KemPharm Taking Ritalin Prodrug Into Phase III For ADHD

Months after reaching agreement with FDA to refile the NDA for its abuse-deterrent opioid Apadaz, KemPharm has gotten the okay to take its prodrug of Ritalin into Phase III for ADHD.

Roughly a year after entering a dispute resolution process with US FDA to refile the NDA for its abuse-deterrent opioid candidate and ultimately prevailing, KemPharm Inc. has obtained the agency’s okay to take its second prodrug candidate, a methylphenidate formulation for attention deficit/hyperactivity disorder, into Phase III.

As a prodrug of the active ingredient in the ADHD stalwart Ritalin, KP415 is intended to offer earlier onset of action and longer duration of effect. Even in a very crowded therapeutic space, the Coralville, Iowa-based firm is confident its candidate will appeal to physicians and patients by offering better durability than the original Ritalin formulation approved in 1955 and two successors – a sustained-release version approved in 1982 and a long-acting formulation approved in 2002. (Also see "June 2002 Approvals" - Pink Sheet, 12 Aug, 2002.)

The goal, KemPharm CEO Travis Mickle explained in an interview, is to improve upon the dwindling efficacy that clinicians report for other long-acting ADHD therapies. Having been the lead inventor of another ADHD mainstay, Shire PLC’s Vyvanse (lisdexamfetamine dimesylate), Mickle’s ambition seems to be to introduce a product offering the potency of the methylphenidate class with the long-lasting action of Vyvanse.

“We’ve received feedback from numerous physicians and key opinion leaders that the methylphenidate products really don’t last 12 hours, [their effect] really tails off at about 10,” Mickle said. “Vyvanse has a robust effect through 13-14 hours, through the end of the day. We see our pharmacokinetic data looks very similar in terms of trend, shape and levels toward the end of the day, similar to Vyvanse.”

KemPharm CEO Travis Mickle

Source: KemPharm Inc.

On Nov. 16, KemPharm announced that it had successfully completed an end-of-Phase II meeting with FDA regarding KP415 – an extended-release, d-methylphenidate prodrug – and established protocols for clinical, non-clinical and abuse-liability studies that could result in initiating a pivotal Phase III study before the end of 2017. Using the “classroom-style” format typical for ADHD pivotal studies, the 140 patient-study is intended to support labeling claims for early onset of action and extended duration of therapy.

To date, KP415 has demonstrated the ability to produce a therapeutic effect within 30 minutes of dosing and a duration of effect for 12.5 hours, Mickle said. “We’ll essentially be measuring the effect through the course of the day, with the first time point that we measure being at a half-hour and the last one at the 13th hour, which is really the last one that you can get to do, because it’s usually at 8 pm,” he said.

Regulatory Pathway Similar To 505(b)2 Process

The agreement with FDA makes the pivotal trial a parallel study to an ongoing Phase II study and enables the company to enroll adolescents and adults along with pediatric subjects. Because KP415 is a prodrug of an approved compound, Mickle described the path forward as “a prodrug [version of] 505(b)2, where in this case the efficacy study is only required to measure duration. That’s our major differentiation for this product – making it the best duration in class. We will measure safety as well, so it is sort of a combined Phase II/III, but it’s a single study.”

KemPharm also will try to demonstrate that KP415 offers no liability for abuse. This would not be a label claim, unlike an abuse-deterrence claim, Mickle noted.

“KP-415, the prodrug behind it, is actually not scheduled, so just like other new molecules in the space, we have to go through a formal scheduling decision, which requires the assessment of abuse liability,” the exec explained. “In this case, we have preclinical data that are very compelling, which show that it’s going to be difficult to abuse this product intranasally or intravenously, and it has such a delayed release … that it may even show some differences when you take it orally. That, in conjunction with it being a new molecule, is really making us very excited about [the lack of] abuse potential here.”

KemPharm has patent protection out to 2032 for the prodrug and is seeking other patent approvals that might extend the life of its intellectual property protection. The company creates prodrugs of already approved molecules using its proprietary LAT (Ligand Activated Therapy) technology platform, which can confer therapeutic advantages over the original version of the molecule.

“We’ve shown we can reduce abuse potential, we can change pharmacokinetics, we can change metabolism, we can target organs, we can enhance permeability.” – KemPharm CEO Travis Mickle

“The number-one distinction here is that we are changing the molecule, so we covalently attach our ligands to it,” Mickle said. “These [molecules] are generally recognized as safe and well understood on how they behave or what their toxicity is, so we don’t have a regulatory burden there, but on top of that they can do far more than what you could do for, say, a formulation-based approach. We’ve shown we can reduce abuse potential, we can change pharmacokinetics, we can change metabolism, we can target organs, we can enhance permeability – the list goes on and on.”

KemPharm’s lead candidate is Apadaz (benzohydrocodone/acetaminophen), for which it is seeking an abuse-deterrent claim as a therapy for acute pain. After it received a complete response letter for its initial new drug application (NDA) for the immediate-release hydrocodone combination product in June 2016, KemPharm went through the dispute resolution process with FDA so it could resubmit the NDA with data needed to support an abuse-deterrence claim. (Also see "KemPharm Seeks FDA Dispute Resolution Over Apadaz's Abuse Deterrence" - Pink Sheet, 16 Sep, 2016.)

On Sept. 12, the company announced that it had resubmitted the NDA, which has an action date of Feb. 23, 2018. (Also see "Keeping Track: Biosimilar Submissions Galore (And An Approval), Bayer Gets An Oncology Approval, KemPharm Resubmits Apadaz NDA" - Pink Sheet, 17 Sep, 2017.) KemPharm told Pink Sheet that the firm had not conducted any additional studies to support the refiled application.