Depression, anxiety and related disorders are serious conditions where treatment is – in many cases – not adequately addressed by existing psychiatric or psychological therapies. Naomi Pearce, CEO and MD, and Alex May, senior associate, of life science patent lawyers, PearceIP, discuss the patenting of psychedelic medicines based on known and new chemical entities
Despite the efforts of those seeking to develop novel treatments for mental health conditions, the past two decades have yielded very little by way of new medicines. The costs involved in developing candidate drugs, conducting pre-clinical studies and clinical trials are significant, and the failure rate in the clinic appears to be considerable.
It has proven similarly difficult to develop novel pain medicines. Many of the existing treatments have serious shortcomings, such as a high risk of addiction or profound side effects. Again, clinical trials of candidate drugs for treating pain-related conditions appear to often fail.
Natural and synthetic psychedelics
For many years (and in some cases, centuries), psychedelic compounds have been known to offer relief to those suffering from the above conditions. It is interesting to note that approximately 50 clinical trials of psychedelics are currently underway, notwithstanding the universal difficulties involved in obtaining government approval to conduct clinical trials using generally prohibited substances (narcotics). Most trials of psychedelics that have reached phase II or beyond relate to the above conditions.
Psychedelics currently in clinical trials include both natural and synthetic compounds.
The natural psychedelics include psilocybin/psilocin, N,N-dimethyltryptamine (DMT)/5-methoxy-DMT (5-MeO-DMT) and mescaline. Psilocybin and psilocin can be extracted from numerous species of fungi found around the world. When ingested, psilocybin is metabolised to psilocin, which is the active compound (extracts of the Psilocybe genus of mushrooms ‒ magic mushrooms ‒ are also the subject of clinical trials). DMT and 5-MeO-DMT can be extracted from many plant species and are a component of ayahuasca tea (which is also the subject of a clinical trial). Mescaline can be extracted from peyote and other Central and South American cacti.
Each of these natural psychedelics has also been synthesised: psilocybin and psilocin were first synthesised at Sandoz in 1958, DMT at the University of Manchester in 1931 (and 5-MeO-DMT five years later) and mescaline at the University of Vienna in 1918.
The synthetic psychedelics include ketamine, methylenedioxymethamphetamine (MDMA) and lysergic acid diethylamide (LSD). Ketamine has been in common use as an anaesthetic for many years and was first synthesised at Wayne State University in 1962. Subsequently, the S(+) enantiomer of ketamine, referred to as esketamine, was isolated and marketed by Pfizer as an anaesthetic, Ketanest. The R(-) enantiomer has also been isolated. MDMA was first synthesised at Merck in 1912 and its S(+) and R(-) enantiomers have since been isolated. LSD was first synthesised at Sandoz in 1943, along with 2-Bromo-LSD, an LSD derivative that does not have psychedelic properties.
Known chemical entities
The fact that all the above-referenced psychedelics are known chemical entities will ‘trump’ the often-contentious issue of whether natural products are patentable. In each case, their chemical structures and methods for their synthesis were disclosed many years ago. Therefore, none of these compounds are patentable as such.
That does not mean that patents cannot be obtained in respect of any of these substances. There are different ways in which patent protection may be obtained for these compounds, although the scope of protection afforded by a secondary patent is not as comprehensive as a patent to the compound itself.
Importantly, in some jurisdictions, the inability to obtain a patent to a psychedelic compound itself may mean that any patent covering a medicine containing one of these compounds may not be eligible for a patent term extension (PTE), which will diminish the length of the monopoly available, and with it the commercial return on investment.
On the other hand, medicines based on known psychedelics should in theory have a head start in the development process – much information should be available as these compounds have been used by humans (at least recreationally) for many years.
Psychedelics already on the market or in clinical trials
The only psychedelic compound so far approved to treat one of the above conditions is esketamine in Janssen’s Spravato nasal spray for treatment-resistant depression. Spravato was approved by the FDA in March 2019 and by the EMA in December that year. Other regulatory bodies around the world, including in Australia, have since followed suit. As noted above, esketamine was a known compound; it had already been isolated and marketed as an anaesthetic. Therefore, esketamine is not subject to compound patent protection in some jurisdictions, including Australia, and secondary patents relating to Spravato may not be eligible for PTE.
The psychedelics currently the subject of clinical trials around the world1 at present include as their active pharmaceutical ingredient psilocybin; psilocin; Psilocybe extract; DMT; 5-MeO-DMT; ayahuasca tea; mescaline; ketamine; esketamine; arketamine; MDMA; R-MDMA; LSD; or 2-Bromo-LSD. Unsurprisingly, these are all known chemical entities.
Until relatively recently, when attitudes regarding the use of psychedelics in medicine changed, there was little motivation for drug discovery or pre-clinical assessment of drug candidates in this field, so one would expect known chemical entities to be the first to enter clinical trials in this emerging field.
Psychedelics in pre-clinical development
The psychedelics currently at the animal or in vitro testing stages2 include (in addition to the compounds mentioned above): a psilocybin derivative; psilocin prodrugs, derivatives and analogues; a deuterated psilocybin prodrug; DMT analogues; and a 5-MeO-DMT analogue.
The sponsors of such compounds do not generally disclose their chemical structures until drug candidates enter clinical trials, to preserve the patent position for the product. The sponsor should seek to patent the compound before it discloses the compound publicly. Such compound patents are also likely to be prima facie eligible for PTE.
As the early drug discovery stage seeks to identify potential drug candidates for pre-clinical testing, the psychedelic compounds being studied at this stage of development are numerous and confidential, though the most promising amongst them will likely be revealed at a later stage of development.
Example claims over new chemical entities
The following patent claims would in principle be available where the psychedelic compound is a new chemical entity. These are claims to psychedelic compounds per se, which protect the compound in whatever form and for whatever purpose it is used. Such claims would not be available for known chemical entities.
- A compound of formula (I), wherein R1 is [an acceptable functional group], R2 is [an acceptable functional group] and R3 is [an acceptable functional group]. Any known chemical entities would be excluded from the scope of the claim based on one or more of the R groups not being acceptable or a different Markush structure
- A compound of formula (I), wherein the compound is [preferred compound]. The preferred compound would be a new chemical entity
- A compound of formula (II) [Markush structure], wherein X1 is deuterium. The compound of formula (II) could be a known psychedelic compound, except that deuterium replaces hydrogen at X1
- A prodrug of [known psychedelic compound].
It is an exciting time in the development of new drugs for treating depression, anxiety, pain and related conditions. The relatively recent change in attitudes relating to the medicinal use of psychedelics has opened a whole new class of compounds for drug development. The compounds currently making their way through clinical trials are all known chemical entities with known psychotropic effects. It would not be surprising to see a number of these compounds succeed therapeutically where conventional candidate drugs have failed.
Equally exciting are the psychedelic compounds currently at the pre-clinical stage. If these new chemical entities can surpass the performance of existing treatments, they will be deserving of their more comprehensive patent coverage and the greater profitability that flows from their potentially extended patent terms.
1 Based on information from Psychedelic Alpha: https://psychedelicalpha.com/data/psychedelic-drug-development-tracker