing, even if the drug only decreases viral load it could still be considered a success, as viral shedding is necessary for herpes transmission. The company itself seems to have a very positive outlook on GEN-003’s chances, and if you’re looking for a biotech that might deliver some spikes in the near term (expect a spike in Q1 2017 if Phase 2 is completed successfully) with good potential for longer term (6mos – 2yrs), GNCA is a good target.

Prediction: Phase 3 Approval

Disclosure: I own a stake in GNCA.