The attention deficit hyperactivity disorder (ADHD) market is $10 billion strong, but grabbing a piece of the pie with so many drugs already on the market, including some generics, requires differentiation.

The current medications can broadly be classified into two categories: stimulants and nonstimulants.

Stimulants such as Ritalin (methylphenidate, Novartis AG), Concerta (a different formulation of methylphenidate, Johnson & Johnson) and Adderall XR (d-amphetamine, Shire plc) work extremely well by stimulating dopamine levels with fast onsets and large improvements in ADHD symptoms.

But the stimulants also come with side effects, including negative effects on sleep and appetite and issues with heart rate and blood pressure. The drugs are also scheduled substances, imposing extra burdens on prescribing physicians to help reduce the likelihood of abuse.

Nonstimulants, including norepinephrine reuptake inhibitor Strattera (atomoxetine, Eli Lilly and Co.) and a pair of alpha2-adrenergic stimulators, Intuniv (guanfacince, Shire) and Kapvay (clonidine, Concordia Pharmaceuticals Inc.), don't have the potential for abuse, but they also don't work particularly well and take awhile to become fully active.

In clinical trials, Kapvay didn't demonstrate efficacy until five weeks of treatment, although positive results were seen as early as week two. Stimulants, by contrast, can work starting as early as the first dose.

And the nonstimulants have their own set of side effects. Strattera, for instance, has a boxed warning on its label about the potential for suicide and warnings about effects on blood pressure and heart rate.

BUILDING BETTER NONSTIMULANTS

Alcobra Ltd.'s MDX (metadoxine extended release) has a novel mechanism of action, inhibiting the 5-hydroxytryptamine receptor 2B (5-HT2B) receptor, a member of the serotonin receptor family, ultimately modulating the gaba-glutamate circuit.

"It's kind of like a yin-yang circuit of learning, memory and attention in the brain," Yaron Daniely, president and CEO of Alcobra told BioWorld Insight. "[MDX] is able to restore a balance between the gaba and the glutamate signaling."

Phase IIb data released in December showed a statistically significant improvement in the Test of Variables of Attention ADHD Score, a computerized test to measure an individual's sustained attention, speed and consistency of responding, and behavioral self-regulation. Unlike other nonstimulants, the onset was quick with benefits from day one.

Alcobra already has started a phase III trial, which is scheduled to read out in the second half of this year. The Tel Aviv, Israel-based company would then have to run a second phase III trial, putting a potential new drug application (NDA) filing by the end of 2015.

Neurovance Inc. is a little further behind, having recently presented phase IIa data for centanafadine SR, a molecule that blocks reuptake of norepinephrine and to a lesser extent dopamine and affects serotonin mildly.

Centanafadine SR produced a 21-point reduction on the ADHD-Rating Scale-IV (ADHD-RS-IV) in 37 adults that completed the trial, which is about what would be expected of a stimulant.

"We didn't expect that. We expected efficacy between the stimulants and the nonstimulants," which give about an 11-point to 12-point improvement on the ADHD-RS-IV scale, Anthony McKinney, president, CEO and co-founder of Neurovance told BioWorld Insight. The drug also produced a "fairly rapid onset of action, which was again a surprise," Mckinney added.

The Cambridge, Mass.-based company is running a study measuring the abuse potential compared to stimulants with the hope that recreational stimulant abusers will like centanafadine SR less than the stimulants.

Following that trial, Neurovance has a plan for a phase IIb trial to begin in the third quarter of next year, which would require raising funds in a series B round, but McKinney said the company has received "inbound interest" and is exploring all its options, including a potential sale after the abuse data become available in the fall.

"The question is what is the price we would get [after the phase IIb trial completed] vs. what is the price we would get now," McKinney said.

Comparing MDX and centanafadine SR at this point is nearly impossible. Not only did the studies use different primary endpoints, but they enrolled different types of patients. Neurovance's trial took all subtypes, while Alcobra's study was in patients with the predominantly inattentive subtype of ADHD.

They're both doing better than Theravance Inc.'s monoamine reuptake inhibitor TD-9855, whose development was scrapped in ADHD after the company said the phase II trial failed to meet its primary endpoint. The company's R&D spinoff, Theravance Biopharma, of South San Francisco, continues to study the compound as a treatment for fibromyalgia.

REFORMULATION

Neos Therapeutics Inc. is making proven ADHD stimulants easier for children to take with oral disintegrating tablets (ODT) and controlled-release liquid formulations.

Its technology uses small ion particles containing the drug, which is coated with a membrane polymer film and put into a suspension or an ODT. While the liquid or ODT is rapidly ingested, the micro particles act like mini individual tablets, allowing for a controlled release.

The Grand Prairie, Texas-based firm has three ADHD medications in development: an ODT version of the active ingredient in Adderall XR, a liquid form of Adderall XR and an ODT version of Metadate (methylphenidate, Celltech Group plc).

Neos expects to file the first NDA late this year or early next year, followed rapidly a few months later by the second and then third NDA for the other formulations.

Going through the 505(b)(2) pathway allows Neos to get approved with relatively limited clinical trial data compared to a new chemical entity, but it means the company will have to compete directly with the other formulations of the same active ingredient.

"The market is so big in ADHD – we're talking about a $10-plus-billion market – so if you can get 2, 3 or 4 percent of the market share, you're talking about a very significant annual sales in terms of dollars," Vipin Garg, Neos' CEO told BioWorld Insight.

Highland Therapeutics Inc., of Toronto, is developing a controlled-release formulation of methylphenidate, HLD-200, which has delayed and extended-release characteristics that allow it to be taken before bedtime and produce next-day therapeutic activity. According to a survey sponsored by the company, 55 percent of families reported challenges with morning ADHD symptoms that were characterized as severe or moderate to severe.

The company started a phase III study in April. If all goes well with the data readout in the fourth quarter, Highland expects to submit an NDA to the FDA in the first half of 2015.

ADULTS ARE KEY

About half of the ADHD prescriptions are written for adults, which is growing by double-digit percentages compared to about 3 percent for children.

Partially driving adult prescriptions is the half to two-thirds of children that are diagnosed with ADHD and show symptoms as adults. The recognition that ADHD is an issue in adults and can increase everything from substance abuse to unwanted pregnancies to car crashes has led to further growth in adult prescriptions.

Only one of the three nonstimulant ADHD medications, Strattera, is approved for use in adults, providing a fairly open market.

Even Neos, whose formulations are primarily designed to be kid-friendly, hopes to get a piece of the adult market. "Everyone knows someone that is scared of swallowing a pill or a capsule," Garg said.