Attention Grabbers

According to the Center for Disease Control, attention deficit hyperactivity disorder (ADHD) affects 3%–7% of children and 2%–4% of adults. About 2.5 million children and 1.5 million adults currently take ADHD medication. And since ADHD is only treatable, not curable, people take drugs for life, equaling a potential boon for pharmaceutical companies. But FDA hearings, concerns over drug safety and abuse, and generic challenges have combined to create unwanted commotion and speculation about the market's future.

IMS Health data show that US sales of ADHD drugs in 2005 hit $3.04 billion, a 14% increase over 2004, but nothing like the huge year-on-year growth witnessed in previous years. Total prescription growth in 2005 also slowed, increasing just 5% to 34.9 million.

All but one of the ADHD treatments fall into two varieties of stimulants: methylphenidates (Ritalin, Concerta, Metadate CD and Daytrana) and amphetamines (Adderall and Adderall XR).

The market leader is Shire's Adderall XR, with $974 million in sales representing 32.1% of total dollar percentage of market share in 2005, according to IMS Health. Adderall XR, introduced in 2001, is a long-acting version of Adderall, approved in 1996.

Concerta, from Johnson & Johnson's McNeil Consumer and Specialty Pharmaceuticals, is second with 27.6% of the market and sales of $838 million in 2005. A 12-hour version was approved in 2000.

Eli Lilly's Strattera, the only nonstimulant, is third with 21.8% of the market share, translating to $662 million in 2005. The drug was approved in November 2002.

Novartis' Ritalin, marketed since 1955, is available in short and long-acting forms, as well as a generic. Novartis also makes Focalin TM, a refined version of Ritalin. Ritalin LA, an eight-hour formulation, placed fourth in total dollar percentage of the ADHD market, with 4.4% in 2005, bringing in $132 million.

Celltech Pharmaceuticals, acquired by UCB in 2004, makes Metadate CD, approved in April 2001. This once-daily formulation had 3% of the market and $91 million in sales in 2005.

The first-ever ADHD patch—Shire's Daytrana—was approved in April for children ages 6–12.

While ADHD medications are highly effective, they carry serious warnings. Side effects range from weight loss, insomnia, aggression and decreased appetite, to stunted growth, visual hallucinations, suicidal ideation, psychotic behavior, hypertension, arrhythmias and possibly death. Furthermore, long-term negative effects, especially on the development of young children's brains, are not well known. All ADHD stimulants are classified as Schedule II narcotics, a designation for medicines with the highest abuse potential and addiction profile.

These concerns have recently been highlighted. On Feb. 9, 2005, Canada's drug regulatory agency, Health Canada, suspended the sale of Shire's Adderall XR in that market due to reports of sudden heart-related deaths in users. And on Feb. 9, 2006, an FDA safety committee hearing voted 8-7 with one abstention to recommend a black-box warning for all ADHD drugs, to highlight the cardiovascular risk.

“Growth in the market is stalled right now,” says Geoff Penney, category business director for psychiatry at market research firm GfK Market Measures. “Whether these recurring safety issues will limit future growth is unclear.”

Yet, there are positives. Adderall XR was reinstated in Canada last August, albeit with revised warnings of risk in patients with heart abnormalities. And in March this year, an FDA safety committee of pediatricians and psychiatrists voted against the black box warning but recommended that patients and doctors be made more aware of potential psychosis, aggression and cardiac effects with ADHD medications.

“When you look at the number of prescriptions that have been dispensed for all ADHD medicines, it helps to show how truly safe and effective they are,” says Matt Cabry, senior manager, corporate communications, at Shire. “We've continued to actually hold, and at certain times grow, our market share over the past 12 to 18 months.”

Nevertheless, growth of the ADHD market has slowed considerably. One explanation could be the limited success ADHD medications have found outside the US. “Growth in Europe hasn't really begun,” Penney states. “Parents and doctors are averse to prescribing stimulants to kids—it is a cultural issue to some degree. America is the biggest consumer of prescription drugs in the world; we have a stronger trust in medicines. In Europe, there is more skepticism.”

Growth could be further impeded by the final FDA decision on black boxes, which if approved could deter physicians and patients from drug treatment. A black-box warning for cardiovascular risk would add to the black box already present on Strattera, warning of potential suicidal thinking in adolescents, and Adderall and Adderall XR, concerning amphetamines' abuse potential. Daytrana, whose approval closely followed the FDA advisory committee hearings, is the first methylphenidate product with a warning about sudden death and use in patients with structural cardiac abnormalities.

Anathea Waitekus, a senior analyst at market research firm Decision Resources, believes there will “eventually be some sort of revision of the labeling, but probably not a black box.”

Waitekus believes market growth will continue, driven by an increase in the diagnosed and drug-treated adult populations, which she says could gain a market share of $1.8 billion by 2014. A recent statistically significant analysis of ADHD medication use by Medco Health Solutions showed that the number of adults aged 20 to 44 using ADHD medicines increased more than 139% from 2000 to 2005, outpacing increases in children 19 and younger by 82%. Yet the study notes that cardiovascular risks associated with ADHD drugs are greater in adults than children; therefore, those safety issues should be taken into account when prescribing.

Females are also increasing their market presence. Medco showed that among women aged 20–44, use increased 164% from 2000 to 2005. During the same period, use in girls ages 10–19 increased 90%, outpacing boys by 45%. Waitekus says, “Physicians are realizing that children don't have to be hyper to have attention deficit, and that has been leading toward diagnosis and drug treatment of the inattentive subtype, which females tend to show more of.”

Promising new drug formulations will also help market growth.  These include Shire's Adderall XR2, a 15-hour extra-extended release version intended for adults; and NRP-104, a new amphetamine formulation that guards against abuse. NRP-104 results from Shire's collaboration with New River Pharmaceuticals, a company specializing in less easily abused formulations of scheduled drugs. A new drug application (NDA) was submitted in December 2005. 

NRP-104's safety profile is especially appealing because of stimulant misuse. The recent study “Non-medical use of prescription stimulants in the US,” conducted by researchers at RTI International and published in the February 2006 online edition of Drug and Alcohol Dependence, was based on a secondary analysis of data collected during 2002 for the National Survey on Drug Use and Health. It found that 7.3 million Americans have misused ADHD stimulants, representing 35% of the total population reporting prescription stimulant misuse, and concluded that about 1 million teenagers and young adults had misused prescription stimulants during a 12-month period, with 75,000 showing signs of addiction. Larry Kroutil, the study's lead author, believes the findings confirmed what people have long suspected: “The misuse of prescription stimulants in general, but particularly those that are prescribed for treatment of ADHD, is a significant problem in the US.” However, he adds that while care in diagnosing and monitoring patients is necessary, the study doesn't advise against medication. “Clearly, there are demonstrated benefits to use of these drugs.”

In addition to abuse, drug treatment in young children is also controversial. Waitekus says children are increasingly diagnosed at younger ages because of structured environments, such as day care, where hyperactivity is more noticeable. “Some doctors are treating these kids, 3-year-olds, with anti-psychotics and ADHD off-label because they don't know what the children have,” she states. Penney agrees, but adds, “There is a natural tendency to limit the use of drugs at that age. It is difficult to tell if you are diagnosing ADHD or if the child is just a normal energetic 6-year-old.” No treatment currently on the market is approved for use in children under the age of 6.

Generic threats also loom. Generics companies Barr, Teva and Impax have challenged Shire's Adderall XR, while Andrx Pharmaceuticals has created difficulty for J&J's Concerta. Shire settled with Impax: Shire has five years to switch patients from Adderall XR, Impax can sell an Adderall XR generic from 2010, and Impax will pay a royalty on generic sales. Shire is also in settlement talks with Barr. Though the pediatric exclusivity period for Concerta was due to expire on March 17, 2004, McNeil Consumer & Specialty Pharmaceuticals has successfully delayed Abbreviated NDA approvals for generic versions.

Between J&J and Shire, Penney thinks Shire will come out ahead. “Generics will likely come,” Penney says, “but the challenge to the generic manufacturers is not reproducing the chemical compound, but the delivery system technology. Concerta will likely be the first to go generic, with Adderall XR to follow some years later.” A spokesperson for J&J declined to comment on how the company plans to maintain Concerta's market share.

Shire's Cabry says, “We have been reasonably successful in defending our intellectual property, so much so that there is no chance that a generic would come on market this year.” Penney agrees, saying Adderall XR's generic challenge “is a non-issue. Adderall XR is king.”

If Adderall XR is king, Shire is its kingdom. Waitekus projects by 2014, Shire will own about 50% of the ADHD market due to a strong pipeline, marketing experience and promising new products. On top of its amphetamine franchise, Shire recently expanded into methylphenidates with Daytrana, allowing more direct competition with Concerta. 

As the first ADHD patch, the jury is still out on Daytrana. While advantageous for its ease of application, lack of negative food interactions and visual verification of compliance, Daytrana also contains a warning regarding contact sensitization—which in its most serious manifestation could render patients incapable of responding to methylphenidate in any form—and its ease in removal raises unique abuse concerns about patch sharing.

Waitekus has mixed views. “I never really thought that the patch would

do that well,” she states. “Patches in general just don't seem to do that well.” However, Penney says, “the patch represents a unique delivery with some advantages. When you can differentiate yourself, you can gain a market share.” And Waitekus admits that “if anything, it just gives Shire another reason to demonstrate its expertise … now it is just one-stop shopping with Shire.”

Shire's pipeline includes Adderall XR2, predicted to be popular with adults who want treatment to last through the workday. But the most promising successor to Adderall XR's throne is NRP-104. Waitekus predicts NRP-104 will become the first ADHD drug to achieve blockbuster status. “If Shire and New River can take this amphetamine formulation and develop a drug that is truly not scheduled or at risk of being abused, and is as effective as amphetamine, they are just going to corner the market. Even if it is scheduled, it will still have an advantage, because it has that aura of not having the potential to be abused.” NRP-104's favorable safety profile also increases the likelihood that it will be successful in markets outside the US.

Challenges exist for Eli Lilly. Strattera, the market's only non-stimulant, is losing share. A label update in December 2004 concerning the risks of liver damage, and a black box warning about suicidal tendencies in adolescents, probably didn't help. Yet Waitekus thinks the true reason for the decline is Strattera's efficacy. “It is hard to compete with methylphenidate and amphetamine,” she says, “those drugs work really well, so Strattera is just not that effective.”

Problems also exist for Cephalon, whose Sparlon—a stronger dosage of sleep disorder drug Provigil—was submitted for treatment of ADHD in children aged 6–17. In March, the FDA's Psychopharmacologic Drugs Advisory committee rejected Sparlon by a vote of 12-1 because of safety concerns related to Stevens-Johnson syndrome, a potentially fatal skin rash. Waitekus thinks if Sparlon receives a black box, “it just won't be able to compete with the amphetamines and methylphenidates.” She also notes that Provigil has been used off-label for ADHD and is not considered very effective. “Psychiatrists use drugs off-label all the time, and they are just not impressed [with Sparlon]. If it was so great, they would already be using it.”

To succeed, any new formulation will have to beat the methylphenidates and amphetamines. “To have a drug that is any better than methylphenidate or amphetamine in efficacy would just be extraordinary,” says Waitekus. She predicts formulations that last longer and have less potential for abuse.