Prodrugs and patents: enhancing therapy adherence and reducing side effects

Patients with schizophrenia experience symptoms such as hallucinations, delusions, confused thoughts and changes in behaviour. Credit: Alphavector / Shutterstock

As the approval date for Bristol Myers Squibb’s (BMS) schizophrenia drug KarXT (xanomeline-trospium) fast approaches, the schizophrenia field eagerly anticipates a potential breakthrough in a treatment area that hasn’t seen one in decades.

With a Prescription Drug User Fee Act (PDUFA) action date set for 26 September 2024, KarXT is backed by strong clinical data, showcasing its differentiated mechanism of action, robust efficacy, and a well-characterised safety profile.

Despite its potential, some have raised some concerns with the drugs’ twice-daily dosing schedule. Schizophrenia is a complex and chronic mental health disorder that demands lifelong treatment to manage its symptoms. The effectiveness of these treatments often hinges on consistent medication adherence – a challenge due to the side effects and rigid dosing schedules associated with traditional antipsychotics.

Sam Clark, CEO of Terran Biosciences, recognised an opportunity to retain KarXT’s formulation while optimising its dosing schedule to a more convenient once-daily oral regimen, and a multi-month injectable. This shift in focus brings attention to prodrugs – medications that start as inactive or less active, and once inside the body, are converted into the active form, usually through natural processes involving enzymes.

BMS declined to comment on this story or on Terran’s development of its own prodrug formulation.

However, Karuna Therapeutics – the original makers of KarXT, had previously discussed the importance of patients’ adherence to the drug. In a Q1 2023 earnings call, Karuna’s former CEO Bill Meury said that adherence to KarXT could be higher than the standard of care schizophrenia drugs: “We don’t have real-world experience yet. But we would expect that adherence with KarXT in the real-world setting could be higher, persistency could be longer and missed days of therapy lower,” he said.

On the same call, Karuna’s former chief commercial officer William Kane said: “Patients, typically about two quarters or 75% of them, will discontinue [taking medication] in the first 18 months, and that’s driven by a lack of either adequate efficacy or intolerability. KarXT may have the opportunity to really address both of those needs in the market.”  

Prodrugs have been around for a long time, with a notable example including codeine, which is a prodrug of morphine. Though not a new concept, researchers are becoming more innovative with how they can be used, said Barbara Slusher, PhD, director of the Johns Hopkins drug discovery programme.

Slusher is involved in the development of DRP-104 (sirpiglenastat), marketed by New York-based biotech Dracen Pharmaceuticals. DRP-104 is a prodrug of 6-diazo-5-oxo-l-norleucine (DON), a compound that was found to be effective against cancer, but also caused serious side effects in the digestive system.

The prodrug version is designed to become active in cancer tumours, while remaining inactive in the gastrointestinal (GI) system, curbing unwanted side effects. DRP-104 is now in Phase I/II clinical trials (NCT06027086) and is being developed under a FDA fast track designation.

Prodrugs can be used to enhance drug delivery, minimise side effects, and improve drug solubility and oral bioavailability, explained Slusher. “People use pro-moieties to direct the localisation of a prodrug, and enhance its tolerability profile. In our case [DRP-104], gets out of the gut, which we knew was the toxic site, and into the tumour, which is the active site,” said Slusher.

Whether it is to improve dosing schedules or curb side effects, prodrugs are here to stay. “We are very excited about the new thing we’ve made, which is a prodrug to improve bioavailability,” says Clark.

Originally developed by Karuna Therapeutics, BMS inherited KarXT as part of a $14bn acquisition which was finalised in March 2024. The combination drug is designed to target and modulate the muscarinic acetylcholine receptors in the brain, aiming to curb the side effects of traditional antipsychotic drugs.

The current treatment landscape for schizophrenia is dominated by dopamine-blocking antipsychotics, which have significant side effects like Parkinsonian symptoms, sexual dysfunction, and weight gain.

Stephen Marder, attending psychiatrist at UCLA’s psychosis clinic says nearly all antipsychotics cause weight gain. “That can also cause an increased vulnerability to developing type 2 diabetes, and that’s a very serious problem in people with schizophrenia who already have a vulnerability to developing diabetes and tend to have problems with obesity and other cardiovascular risk factors,” says Marder. Based on the data, Marder says it is unlikely that KarXT will be associated with weight gain or diabetes risks.

The excitement surrounding KarXT is mainly because it doesn’t seem to have these side effects and demonstrates an effect on both positive and negative symptoms of the condition. Positive symptoms refer to any change in behaviour or thoughts, such as hallucinations or delusions. Negative symptoms include a lack of interest in everyday social interactions, low mood, and the appearance of withdrawal from normal life. Data from the Phase III EMERGENT-3 trial (NCT04738123) showed that KarXT showed a 8.4-point reduction in Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at week five.

However, Clark says Terran’s value proposition is that it addresses a limitation with KarXT.

Medication non-compliance is one of the major issues in schizophrenia, leading to patients dropping below the treatment threshold, and causing more positive or negative symptoms, says Clark. Terran Biosciences is now developing two prodrug versions of KarXT, a once-daily oral candidate called TerXT, and a multi-month injectable called TerXT LAI. Marder says long-acting injectables can help avoid issues with adherence.

Despite the twice-daily dosing schedule limitation, Marder says if KarXT can avoid some of the adverse effects like decreased motivation that are common with dopamine-blocking drugs, patients may be less reluctant to take it twice daily. He notes that the real-world adherence and acceptance of KarXT would need to be evaluated, as clinical trial settings may not fully capture these issues.

If approved, KarXT is set to pull in $2.99bn in sales in 2030, according to GlobalData forecasts. The schizophrenia market is projected to reach $21.2bn globally by 2032, according to a report on GlobalData’s Pharma Intelligence Center.

GlobalData is the parent company of Pharmaceutical Technology.

To bring TerXT to market quickly, Terran is utilising a unique regulatory pathway made possible for prodrugs.

When the original composition of matter patent on a drug expires, companies can develop prodrug versions to bypass any remaining patents on the formulation or combination of the original drug. Developing a prodrug creates a new patentable molecule, allowing the company to get a new 20-year patent on the prodrug, says Clark. As long as the original composition of matter patent has expired, the prodrug can be approved and marketed without being blocked by the remaining patents on the original drug formulation.

This should allow Terran to market the prodrug more quickly and potentially expedite FDA approval using the 505(b)(2) pathway, which is for new chemical or molecular entities or candidates that involve changes made to previously approved drugs. The NDAs for this pathway can contain safety and effectiveness data from studies that the applicant may not have run.

In an interview with Clinical Trials Arena in May 2024 interview, Clark had said the company is looking to launch two Phase I trials, one for each of the KarXT versions to confirm safety and pharmacokinetics. However, the company would still need to wait out BMS’s five-year marketing exclusivity period to get its products to consumers New pharmaceutical chemical entities get five years of market exclusivity to prevent generic competition, starting from FDA approval.