ADHD Check-Up: Which Future Medications Have The Greatest Potential?

by: Kenneth Pittman


The ADHD market is crowded, but new compounds could still get a piece of a large market.

Despite the crowded market, there are still niches available for new compounds.

Supernus, Kempharm, Sunovion, and Arbor are some of the potential winners in this.

ADHD Treatment Is a Crowded Space

ADHD is a common disorder impacting approximately 11% of children, 8.7% of adolescents, and 4.4% of adults, according to the NIMH. For background on the disorder, I recommend reading the following articles on Seeking Alpha:

There are currently approximately 32 ADHD medications currently being used on the market (counting brands that have a generic one time only). Of these, 13 are methylphenidate stimulants, 11 are amphetamine stimulants, 1 is a selective norepinephrine reuptake inhibitor, 5 are alpha agonists, 1 is a dopamine reuptake inhibitor, and 1 has a mixed mechanism of action (counting common off label medications with good levels of evidence). 27 of these are approved for ADHD and the other 5 are medications with significant positive research in ADHD or alternate delivery forms of currently approved ADHD medications. These are summarized in the table below:

Brand Name Generic Name Class Dosage Form Approved Generic? Notes
Concerta Methylphenidate ER MPH Caplet (Swallowed Whole) 2000 Yes 1st in MPH Scripts, 2nd Overall
Focalin XR Dexmethylphenidate ER MPH Capsule 2005 Yes 4th Overall in Scripts
Ritalin LA MPH ER 50-50 MPH Capsule 2002 Yes
Metadate CD MPH ER 30-70 MPH Capsule 2002 Yes
Aptensio XR MPH ER 40-60 MPH Capsule 2015 No
Quillivant XR Methylphenidate ER Liquid MPH Liquid 2012 No
Quillichew ER Methylphenidate ER Chewable MPH Chewable 2015 No
Cotempla XR-ODT Methylphenidate ER ODT MPH Orally Dissolving Tablet 2017 No
Daytrana Methylphenidate ER Patch MPH Transdermal Patch 2006 Late 2018
Ritalin Methylphenidate MPH Tablet 1955 Yes Short-acting
Focalin Methylphenidate MPH Tablet 2001 Yes Short-acting
Methylin Solution Methylphenidate Liquid MPH Liquid 2002 Yes Short-acting
Methylin Chewable Methylphenidate Chewable MPH Chewable 2003 Yes Short-acting
Adderall XR mixed amphetamine salts XR AMP Capsule 2002 Yes 1st Overall in Scripts
Vyvanse lisdexamfetamine AMP Capsule and Chewable 2012 No Prodrug, 3rd Overall in Scripts, #1 Branded
Dexedrine Spansule dextroamphetamine ER AMP Capsule 1976 Yes
Mydayis mixed amphetamine salts AMP Capsule 2017 No
Adzenys XR-ODT amphetamine ER ODT AMP Orally Dissolving Tablet 2016 No
Adzenys ER Liquid amphetamine ER liquid AMP Liquid 2017 No
Dyanavel XR amphetamine ER liquid AMP Liquid 2015 No
Evekeo racemic amphetamine AMP Tablet 2014 No
Adderall mixed amphetamine salts AMP Tablet 1996 Yes Short-acting
Dexedrine & Zenzedi dextroamphetamine AMP Tablet 1937/2013 Yes Short-acting
Procentra dextroamphetamine AMP Liquid 2008 Yes Short-acting
Strattera atomoxetine SNRI Capsule (Swallowed Whole) 2002 Yes 5th Overall in Scripts
Provigil modafinil DRI Tablet Not for ADHD Yes Adverse Events in Kids
Intuniv guanfacine ER AA Tablet (Swallowed Whole) 2009 Yes
Kapvay clonidine ER AA Tablet (Swallowed Whole) 2010 Yes
Tenex guanfacine AA Tablet Not for ADHD Yes
Catapres clonidine AA Tablet Not for ADHD Yes
Catapres-TTS clonidine ER patch AA Patch Not for ADHD Yes
Wellbutrin XL buproprion XL NDRI/Mixed Tablet (Swallowed Whole) Not for ADHD Yes

Opportunities Still Exist in the ADHD Market

Despite the long list of ADHD medicines above, there is still no "perfect" ADHD medication, and there are niches within the market where a drug could not only succeed but also have a potential for blockbuster status. To better understand these, I will look at each of the key features in an "ideal" stimulant ADHD medication and also comment on non-stimulant options as they relate to these.

1) Duration of action of about 12-14 hours - Most of the current stimulants on the market do not last this long (even if they are long acting). There is one stimulant that lasts longer than this - Mydayis by Shire (SHPG). I would estimate that approximately 4 methylphenidates and 4 amphetamines that are currently on the market last close to this range. Most new stimulants target this range (or longer in teens/adults). While it is unlikely that any stimulant will improve much on duration of action compared to current options, there is room for improvement in many of the longer acting stimulants with regards to onset, appetite suppression, and sleep disruption in particular. In fact, if it were possible to have stimulant activity all day without sleep disruption, then this would likely be the ideal rather than 12-14 hours.

Non-stimulant options often target all-day control but have to date been less efficacious than stimulants. If a non-stimulant could be developed that worked as well as stimulants, then this would be a multi-billion dollar market opportunity.

2) Onset within 15-30 minutes - The short-acting stimulants have generally had quicker onsets with some of the "mixed" short/long acting products also reaching this. However, some of the better long-acting stimulants in terms of duration of action (including Vyvanse by Shire and the generic of Concerta) do not do as well with regards to onset. Maintaining a quick onset and combining that with long duration of action is important for any new stimulant that is introduced.

This factor is less important for non-stimulants as they are generally designed to last all day. Instead, non-stimulants are generally challenged in terms of initial onset at the start of treatment. Strattera by Eli Lilly (LLY), for example, generally requires a build-up of 4-6 weeks before it is effective. If a non-stimulant could achieve a 1-2 week initiation onset, then it would be a more serious competitor to stimulants.

3) Limited appetite suppression and sleep disruption - Appetite suppression is the Achilles heel of most stimulants. This is especially true to the longer acting stimulants. The longest acting stimulants also have more problems with sleep disruption, including Mydayis. There has only been one stimulant that has shown significantly less appetite suppression in larger studies, and that is Evekeo by Arbor Pharmaceuticals. There are others that have limited evidence of less appetite suppression in smaller studies - particularly when it comes to longer-term use of the stimulant. While Evekeo should have a major advantage due to this fact, it has been tempered by a shorter duration of action compared to several of its amphetamine peers. A significant opportunity exists for a long acting stimulant (either amphetamine or methylphenidate) that shows significantly less appetite suppression in large, extended studies.

Appetite suppression and sleep disruption are smaller issues in non-stimulant medications but still can be present (especially with Strattera). Some non-stimulants (like clonidine/guanfacine) can have the opposite effect in daytime sedation. An ideal non-stimulant would have no significant daytime drowsiness or sleep disruption. It would also be weight neutral.

4) Few addictive properties, abuse deterrence would be most ideal - Like opiate pain medications, there is concern for abuse with stimulant medication use in ADHD. Therefore, any stimulant that can show fewer addictive properties or even abuse deterrence would have a significant advantage. The only stimulant to date that has somewhat positive data with regards to addictive properties is Vyvanse (which is a prodrug) - and this advantage was not significant enough to allow Shire to directly market it. If a company could show reduced addictive properties and be allowed to present this data in their PI and marketing materials, then it would almost certainly have blockbuster potential. This is particularly needed in a methylphenidate but would also be beneficial for any amphetamine that was superior to Vyvanse in this area.

Non-stimulants are not generally an addictive concern and have a significant advantage based on this.

5) Limited impact on heart, headaches, and stomach aches - Heart-related side effects (tachycardia, palpitations, blood pressure), headaches, and stomachaches are some of the other more common side effects of stimulants. More recent stimulants have not had as significant of a problem with these as older stimulants, but they are still a concern when evaluating any future stimulants.

Non-stimulants can also have these and any newer-generation version of Strattera could benefit from improvement with regards to stomachaches in particular.

6) Lack of "crash" when medicine wears off in the evening - This is a significant issue with all of the short-acting stimulants and several of the long-acting ones, including Adderall XR, Metadate CD, Ritalin LA, and Focalin XR. A "smoother" PK curve with regards to elimination is necessary to prevent this. One of the reasons that Vyvanse has been so successful is a lower incidence of crashes as it more gradually wears off. Future stimulants should include this as well - although it can be challenging to have both this and a lack of sleep disruption.

Non-stimulants do not generally have a crash and have a significant advantage with regards to this factor.

7) Simple administration for all ages - This has historically been a void in the space as several of the longer-acting stimulants required the ability to swallow a pill or required opening capsules and mixing with a food or beverage for administration. Daytrana was the only significant exception for several years, but the transdermal system could not be tolerated by those with significant skin issues. However, the last 5-6 years have given us several options for liquid, chewable, and orally dissolving tablets. New ADHD medications may further attempt to fill this gap, but having this feature solely to address those who can't swallow pills may not be advisable as it is now a very crowded, competitive space. That said - have an option for liquid/chewable/ODT while simultaneously addressing the other "ideal" characteristics would be beneficial.

Approved non-stimulant ADHD medications (Strattera, Intuniv, and Kapvay) currently do not address this need as all of them must be swallowed whole. Strattera can be compounded into a liquid but is extremely bitter when this is done. Intuniv and Kapvay have shorter-acting versions that offer easier administration, but these require more frequent dosing and are not specifically approved for ADHD. A medication with the properties of Intuniv that was in a liquid/chewable/ODT form would do very well in the market in my opinion.

How Will Current Pipeline Drugs Fit In?

There are several drugs in the ADHD pipeline that have the potential to meet several of the above needs in a way that no current ADHD medications have been able. Of these, there are 5 that are nearing the "finish line" and each of them has significant potential to fill a gap. There are several other drugs in development that could also fill gaps. The ones closest to the "finish line" will be covered in this article in more depth (with the closest to market first).

Sunovion's Dasotraline

Dasotraline is a DNRI, or dual dopamine and norepinephrine reuptake inhibitor. This is somewhat similar to Eli Lilly's Strattera. It is a non-stimulant product. Dasotraline is a product of Sunovion, which is an American division of the Japanese company Sumitomo Dainippon Pharma. Sumitomo Dainippon is listed on the Tokyo Stock Exchange as Stock #4506 and has a listing in the US on the OTC Pink Sheets, Dai Nippon Pharma (OTCPK:DNPUF).

Dasotraline is a level-based medicine like Strattera but only takes approximately 2 weeks to reach steady state and does not seem to require the dose titration that Strattera does. The results of a Phase 3 Study of Dasotraline are shown below with my commentary added (all graphics are from the Phase 3 Study poster).

The study design was a fairly standard laboratory classroom study that is used in ADHD. The study was double-blind and randomized and only required 2 weeks' worth of dosing prior to the endpoint at Day 15.

Dasotraline improved SKAMP-CS scores by approximately 5 points on average, but this average was somewhat distorted by the 8 AM measurement where both baseline and placebo showed much lower scores than the remainder of the day. This finding is consistent with many other similar studies in ADHD. If the 8 AM measurement is excluded, then it appears that the average improvement in SKAMP would be about 6 points. This is not as good as most stimulants (~8-10 points) but is still significant improvement and is better than the SKAMP improvement with Strattera of approximately 3.6 points. Additional data from the same study showed that dasotraline performed well on inattentive and behavior subscales as well as the PERMP, which is used in ADHD studies to test the ability to do repetitive tasks. Dasotraline was generally well tolerated with insomnia, headache, and decreased appetite being the most common side effects. However, all of these occurred less often than they typically do with stimulants and on par with Strattera. Stomachaches and vomiting occurred less often than both stimulants and Strattera. There were some issues with hallucinations in the Dasotraline arm, but this was primarily in the 6mg arm that was discontinued (the study results above are all at 4mg).

Dasotraline has a PDUFA date of August 31, 2018, and approval is likely. I would expect that Dasotraline will be as successful as Strattera was, if not more so. Strattera sales peaked at $854 million, and with added inflation, I would not be surprised to see Dasotraline reach $1 billion in sales. Dasotraline will have competition from the generic Strattera and may require step therapy for insurance formularies, including generic Strattera failure but should have a clinical advantage over Strattera.

Kempharm's KP415 (and KP484)

Readers of my previous articles are likely familiar with my views on KP415 and KP484 by Kempharm (KMPH). My most recent article highlighted the excellent abuse potential study that was completed. Results for additional abuse potential studies are expected soon. Agamemnus recently wrote an excellent overview of KP415's advantages.

Kempharm released Phase 3 trial results for KP415 (now clarified to contain serdexmethylphenidate or SDX) and they were generally positive. However, the market was disappointed with some statistical anomalies in the study that led to some post-hoc analysis. Even without this post-hoc analysis, results were positive on all measures except the SKAMP scores at 0.5 hours and 12-13 hours. The PERMP scores were significantly improved from 0.5 hours to 13 hours. The only other slight disappointment may have been the magnitude of the SKAMP score difference - which was slightly lower than some other stimulant trials.

I am not at all concerned about whether or not KP415 kicks in within 30 minutes - it contains the generic equivalent of Focalin in short acting form, and that component alone should lead to 30 minute onset. The only question is clinical duration, and I believe the study supports at least some positive effects through 13 hours. It is not unusual for the PERMP (which is more of an objective test) to show positive results for longer than the SKAMP (which is more subjective). Patients will often report that their stimulant has "worn off" even when they are still objectively better than their baseline symptoms.

Overall, SDX demonstrated SKAMP and PERMP scores that were as good as most of the modern stimulants. It is important not to miss the fact that duration of effect is not the "secret sauce" for SDX, though. If SDX is going to be a "next wave" stimulant with significant sales, then it will be because of the Human Abuse Potential Studies. Without them, SDX is a solid option similar to Aptensio XR, but may lack significant sales. With the differentiation of the HAP Studies, SDX could be a market leader in the methylphenidate class of stimulants.

Simply put - no other stimulant drug on the market currently has abuse potential studies as good as SDX's. Vyvanse is the only one that is even close. Of the 7 features listed above, SDX is almost certainly better than Vyvanse in two of them (onset and abuse potential). I think that it is quite possible that the clinical duration will be better. KP415 should be close to equal on all 4 of the other categories with the potential for some slight variation in either direction on side effects. An NDA is expected for KP415 in early 2019, and approval could come by late 2019. Kempharm expects to partner SDX for marketing and Shire/Takeda has the right of first refusal for this.

KP484 adds another revenue possibility for Kempharm and represents an even longer-acting version of KP415. Results for this drug are expected in 2019, and it will likely have more appeal to adults and older adolescents.

Supernus's SPN-810 and SPN-812

Supernus (SUPN) has two ADHD drugs in their pipeline that are near the "finish line." The first of these is SPN-812 (viloxazine) and the second is SPN-810 (molindone). I have covered both of these in a previous article about Supernus. Both compounds are projected to have results in Q1 2019. Supernus has indicated that they will likely stagger the NDA for the two compounds with an expectation that SPN-812 would come first.

SPN-812 is a selective norepinephrine reuptake inhibitor. This puts it in the space of Strattera and dasotraline. SPN-810 is an old antipsychotic being used in a small, modified dosing to treat impulsive aggression in ADHD. This is a large market with the newer diagnosis of "Disruptive Mood Dysregulation Disorder" commonly being used in these cases. Supernus also plans to study SPN-810 for impulsive aggression in autism, PTSD, and bipolar disorder.

As I have said in previous articles, I believe that Supernus is somewhat overestimating the market potential of SPN-812. This is in part due to the fact that Sunovion is beating them to market with dasotraline as a nonstimulant option. However, I believe that Supernus is underestimating the potential of SPN-810 for impulsive aggression in ADHD alone. If effective, I believe that this drug could be the most successful new psychiatric drug since at least Vyvanse and quite possibly since Risperdal and Abilify. It has the single most potential of any investigational psychiatric drug that I am aware of that will be used in children. If it were eventually approved for impulsive aggression in ADHD, Autism Spectrum Disorders, and PTSD, then I believe it could exceed sales of $3 billion/year.

Supernus is a solid company that is worth holding for many reasons, but the potential of this pair of drugs (and particularly SPN-812) seems to be largely ignored by a market that is focused on sales of Trokendi and Oxtellar. Supernus trades at 1/3 of the market cap of Sage Therapeutics (SAGE), and I believe that SPN-812 is worth mentioning in the same breath as Brexanolone (the major value driver for Sage). Both of these drugs have tremendous potential. Sage doesn't have two compounds already to market that are producing profits for the company like Supernus does.

Arbor's AR19

Arbor's AR19 may be the wild card entry into the ADHD sweepstakes. Arbor Pharmaceuticals is a private company that may be best known in the public sphere for acquiring Xenoport (XNPT) in 2016. Arbor currently produces Evekeo, a medium-duration ADHD amphetamine product that is taken once or twice a day. Evekeo is most notable for its reduced appetite suppression compared to other stimulants. Arbor has a compound in their portfolio called AR19 that is near the end of Phase 3 studies. Since Arbor is private, they are tight-lipped on what exactly AR19 is. However, their webpage says that it is a product for Pediatrics and Psychiatry. Another ADHD treatment is the most likely area of overlap for Pediatrics and Psychiatry.

Evekeo is an amphetamine and most companies tend to stick close to what they know. One could ask what areas of amphetamine treatment represent a gap that Arbor could be trying to fill? While I am not certain what they are doing, there are two logical areas that this could be. One of these would be a longer-acting version of Evekeo that maintains the reduced appetite suppression. The other would be an amphetamine with improved Human Abuse Potential studies like Kempharm has shown in methylphenidates. Arbor could be doing one of these, both, or neither (they also have a compound called AR20 that is earlier in development). Another possibility is that they somehow found a way to make a methylphenidate that does not have as much appetite suppression. Of course, Arbor could just be making a "me too" type product without filling treatment voids. However, I have seen enough of this company (despite it being private) to believe that they will be innovative and therefore have included them on this list. It is my hope that Arbor is eventually a public company so that I can dive deeper into coverage of their pipeline.


In spite of the crowded market, I believe that there are still opportunities for blockbuster-type drugs in the ADHD space. I believe that there are 5 compounds close to approval that have this possibility. Kempharm and Supernus are my two top holdings due to this fact. While more complicated for US investment, Sunovion (part of Sumitomo Dainippon Pharma) also has solid prospects. Finally, Arbor Pharmaceuticals represents a private company that would be have significant investment potential if they were to go public.

Author's note: Thank you for reading my article. Please follow me for additional articles covering the biotech space with an emphasis on neuroscience. As always, I will disclose below which drug companies I have mentioned in the article for which I am the recipient of direct marketing. My articles include my personal opinions and are neither financial nor medical advice. They are solely intended to show my perspective and due diligence on a given subject. Please consult with the proper professional if you are looking for specific advice for your situation.

Disclosure: I am/we are long SUPN, KMPH.

I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: I am contracted to speak for Tris Pharmaceuticals, a private company whose interests include 3 of the ADHD medications listed in the table, but which is not otherwise mentioned in this article.

I have had ~4 marketing lunches provided to my office in the last year by Shire and Neos. I have had ~12 marketing lunches provided in the last year by Arbor Pharmaceuticals (a private company referred to in this article). I have had ~3 marketing lunches provided by Takeda. In the past, I have had marketing lunches provided by Eli Lilly, but none in the past year. I have never had direct marketing from KemPharm or Supernus. I anticipate that all of these companies may/will provide additional marketing lunches in the future. I have never been paid by any of the above companies for speaking or writing articles.

Editor's Note: This article covers one or more microcap stocks. Please be aware of the risks associated with these stocks.