Malgré les réactions négatives au profil d'innocuité, les résultats Zygel de Zynerba sont en réalité assez normaux

Malgré les réactions négatives au profil d'innocuité, les résultats Zygel de Zynerba sont en réalité assez normaux

octobre 8, 2019 0 Par admin

Translating…

The confusing case of Zynerba (ZYNE) continues to show that the medical cannabis space is basically completely unpredictable. The stock is down about a third since announcing what it called positive results for its Zygel transdermal cannabidiol [CBD] treatment for various forms of childhood epilepsy. Traders didn’t see it that way it seems, even though the results at this stage were not that much different from the results of GW Pharmaceuticals’ (GWPH) Epidiolex. Both in terms of efficacy and safety, results for these two different forms of CBD treatment were qualitatively similar.

Safety

What traders appeared to respond negatively to in particular was the preponderance of adverse events in the trial and the fact that a small number of them were severe. 96% of patients experienced some kind of adverse event after treatment. 60% were deemed related to treatment, with most of these side effects being mild to moderate, the most common ones being application site dryness, site pain, and drowsiness. 10 patients reported a serious adverse event, with two of them being possibly related to treatment. 8 patients discontinued the study because of adverse events.

It wasn’t a particularly big trial, only enrolling 48 patients open label. Since the active ingredient here is the same as Epidiolex, we can compare the safety results here to an earlier trial of Epidiolex for similar epileptic disorders to see where on the map we are. An earlier study published in early 2017 for Epidiolex on 120 patients, 61 in the active CBD arm, was not much better than Zygel in terms of safety data. Both trials had a similar number of patients on active drug. 93% of patients in the CBD arm for Epidiolex reported adverse events, similar to Zygel’s 96%. 70.5% of these adverse events were deemed treatment-related. That was worse than the lower 60% deemed related to Zygel. 9 patients in the earlier Epidiolex trial in the CBD arm withdrew due to adverse events, (8 for Zygel) 10 adverse events were serious (same for Zygel), and 5 of those 10 were determined to be treatment related for Epidiolex versus 2 for Zygel.

There isn’t much use in dissecting every metric of the two with statistical rigor because these were both early-stage trials that expanded into bigger Phase III pivotal studies later. Also, the Epidiolex trial here was placebo controlled, and Zygel’s was open label. The general point though in comparing the two here is not to equate them, but just to put Zygel’s safety statistics in a bit of context. Its safety profile really isn’t that discouraging when looking at Epidiolex’s earlier results.

Efficacy

In terms of efficacy, results between the two at this stage were similar as well. For Epidiolex, 43% of patients in the CBD arm had a 50% reduction in convulsive seizures. 62% of caregivers reported anywhere between « Very much improved » to « slightly improved » on global impressions. For the Zygel trial, 55% of patients had a greater than 50% responder rate (better than Epidiolex) and a 51% median reduction in seizure frequency. See the table below:

FIAS and convulsive seizures

Month 1(n=33)

Month 2(n=33)

Month 3(n=33)

Month 4(n=32)

Month 5(n=32)

Month 6(n=29)

Median % reduction in seizure frequency

16%

44%

44%

47%

58%

51%

≥50% responder rate

30%

42%

46%

47%

63%

55%

These results should not be too surprising given that Zygel and Epidiolex are basically the same thing, just administered in a different way.

Unfortunately, the kneejerk reaction of the shares to the perceived negative results has inspired investigations into the company. They stem from the discrepancy between the company’s description of Zygel as « well-tolerated » versus the safety results above. This probably won’t amount to anything as « well-tolerated » is a relative term.

What About The Liver?

What is even stranger about the results reported and the reaction is that the potential advantages of Zygel over Epidiolex were not even explicitly reported in the data release. For Zynerba investors, what is important to know fundamentally is whether there were any abnormal readings in liver metabolism in Zygel patients. We could expect the safety and efficacy profiles to be relatively similar between the two relative to seizures, which they generally were, but what could end up being different based on the way the two drugs are administered would be specifically the effects on the liver. As I covered in my earlier Zynerba piece, elevated liver transaminases more than 3x above normal were detected in 13% of Epidiolex patients in the pivotal study that led to its approval. Less than 1% showed levels more than 20x above normal, in some cases requiring hospitalization.

Elevated transaminases are an indication of liver damage. These compounds are enzymes found in liver cells involved in the breakdown of proteins and if there is a higher level of them in the blood it indicates that liver cells are damaged and leaking them out. Since Epidiolex is ingested orally, it is metabolized first by the liver. Zygel however is absorbed through the skin and gets into the blood before it goes through the liver. What we do know is that a separate 20-patient trial published in August on patients with fragile X syndrome showed no clinically significant changes in liver function tests from Zygel, so there is reason to believe that transdermal administration may have solved that problem at least.

Fundamentally though, these results don’t tell us much of what we didn’t already know. Namely, that CBD is effective in treating pediatric seizure disorders and that side effects are common though generally mild. There doesn’t seem to be any fundamental reason for Zynerba to fall like it did simply because of the results as reported. It looks to be more of a function of investors confused about what it is they should actually expect from this class of drugs.

What can be said though is that at least now, the downside for Zynerba is less than it was before these results were published. So if you want to get in on this sort of speculative cannabis asset, then now would be a relatively better time to take a position, just mathematically speaking. I still wouldn’t recommend it though, because we still have very little idea of what sort of sales these drugs can command on the market. GW Pharmaceuticals sold about $100M worth of Epidiolex in the first half of 2019 according to its latest quarterly, though Zygel has years to go before it makes it to market let alone reaches these sorts of sales numbers. Therefore, valuation for this company is still way up in the air.

Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.


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