Attention Deficit Disorder Focus Turns to Side Effects

September 20, 2018 Attention deficit disorder focus turns to side effects

Jonathan Gardner

Limiting abuse and reducing risks are the differentiating factors for projects from Kempharm and Supernus.

Attention deficit/hyperactivity disorder has been ceded largely to generics and small speciality pharma groups, as the field has moved towards longer-duration agents and improving side effects, often by repurposing existing molecules. Two late-stage companies exemplify this trend, with Kempharm nearing submission for its stimulant KP415, and Supernus expecting pivotal data by year-end for its non-stimulant SPN-812.

Kempharm has reported human abuse potential data for KP415, a prodrug of Ritalin, which could clear the way for US FDA submission and potential licensing deals. Supernus, meanwhile, has completed enrolment into three of its four phase III trials ahead of schedule. The company needs SPN-812 to be free of liver and cardiovascular risk, a problem that kept Lilly's similarly acting product, Strattera, from becoming a big seller.

Thanks to blockbusters like Adderall, Ritalin, Concerta and, most recently, Vyvanse, ADHD grew to a $5.5bn category in 2017. However, the entry of generic drugs is taking its toll and only Vyvanse is forecast to exceed $1bn in sales this year, according to EvaluatePharma’s consensus of sellside analyst. Forecast for marketed ADHD products

Sales ($m)

Product Company Pharmacology class 2018e 2020e 2022e 2024e

Dopamine agonist & Vyvanse Shire norepinephrine 2,129 2,267 2,374 1,631 reuptake inhibitor

Mydayis Shire Psychostimulant 74 242 352 443

Johnson & Concerta Psychostimulant 658 524 450 421 Johnson

Methylphenidate Teva Psychostimulant 481 374 302 234 (Ritalin generic)

Norepinephrine Strattera Lilly 441 263 227 187 reuptake inhibitor

Alpha 2A adrenoceptor Intuniv Shionogi 39 92 137 172 agonist

Adderall XR Shire Psychostimulant 308 185 138 120

Cotempla XR- Neos Psychostimulant 21 59 87 114 ODT Therapeutics

Neos Adzenys XR-ODT Psychostimulant 28 65 90 109 Therapeutics

Metadate CD UCB Psychostimulant 94 92 92 92

Total (all marketed products) 4,819 4,606 4,676 3,937

Source: EvaluatePharma.

In addition to generics, concerns about stimulant abuse and overmedication have limited enthusiasm for ADHD research, although the sector is expected to bounce back thanks to Shire’s latest entry, Mydayis, along with assets from Supernus, Kempharm and Sumitomo Dainippon Pharma, which are expected to drive new growth.

Stimulants like Ritalin and Mydayis are viewed as more effective than norepinephrine reuptake inhibitors like Strattera, despite side effects with the former that can include sleep disturbances, anxiety, delayed growth, tics and irritability when drugs wear off – hence the desire for longer-acting agents. In addition, Ritalin and others can result in feelings of euphoria, which can lead to abuse.

Thus, data earlier this week with Kempharm’s KP415 (serdexmethylphenidate) were key for submission to the US FDA. The prodrug, delivered intranasally, resulted in lower “drug liking” scores than did methylphenidate, the active ingredient in Ritalin. The company hopes that these data can be included in the label if the project is approved, and that they will result in less restrictive regulation by the US Drug Enforcement Administration. Waiting in the wings: late-stage ADHD projects

Sales ($m)

Product Company Pharma class 2018e 2020e 2022e 2024e

Submitted

5-HT, dopamine & Sumitomo norepinephrine SEP-225289 Dainippon 16 132 212 284 reuptake inhibitor Pharma (SNRI)

Phase III

Norepinephrine SPN 812 Supernus - 21 165 293 reuptake inhibitor

SPN-810 Supernus Dihydroindolone - 2 137 289

KP415 Kempharm Psychostimulant - 86 183 247

5-HT, dopamine & Centanafadine Otsuka norepinephrine - 15 44 58 SR Holdings reuptake inhibitor (SNRI)

Total 16 256 741 1,171

Source: EvaluatePharma.

Kempharm’s chief executive, Travis Mickle, said the company could submit its application to the FDA as early as the first quarter of next year. He added that a “competitive” partnering process for KP415 should be completed by the end of the year.

Non-stimulant

Meanwhile, Supernus is banking on improving the track record of non-stimulant agents with SPN-812, an extended-release version of viloxazine hydrochloride, which Astrazeneca marketed for depression in Europe under the brand name Emovit.

In a presentation to the Wells Fargo healthcare conference earlier this month, Supernus's chief executive, Jack Khattar, said non-stimulants represented 8% of all US prescriptions written, and there was “no reason” for the share to be that small. “If you have a choice as a parent you would always choose a non-stimulant,” he said.

That will, of course, depend on the safety profile. While SPN-812 probably will not be able to avoid getting a black box for suicide ideation, like most antidepressants, it might be able to differentiate itself by avoiding side effects seen with stimulant-based drugs like decreased appetite and weight, irritability and insomnia – provided, of course, that it passes liver and cardiovascular safety tests.

Three of four phase III trials have completed enrolment – those testing low and high doses in patients aged 6- 11, and a low-dose study in patients aged 12-17. A high-dose adolescent trial is still enrolling and will not read out until 2019.

A second Supernus project, SPN-810, is targeting impulse aggression in ADHD. This candidate consists of an old antipsychotic called molindone. A Mizuho analyst, Irina Koffler, regards this as a higher-risk project, in part because the measurement tool used in trials consists of a caregiver diary that has not been fully validated by regulators.

Another ADHD candidate in the non-stimulant category is SEP-225289 (dasotraline hydrochloride) from Sumitomo Dainippon Pharma, a project that came to the Japanese group from its 2009 buyout of Sepracor, which is now known as the subsidiary Sunovion. Dasotraline received a complete response letter in August, with a request for more clinical data, suggesting that launch would be delayed for some time. Dasotraline showed improvement in ADHD symptoms in children, but missed in adults.

Otsuka's centanafadine hydrochloride will not immediately compete with Supernus as the former is being tested in adult ADHD. Development of this project has been slow, as the first phase I trials took place in 2012. As of the end of July, three phase III trials were listed on clinicaltrials.gov with a combined 1,620 patients. Development of central nervous system drugs is one of the riskier areas of drug research, and since ADHD remains one of the more controversial conditions, owing to worries about overdiagnosis and medication abuse, it is no surprise that big companies are reluctant to invest in R&D. Making existing products better and repurposing older drugs represents incremental innovation, but since so many patients are dissatisfied with their treatments there is room for more dynamic improvements.