While opioids continue to be the sweeping force behind global use disorders and the catalyst for pharma involvement in the broader substance use disorder (SUD) indication, stimulants are stepping into the limelight with the support of academia, agency, and industry.

As reported by biotechnology trade association BIO in February 2023, the past ten years have seen an estimated $130m venture investment directed towards addiction therapeutics – a stark contrast to oncology programs which have received 270 times greater investment.

In addition, as outlined in a 2023 World Drug Report released by the United Nations Office on Drugs and Crime (UNODC), an estimated 39.5 million people were affected by drug use disorders in 2021, only one in five people received treatment.

Most of the treatment focus has been on opioid use disorder and that comes down to the lack of stimulus for innovation in stimulant use disorders, explains Jeffrey Reich, CEO of biopharma Sparian Biosciences. However, that will change quickly and is actively changing now. With the US Food and Drug Administration (FDA) releasing its first-ever draft guidance for stimulant use disorders in October 2023 and academia continuing to drive innovation in the space, experts underscore the need for comprehensive endpoints and active pharma involvement to expedite drug development for this critically unmet need. 

Navigating challenging heterogeneity

The challenging issue with stimulant use disorder clinical trials boils down to the heterogeneity of the disorder. With the heterogeneity in both use patterns and the consequences related to use, the resulting pool of participants entering a trial is quite mixed, explains Brian Kiluk, associate professor of Psychiatry at Yale School of Medicine. As most medications are limited to treating a certain percentage of the participant pool, having a heterogeneous sample makes it harder to detect treatment effects.

“The heterogeneity across individuals with stimulant use disorders is profound. Diagnosis for a clinical trial is based on DSM-5 criteria but the aetiology of getting a diagnosis of use disorder, its progress, or how it gets resolved isn’t really defined by a DSM-5 criteria,” says Kathryn Cunningham, a professor in the Department of Pharmacology and Toxicology at The University of Texas Medical Branch at Galveston.

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The DSM-5 is the standard which clinicians and researchers use to diagnose stimulant use disorder. There are 11 symptomatic criteria, which characterise the disorder and the number of criteria a patient meets determines the level of severity of the disorder.

How the field has operated in the past number of years to mitigate the heterogeneity of stimulant use disorders in clinical trials is to enrol patients that are moderate or severe in terms of their disorder. This means that a patient must meet four or more criteria to be enrolled in a study, explains William Stoops, a professor in in the Departments of Behavioral Science, Psychiatry, and Psychology at the University of Kentucky. The logic behind this threshold is that there is more likely to be overlapping symptoms in groups of patients that meet five criteria versus in groups of patients that meet any two out of the 11 criteria.

“There are so many different types of stimulants, their route of administration can differ—intranasally versus smoking versus injection—and the way that a stimulant is measured is not standard,” says Kiluk.

With alcohol, there is a defined standard that can be used to measure equivalence across different types of alcohol. Conversely, there is no set standard for illicit substances like stimulants because they come in many different forms and are sold in illegal black markets. This makes it difficult to distinguish how much substance is being consumed.

Craving is a valuable endpoint

“With the heterogeneity of the disorder—people using at different rates, different amounts, and different types of substances—it is difficult to figure out what amount of decrease or reduction would be valuable or deemed clinically meaningful, explains Kiluk, whose research group focuses on identifying clinically meaningful indicators of treatment benefit aside from a sustained period of abstinence. Kiluk believes that demonstrating a reduction in use (in severity) on a predetermined scale of use would be a clinically meaningful measure.

In clinical trials, people need to meet the DSM-5 disorder criteria to enrol in the trial. But there is usually never any follow-up assessment of whether the patient still meets the criteria at the end of the trial or during a follow-up period, says Kiluk. Since the DSM-5 criteria reflect meaningful symptoms of the disorder, demonstrating changes in the severity of those symptoms could be a meaningful outcome as opposed to demonstrating changes in the number of days of use or amount of use, he adds.

One such meaningful symptom is craving, say Stoops and Cunningham. “Craving is a diagnostic criterion, but the FDA does not recognise craving as a measure in a clinical trial that will figure into the request for approval,” says Cunningham. If a patient spends the day preoccupied with wanting to use cocaine or methamphetamine, this is an indication that they are not able to engage with their immediate surroundings. Craving the drug is a clinically significant impairment because it ultimately negatively impacts an individual’s life in a significant way.

Typically, a given medication will impact the actual frequency or quantity of use of the substance by targeting physiological aspects of the substance such as the desire for use, tolerance of use, and withdrawal explains Kiluk. However, frequency and quantity of use are not factors on the DSM-5 criteria when a patient is diagnosed with the disorder. So, there needs to be a way to link symptom criteria with reduction in use to capture the significant aspects of the disorder. 

Adherence makes or breaks trials

Where current stimulant use disorder trials fall short is verifying adherence. “It is hard to verify adherence and frankly, some medications have failed simply because patients weren’t adhering to the regimen of treatment,” says Stoops.

Oftentimes in substance use disorder trials, the measurement of success is abstinence that has been confirmed using a biological measure such as a urine test. This is different from other trials in psychiatric conditions where there is not a biological indicator of the disorder, explains Kiluk. So while having a biological measure is a benefit for the substance use disorder treatment field, it also makes evaluation quite challenging in the sense that if a trial relies on data from a biological indicator such as a urine sample, practical and logistical hurdles such as frequency of urine tests and adherence of testing need addressing, he elaborates.

Over the next few years, the industry will see many improvements in self-report data that correlate to the sophistication of technology, says Reich. Technological and digital advancements will help validate data and allow for the collection of much more sensitive and accurate markers of usage than a simple diary. 

Pharma neglect gives academia indication reign

As per GlobalData’s Clinical Trials Database, nearly 80% of clinical trials for addiction treatments are sponsored by academic institutions.

GlobalData is the parent company of Clinical Trials Arena.

“Academia has the clinical trial expertise and the clinical expertise. But there has to be a transition to industry to allow for larger scale studies that are registrational quality,” says Reich. The problem is the disconnect between pharma and academia which is exacerbated by the simple lack of interest from pharma. There is a significant therapeutic void to what is a critical unmet public health need, but big pharma and biotechs don’t invest in this space, he adds.

The lack of pharma involvement in the indication is worrying, says Stoops. However, the guidance makes it clearer and easier for the industry to enter the space and also highlights that the indication has a high and unmet need. And where there is a need for intervention, there is a subsequent profit to be made.

“Methadone is not a moneymaker, but buprenorphine has been developed and formulated by many different companies. So, there is a visible profit margin,” says Stoops.

“Every therapeutic application is an ecosystem,” says Reich. For pharma to invest in stimulant use disorder, they need to see that the indication generates returns and has a sustainable market with reimbursement; there needs to be addressable demand and the personnel with the capability to treat the population, he explains.

He adds: “The ecosystem is there, and it will develop as we’ve seen with many indications when there are new drugs available: the indication fosters and cultivates that ecosystem. Pharma just needs to recognise it.”