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The Race to Get a Cannabidiol Product Approved: Why Is It Taking So Long?
Several companies have been competing to get the first cannabidiol product to market. Both investor and patient interest are high but the recent news includes more setbacks. What is different about cannabidiol (CBD) products and what could Zynerba Pharmaceuticals, Inc. have done differently?
As we have previously blogged, there are currently no cannabis-derived drug products approved in the US. There are several synthetic tetrahydrocannabinol (THC) approved for anorexia associated with weight loss in patients with AIDS, and nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. These products have not enjoyed strong sales in the market. Issues with gastrointestinal tolerability and psychoactive side effects have been reported.
CBD (cannabidiol) is the second most prominent cannabinol in the marijuana plant and lacks the psychoactive properties of THC. Several companies are developing CBD products for rare epileptic seizure syndromes such as Dravet and Lennox–Gastaut. Several of these products have been granted orphan designation. Other indications being investigated clinically include various tumors, neurological, and psychological conditions.
GW Pharmaceutical’s (GW) purified cannabidiol product, Epidiolex®, is probably the most advanced candidate with positive Phase 3 results studies reported in April in children with Dravet syndrome. GW has at least 44 other clinical studies planned or underway for various indications. Insys has 9 cannabidiol clinical studies listed in the US, and Phytotech has two studies.
In the wake of GW’s positive results in children with Dravet syndrome, Zynerba Pharmaceuticals recently reported negative results for their Phase 2 study in adults with refractory epilepsy with focal seizures. A week later, Zynerba had similar bad news in their Phase 2 study with the same product, ZYN002-CBD Gel for an osteoarthritis indication.
There are several things that could account for the negative results in Zynerba’s studies. The first problem is the indication. Osteoarthritis is a difficult indication upon which to meet primary endpoints due to the high placebo effect.
Although it is a lucrative market, an osteoarthritis product would need to produce a very high effect size to overcome the high placebo effect and demonstrate efficacy. This is a risky proposition for CBD. The analgesic effects of cannabis are frequently attributed to THC rather than CBD. If CBD does have analgesic properties, studies would need to be adequately powered to demonstrate such an effect.
However, osteoarthritis is not the only failure for ZYN002. The product also failed to meet primary endpoints in an adult epilepsy study. Careful selection of the patient population may be important. There is less data suggesting that CBD is effective in preventing adult seizures as pediatric. The risk multiplies.
The next suspects are the route of administration and dosage form. ZYN002 is a permeation-enhanced gel for transdermal drug delivery into the system circulation. Without access to Zynerba’s pharmacokinetic (PK) data, we can’t say for sure, but we suspect some answers may lie there.
As the Phase 2 studies for both indications failed, and a dose-response relationship was lacking, close scrutiny of Zynerba’s PK studies is warranted. Camargo welcomes the opportunity to help Zynerba find solutions in the PK data or to propose the right studies, if needed, to solve the problems.
There may be problems with achieving adequate systemic levels of drug with the transdermal gel. These problems should be addressed as early as possible in a development program.
According to their press releases, Zynerba is requesting an end-of-Phase 2 meeting and preparing to continue to Phase 3 studies for both indications. Further, results from their Phase 2 Fragile X syndrome study are expected by the end of this month (September 2017).
At Camargo, we perform a thorough analysis of PK data to ensure the best chance of success in efficacy studies. We also assess the optimal indication, patient population, and study design to capture the effect of the product.
Camargo can provide a feasibility and drug development analysis early in your development program and follow-up with thorough PK assessments. Contact us to improve your chance of demonstrating the efficacy of your product.
Authors: Angela Drew, PhD, Product Ideation Consultant, Camargo Pharmaceutical Services
Ruth E. Stevens, PhD, MBA, Chief Scientific Officer, Executive Vice President, Camargo Pharmaceutical Services
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