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Racing Beyond Racemic: A Look at Ketamine Drug Development Ahead of atai’s PCN-101 Phase 2a Readout

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This week, Psychedelic Alpha’s Noah Smith takes a look ahead to one of the most eagerly anticipated data readouts of the year, Perception Neuroscience’s (part of the atai platform) Phase 2a trial of PCN-101 (R-ketamine or arketamine) for treatment-resistant depression (TRD).

Here, Noah explores the history of ketamine and its two enantiomers (S-Ketamine, marketed as Spravato, and R-Ketamine), before providing a summary of Perception’s PCN-101 drug development program.

Ketamine: from Anesthesiology to Psychiatry

While it may not fit neatly into the ‘classical psychedelic’ mould, racemic ketamine (equal combination of S- and R-ketamine) has certainly become an important fixture in the realm of emerging, ‘next-generation’, or ‘breakthrough’ psychiatric treatments.

Since the early 1970s, the dissociative properties of ketamine have been leveraged for use in anesthesiology. However, following the publication of a small (n=7) study in 2000, ketamine began to gain attention for its apparent rapid-acting antidepressant effects. Since then, a wealth of research has emerged to corroborate these early findings. Today, in addition to its more traditional medical uses, ketamine is also prescribed as an off-label treatment (“using a drug for an illness or disease other than the authorised reasons for use”) for some psychiatric indications, such as depression.

Enter the Enantiomers: S-ketamine Marketed as Spravato

In the late 1990s, S-ketamine (or, ‘esketamine’), an enantiomer of racemic ketamine, began to be used for its anaesthetic and analgesic properties (see our August 6, 2021 Bulletin for a primer on enantiomers). However, like its racemic counterpart, the antidepressant effects of S-ketamine would pique the interest of researchers, and eventually the pharmaceutical giant Janssen (part of the Johnson & Johnson family).

Janssen began a program of developing an S-ketamine nasal spray treatment, which eventually assumed the brand name ‘Spravato’ (SPRAVATO®). In 2013, Spravato for treatment-resistant depression (TRD) received a breakthrough therapy designation (BTD) from the FDA. Three years later, the FDA would once again grant a BTD to Spravato, this time as a treatment for major depressive disorder (MDD) with suicidal ideation. 

In 2019, Janssen’s Spravato nasal spray was approved by the FDA for use alongside an oral antidepressant (OAD) as a treatment for TRD. A little over a year later, Janssen announced that the FDA had approved its supplemental new drug application, allowing S-ketamine to be used alongside an OAD in adults suffering from MDD with acute suicidal ideation or behaviour.

Practical Challenges: REMS, Reimbursement and Regulators

Despite data suggesting their efficacy as rapid-acting antidepressants (though, in the case of S-ketamine this has been prominently questioned; see Erick Turner’s 2019 article for more), the administration of both racemic ketamine and S-ketamine is often accompanied by some side effects that limit their therapeutic reach. Given their early use as anaesthetics, it is perhaps unsurprising that even at lower doses, ketamine and S-ketamine produce sedative and dissociative effects. These side effects of concern led to the establishment of a relatively restrictive Risk Evaluation and Mitigation Strategy (REMS) for Spravato. Consequently, Spravato is not to be dispensed for use outside of a certified healthcare setting. Additionally, patients who are administered the nasal spray treatment are to be monitored in a healthcare setting “for at least 2 hours”, among other restrictions stipulated by the REMS.

However, it is important to note that these REMS requirements don’t apply to racemic (‘normal’) ketamine formulations. Despite often being administered in a clinical setting, racemic ketamine has, over the last couple of years, increasingly been prescribed off-label for use as an at-home psychiatric therapy; a far cry from Spravato. 

Relaxed drug prescribing regulations in the US emerging from COVID-19-related restrictions enabled a market of ketamine telehealth providers to take off. Following the enactment of the Ryan Haight Online Pharmacy Consumer Protection Act, physicians were required to, in most cases, conduct at least one in-person patient assessment before a controlled substance could be prescribed. However, the requirement of an in-person evaluation was put on hold in 2020 in an effort to improve patient access to necessary treatments in light of widespread pandemic-related restrictions. 

Due to its abuse liability and dissociative effects, racemic ketamine is a Schedule III drug in the US. Consequently, prior to the relaxation of these drug prescribing laws, patients would have had to attend in-person consults with a prescriber in order to access racemic ketamine off-label as a psychiatric treatment. However, more relaxed prescribing laws have since allowed prescribers to conduct online patient assessments and have supported the facilitation of an entirely virtual ketamine therapy process. 

Companies such as Nue Life and Mindbloom have taken advantage of these regulatory changes to offer individuals living in some US states access to online ketamine therapy. Nonetheless, the at-home dosed ketamine sessions still require in-person support and monitoring from what these companies have described as a “Sitter” or “Peer Treatment Monitor”. Should a family member or friend act as a volunteer in this monitoring process, patients can certainly save on the healthcare delivery costs (see the significantly cheaper price of Mindbloom’s offering in the table below, for example) that add onto the often out of pocket financial expense of in-clinic racemic ketamine or appropriately supervised Spravato administrations.

Out of Pocket

To date, racemic ketamine has largely failed to make its way onto most public or private insurance plans for the treatment of mental health disorders. In fact, a 2022 retrospective cohort study of patients receiving intramuscular ketamine therapy found that of 2,248 clinic visits, 2,230 (99%) were paid for, in full, by the patient.

This lack of public coverage also applies to Spravato. Since 2018, Janssen has been trying to convince the UK’s National Institute for Health and Care Excellence (NICE) to recommend that the National Health Service (NHS) adopt Spravato as a treatment used in concert with an oral antidepressant (OAD) to treat its authorised indications.

In January 2020, citing uncertainties related to clinical and cost-efficacy, NICE issued initial draft guidance that did not recommend making Spravato available on the NHS for use within its marketing authorisation. The COVID-19 pandemic would subsequently delay the remainder of the appraisal process, and NICE wouldn’t issue its final draft guidance until the middle of 2022. 

However, in its final guidance, the institute again did not recommend S-ketamine. Citing the same critical uncertainties, NICE stated that S-ketamine was “unlikely to be an acceptable use of NHS resources”. Soon thereafter Janssen appealed the Appraisal Committee’s conclusions to no avail. Recently published post-appeal guidance shows that NICE has since sustained its earlier determination.

NICE’s recommendations (or lack thereof) are not the only time that concerns related to Spravato’s cost-effectiveness have been raised. Towards the beginning of 2021, the Canadian Agency for Drugs and Technologies in Health (CADTH) published a detailed pharmacoeconomic report of S-ketamine for major depressive disorder (MDD) in adults.

The agency found there to be a “1% likelihood that esketamine plus oral antidepressant would fall below the $50,000 per QALY” willingness to pay threshold (WTP) that is set by CADTH. As a result, “esketamine would require a price reduction of approximately 60% to be considered cost-effective versus oral antidepressant.”

These findings are important given the high direct drug costs involved in ketamine or S-ketamine treatments. For example, in its report, CADTH attributed an average annual cost of CAD $18,564 – $45,591 directly to the Spravato drug. Without reimbursements, access to these treatments is severely restricted.

However, the cost of the drug is not the only element of ketamine and S-ketamine treatments that lead to higher overall costs. Requisite supervision from medical professionals or ‘trained’ personnel, as well as suitable spaces to host the treatments, also introduces additional healthcare costs and resource barriers that can restrict access to these treatments.

While some have proposed concurrent in-person or virtual multi-patient monitoring as a cost-saving solution, scheduling these multi-patient sessions is sure to be a logistical challenge. From a time and accessibility perspective, the need to attend in-clinic treatment sessions can also act as a barrier to care for many prospective patients. These concerns are particularly relevant considerations given the in-person treatment models being pursued by many psychedelic drug developers.

The number of dosed in-person sessions any given patient might require across the acute, continuation, maintenance phases of their treatment will depend on, amongst other things, their response to the treatment and its durability. Accordingly, as with many medical treatments, the cost of ketamine or S-ketamine treatments appear to vary significantly patient-to-patient. 

Enter R-Ketamine: A Safe and Effective Alternative?

In spite of their promising efficacy, the aforementioned challenges limit the therapeutic reach and health impact of racemic ketamine and S-ketamine. However, early-stage research suggests that another ketamine enantiomer, R-ketamine, may be able to overcome the challenges that have, to date, limited the reach of its predecessors in psychiatry. 

Early Head-to-Head Studies of R- vs S-ketamine

Since the early 1980s, researchers have commented on R-ketamine’s lower anaesthetic and analgesic potency relative to the S-ketamine isomer. In fact, in 1985, White et al. described how, based on certain clinical endpoints used for assessing analgesic and anaesthetic effects, S-ketamine was found to be “approximately four times more potent” than R-ketamine. 

Given the historical focus placed on using ketamine as an anaesthetic or analgesic drug, the lower potency of R-ketamine certainly didn’t position it as a clinically advantageous alternative for surgeries and sedation. However, those same attributes that had previously limited R-ketamine’s clinical usefulness would later attract the attention of researchers investigating ketamine and its enantiomers as psychiatric treatments. 

In 1997, a study from Vollenweider et al. compared the psychopathology of both S- and R-ketamine. Through the study, researchers reported that unlike S-ketamine, equimolar doses of R-ketamine did not elicit “psychotic symptoms, but a state of relaxation and a feeling of well being” in healthy volunteers. The study also described how, “at 60% of a racemic dose S-ketamine produced virtually the same psychotic reactions as racemic ketamine”. From this, researchers postulated that S-ketamine may be the enantiomer responsible for the acute ‘psychotomimetic’ effects of racemic ketamine. 

Nonetheless, some participants dosed with R-ketamine reported experiencing, “a state of heightened awareness and sensitivity that was characterized by facilitated introspection, and a slight change in the sense of time, comparable to a meditative state.” These effects are, in retrospect, suggestive of R-ketamine’s therapeutic potential in psychiatry, even in the purported absence of substantial acute effects. 

Exploring the Potential of R-ketamine in Psychiatry

Beginning in the early 2010s researchers began to explore R-ketamine’s psychiatric therapeutic potential. In a 2013 publication from Zhang et al, researchers found that, in animal models, “R-ketamine produced rapid and long-lasting antidepressant effects.” Additionally, the isomer may lack many of the acute side effects that are characteristic of S-ketamine and the racemic mixture. 

This body of evidence would continue to grow through preclinical studies up until 2019, when researchers in Brazil initiated a small open-label pilot study (n=7) of IV R-ketamine for treatment-resistant depression (TRD) in humans. The results, published in 2020, point to R-ketamine’s ability to elicit “fast and robust” antidepressant effects in individuals with TRD. 

In statistical terms, a single 0.5 mg/kg IV dose of R-ketamine led to a mean reductions in MADRS scores from baseline of 20.3 points at day 1, 20.3 at day 3, and 16.7 at day 7. Citing important trial limitations and the difficulty of comparing outcomes across studies, the authors cautiously stated that R-ketamine produced “more potent and longer-lasting antidepressant effects” compared to both racemic and S-ketamine. 

Furthermore, due to its apparent lack of significant dissociative effects, R-ketamine was found to have a more favourable safety profile than racemic or S-ketamine. These findings are in line with the evidence generated through prior preclinical studies. 

While the small size of this first-in-human study certainly limits the generalizability of its results, the findings are, nonetheless, promising and significant. If, through larger pivotal studies, R-ketamine proves to be a more efficacious treatment with a more favourable safety profile, it would be well-positioned to overcome the aforementioned barriers that have limited the use of racemic ketamine and S-ketamine in clinical practice. 

Perception Neuroscience’s R-ketamine Candidate: PCN-101

The drug development company Perception Neuroscience has, for a number of years, been working to develop R-ketamine as a new psychiatric treatment option. As we discussed in a previous bulletin, in 2017 the company, under the leadership of Jonathan Sporn (who now heads up Gilgamesh Pharmaceuticals), entered into an agreement with Chiba University in Japan through which Perception gained exclusive rights over intellectual property and certain relevant patents related to R-ketamine. 

Chiba University has historically been a global leader in R-ketamine research. The university is home to Professor Kenji Hashimoto, one of the world’s preeminent and most influential researchers in the field. Since 2002, Hashimoto has been the most productive author on topics of R-ketamine and its antidepressant effects (He et al., 2022). The research conducted by Kenji Hashimoto and others at Chiba led to the generation of important intellectual property and certain patents that Perception now has exclusive rights over.

On November 5, 2018, (then) recently-founded atai Life Sciences moved to acquire a majority stake in Perception Neuroscience. However, the acquisition was not announced publicly until the start of 2019. While atai’s drug pipeline has grown since its acquisition of Perception Neuroscience  acquisition, its PCN-101 R-ketamine candidate remains one of its flagship programs. 

Beyond its more advanced R-ketamine program, the broader atai pipeline consists of both psychedelic and non-psychedelic compounds including ibogaine, DMT, an MDMA derivative, deuterated etifoxine, and deuterated mitragynine. This broad pipeline includes candidates that are being developed for use inside and outside of clinical settings to treat indications such as TRD, cognitive impairment associated with schizophrenia, generalised anxiety disorder, opioid use disorder, and post-traumatic stress disorder. 

In March 2021, atai’s Perception Neuroscience entered into an agreement with the Japanese pharmaceutical company Otsuka. Through this licence and collaboration agreement, Otsuka was granted “exclusive rights to develop and commericalize products containing PCN-101 in Japan.” Following the agreement, Otsuka provided Perception with a $20 million upfront payment. The agreement details how, moving forward, if “development and regulatory” and “commercial” milestones are satisfied, Perception is entitled to subsequent payments of $35 million and $66 million respectively. Also baked into the agreement are “tiered, double-digit” royalty obligations from Otsuka to Perception on net PCN-101 product sales in Japan. 

As was noted in a previous bulletin, it would appear that Otsuka has long been interested in the therapeutic potential of racemic ketamine, its enantiomers, and metabolites. A more detailed look at publications from prominent ketamine researcher Kenji Hashimoto reveals that the academic has previously received research support from Otsuka, with early declarations of this support found in R-ketamine-related publications from as early as 2014.  

Since the atai acquisition, Perception completed a Phase 1 safety and tolerability study of its PCN-101 R-ketamine candidate. Subsequently, in September of 2021, the company initiated a Phase 2a trial of PCN-101 as a treatment for patients suffering from TRD. The placebo-controlled study, which atai has described as a “proof-of-concept trial”, enrolled 102 participants across three trial arms and will assess changes in MADRS scores at 24-hours from baseline as its primary endpoint. The company has also announced a drug interaction study that was given the greenlight earlier this year. 

atai has been vocal about its aim to develop PCN-101 as an at-home treatment for TRD. This is perhaps unsurprising given the aforementioned challenges that patients might face in accessing ketamine or S-ketamine treatment, and R-ketamine’s ostensibly more favourable safety profile. 

If PCN-101 truly lacks the dissociative, sedative, and other adverse side effects as well as the abuse potential, the drug could, in theory, be bound to less restrictive risk mitigation requirements than those which are written into Spravato’s REMS. As a result, unlike Spravato, PCN-101 could foreseeably not require medical supervision during and after dose self-administration. Developing a drug that is not limited to use in certified healthcare settings is certainly one pathway towards a more accessible, and consequently scalable, treatment option. 

Flipping from IV to Subcutaneous

However, there are other important considerations and challenges that the company must work through before its vision for PCN-101 as an at-home treatment can be realised. In humans, R-ketamine has been, thus far, investigated using IV drug formulations. This is true for Perception’s ongoing Phase 2a trial, in which the company is studying different doses of an IV formulation of PCN-101.

While this route of administration (IV) is used by many ketamine treatment centres for in-clinic sessions, it is not a suitable means of delivering an at-home, self-administered treatment. To overcome this treatment barrier, atai has disclosed that it intends to leverage a formulation of PCN-101 for subcutaneous injection. To this end, atai has announced a new Phase 1 “relative bioavailability” trial of a subcutaneous formulation of R-ketamine that is set to begin in the first half of 2023. 

Subcutaneous delivery has long been an acceptable means of enabling a patient to self-administer drugs. Common examples include insulin, adalimumab (Humira), heparin, etanercept (Enbrel), ustekinumab (Stelara), and dulaglutide (Trulicity). This route of administration can be achieved using a range of different delivery devices. Traditionally, these have taken the form of preloaded syringes and autoinjector pens. 

More recently, technological advancements have led companies to develop new infusion pumps to support subcutaneous drug delivery. Bexson Biomedical is one such company working to develop an infusion pump that can be used to deliver a wide array of different drugs, including its own BB106 subcutaneous ketamine formulation. 

Subcutaneous delivery has certainly been lauded for its ability to enable at-home drug delivery and consequently greater access to care (Jones et al., 2017). However, should PCN-101 be brought to market, one would still expect there to be a need for a limited number of in-person sessions for patient education and teach-back to ensure individuals are familiar with how to properly administer the drug. Though, over the long run, there is no doubt that such a treatment would be more accessible than many alternative ketamine and S-ketamine therapy options. 

What To Watch For (Outstanding Questions & Concerns)

While existing evidence points to PCN-101 as being well-positioned to become a more accessible treatment than racemic and S-ketamine, its viability moving forward will be contingent on whether results from the company’s ongoing clinical trials can confirm its putative efficacy, safety, and tolerability.

If tweets from top executives at atai are reliable indicators, one might expect some of this evidence to arrive sooner rather than later. After all, the company has shared that it anticipates publishing topline data from its Phase 2a “proof-of-concept” clinical trial before the year’s end. 

Unfortunately, the limited scope of the study won’t allow for all questions to be answered. With the company studying the effects of a single dose, important factors such as long-term efficacy and the effect of repeat dosing won’t be answered until later stages of development.  

Regardless, this topline data should help shed more light on whether R-ketamine elicits dissociative or sedative effects at different dose levels. Additionally, it will provide the first placebo-controlled comparison of R-ketamine’s efficacy and durability in humans. 

So while ‘good’ results would surely de-risk the PCN-101 development program, they likely won’t be enough to determine whether R-ketamine will one day supplant its racemic and S-ketamine competitors.

And, of course, atai (via Perception Neuroscience) isn’t the only company with a horse in the race when it comes to developing new ketamine therapeutics…

We will provide snap analysis of the PCN-101 Phase 2a readout when it’s made available. If you haven’t already, consider joining our weekly Bulletin for more.