Welcome to your weekly digest of approaching regulatory and clinical readouts. In the coming months phase III data are expected from Johnson & Johnson's (NYSE:JNJ) antidepressant esketamine, an analogue of ketamine whose selling point could be its nasal administration; however, hallucinatory side effects could put a damper on its commercial prospects.
Also offering an alternative route is NeuroDerm's (NASDAQ:NDRM) high-dose levodopa/carbidopa, ND0612H. This is continuously delivered via a belt pump for advanced Parkinson’s disease patients, and will generate phase II data in the first quarter. Its US path to market might have become less risky since the FDA agreed to pharmacokinetic studies in place of phase III trials.
Esketamine is being tested in treatment-resistant depression, and Clinicaltrials.gov lists two phase III trials, Transform-2 and Transform-3, expected to be completed in March and July respectively.
The studies switch patients from prior antidepressants, to which they have not responded, to either intranasal esketamine plus a new oral antidepressant or a new oral antidepressant plus intranasal placebo. Transform-3 is enrolling patients over the age of 65 while Transform-2 is for those between 18 and 64.
The primary endpoint for both trials is change from baseline in the MADRS depression scale at week 4, and both test flexible dosing.
Ketamine was historically used as a general anaesthetic, and esketamine, its S-enantiomer, is J&J’s most advanced CNS project, due to be filed next year. 2022 revenues are expected to reach $491m, according to EvaluatePharma sellside consensus, while Jefferies analysts have pegged peak sales at a hefty $3bn.
The phase II Synapse trial showed statistically significant improvement of depressive symptoms in patients taking intranasal esketamine versus placebo. Adverse events were similar to those previously observed with ketamine, including headache, hypersomnia, nausea, sedation and dissociative symptoms.
However, any psychotomimetic side effects will be closely monitored, and could lead to esketamine getting a restricted label. Allergan has its own NMDA modulator, Rapastinel, which is delivered intravenously and which according to Leerink analysts has not shown hallucinatory side effects so far. This is in phase III for major depressive disorder.
Meanwhile, NeuroDerm's 006 phase II trial is testing the use of ND0612H, a high-dose version of the product, over an extended period of 24 hours to evaluate whether this confers a benefit over 14-hour daytime dosing. Night-time dosing could improve a patient’s quality of sleep and produce an extended morning “on” time. 38 patients with advanced Parkinson’s disease have been enrolled, and the primary measure is change from baseline to day 28 in daily “off” time.
The project delivers high subcutaneous doses of levodopa/carbidopa into the bloodstream via a small belt pump, which the company says is unlike other infusion systems that have to be surgically routed to the small intestine. It is designed for advanced Parkinson’s disease patients with motor fluctuations that cannot be adequately controlled with oral therapy.
The US FDA last year told NeuroDerm that it could perform pharmacokinetic equivalence trials in the US, as opposed to phase III efficacy studies. The company is therefore discontinuing phase III preparations, and has suspended its Indigo trial for low-dose ND0612, known as ND0612L ; its shares rose 26% on the news, as the comparative trials will most likely be smaller and quicker.
Thus, armed with positive phase II data, NeuroDerm would likely require only to demonstrate equivalence to Abbvie's Duopa, a levodopa/carbidopa gel delivered by a 16-hour pump directly into the duodenum via a tube fitted by endoscopic gastrostomy. These trials are due to start in the coming months, while a bioequivalence pathway is already being pursued in Europe.
A long-term safety trial called Beyond will now include an additional 50 patients on a different dosing regimen, and after results are reported next year it will form part of the NDA submission.
Duopa was approved in the US last year for the treatment of motor fluctuations in Parkinson’s, and has orphan drug designation in the US and Europe.
Jefferies analysts note that Duopa's orphan status could be broken, potentially setting a new precedent, should NeuroDerm demonstrate bioequivalence alongside the added safety benefits of not needing surgery.