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NEWS & ANALYSIS

FRESH FROM THE PIPELINE Atomoxetine hydrochloride

Melissa Garland and Peter Kirkpatrick Atomoxetine

In November 2002, atomoxetine hydrochloride functions such as attention — are dysregulated for ADHD9.Signs and symptoms of ADHD (Strattera; Eli Lilly), a noradrenaline-reuptake in ADHD, and the efficacy of in were evaluated by a comparison of mean inhibitor, was approved by the US FDA for the ADHD is thought to result from their influ- change from baseline to endpoint for atomoxe- treatment of attention-deficit–hyperactivity ence on these neurotransmitter systems4,5. tine hydrochloride-treated and placebo-treated disorder. As the first non- drug for this The implication of the dopaminergic and patients using an intent-to-treat analysis of the common but controversial condition, and also noradrenergic systems in ADHD has also primary outcome measure, the investigator- the first approved for the treatment of adults, provided the rationale for testing a range of administered and -scored ADHD Rating Scale- what influence has it had on the market since other agents known to affect them, including IV-Parent Version (ADHDRS) total score. In all its introduction? various . four trials, which lasted six to nine weeks, improvements in ADHD symptoms were Attention-deficit–hyperactivity disorder Drug properties significantly superior in patients receiving (ADHD), which usually begins in childhood, Atomoxetine is a selective inhibitor of the atomoxetine hydrochloride compared with is characterized by developmentally inappro- presynaptic noradrenaline transporter, and those receiving placebo9. priate hyperactivity, and inatten- so prolongs the activity of noradrenaline Atomoxetine hydrochloride was also studied tion1.It has been estimated to affect ~4% of released into the synaptic cleft6.It was initially in two randomized, double-blind, placebo- the paediatric population, and has a major identified more than 20 years ago as part of a controlled studies involving 536 adult patients impact on society in terms of its financial programme aimed at the discovery of anti- who met DSM-IV criteria for ADHD9.Signs cost, stress to families and adverse effects on depressants6,7,but although it entered clinical and symptoms of ADHD were evaluated academic performance1–3.Although it was trials, it was dropped from development for using the investigator-administered Conners previously thought to remit largely during , as a related compound, Adult ADHD Rating Scale Screening Version adolescence, there is growing evidence that (Prozac; Eli Lilly) looked more promising. (CAARS). In both studies, which lasted ten the disorder and/or associated impairment However, initial trials in ADHD indicated weeks, ADHD symptoms were significantly can persist into adulthood in many cases3. that it had potential for this condition8. improved in those patients receiving atomox- Psychostimulant drugs, such as methyl- etine hydrochloride9. phenidate and formulations, Clinical data have been the mainstay of pharmacological Atomoxetine hydrochloride was assessed in four Indications treatment of ADHD for several decades, and randomized, double-blind, placebo-controlled Atomoxetine hydrochloride is indicated for the in general can result in immediate and often studies involving 759 paediatric patients (ages treatment of attention-deficit–hyperactivity dramatic improvements in behaviour1.The 6 to 18 years old) who met Diagnostic and disorder9.It is approved for use in children, more recent development of long-acting Statistical Manual 4th edition (DSM-IV) criteria adolescents and adults. ▲ stimulant formulations that allow convenient dosing regimes has also helped to cement these drugs as first-line pharmacotherapies acCF3 for ADHD. However, a significant proportion of O O CH3 CH3 patients — generally reported to be about N N one-third — do not respond to stimulants, H H • HCl or are unable to tolerate their side effects, such as nausea and insomnia3.In addition, Fluoxetine Atomoxetine hydrochloride (-)-N-methyl-3-phenyl-3-(o-tolyloxy)- these drugs are controlled substances owing propylamine hydrochloride; to their abuse potential, and so parents can b H3CO C17H21NO•HCl; Mr = 291.82; have reservations about administering them CAS number: 82248-59-7 to their children. These factors have increased O CH3 demand for non-stimulant drugs that can be N used for the treatment of ADHD. H

Nisoxetine Basis of discovery The pathophysiology of ADHD is not fully understood, but it seems to have a substantial Figure 1 | Atomoxetine hydrochloride. During the 1970s, researchers at Eli Lilly identified several related compounds that selectively and potently inhibited the uptake of (for example, fluoxetine (a)) genetic basis1,2.There is considerable evi- or noradrenaline (for example, (b)). An analogue of nisoxetine, LY135252, with a longer duration dence indicating that dopaminergic and of action was reported in 1982 (REF.6). It was also found that the (–)-isomer of LY135252 — later named noradrenergic neurotransmission — well tomoxetine, and then atomoxetine — was ~10 times more potent than the (+) isomer6, and so the (–)- known to have a key role in higher cortical isomer was chosen for development.

NATURE REVIEWS | DRUG DISCOVERY VOLUME 3 | MAY 2004 | 385 NEWS & ANALYSIS

ATOMOXETINE HYDROCHLORIDE | MARKET ANALYSIS

In 2002, sales of therapies used to treat ADHD ADHD. Its launch in the ADHD market was market by 2007 owing to its marketing and in the seven major markets totalled US $1.4 met with great enthusiasm, as physicians and logistical advantages as a nonstimulant therapy, billion (FIG. 2a).The United States — where parents welcomed a therapy that satisfied as well as its higher price compared with leading physician awareness and acceptance of ADHD their desire for an effective, nonstimulant long-acting psychostimulant products. as a valid disorder is higher than in Europe and treatment option. So, uptake of this agent into Atomoxetine’s potential is further enhanced Japan — was the overwhelming leader in medical practice and treatment algorithms by the growing awareness among physicians terms of ADHD sales, dominating the market has been rapid. and the public of ADHD’s persistence into with a 97% share of sales for this indication. Atomoxetine’s successful debut in the ADHD adulthood. Atomoxetine was approved for use Although psychostimulants (for example, market has been driven not only by its ability to in adult ADHD sufferers — presently an formulations such as Ritalin fill a market need, but also by an aggressive sales underdiagnosed and undertreated popula- (Novartis) and Concerta (McNeil Consumer & effort. This sales campaign, coupled with a tion — before its two closest competitors, Specialty Pharmaceuticals) and amphetamine robust direct-to-consumer advertising effort XR and Concerta. (Adderall XR was formulations such as Adderall and Adderall XR via television and print media to raise awareness approved for use in adults in October 2003, (Shire)) are generally very effective in treating among parents and patients, helped atomox- and Concerta is currently undergoing Phase III ADHD symptoms, many factors hamper the etine capture nearly 20% of US ADHD sales studies in adult ADHD patients.) So, increasing uptake of these agents by as many patients who during its first year on the market, with sales diagnosis and drug treatment rates among adult could potentially benefit from their use. Because totalling ~ US $387 million in the United ADHD sufferers will further drive atomoxetine’s psychostimulants are controlled substances, States (FIG. 2b). sales potential. conveniences afforded to most other drugs (for Although there are logistical hurdles and example, mail-order availability and phone-in Future outlook abuse concerns associated with psychostimulant refills) are not available for agents in this class. Atomoxetine’s approval by the FDA was based use, we believe psychostimulant agents will Children taking psychostimulants for ADHD on results from multiple placebo-controlled retain an important position in future ADHD must visit a nurse or school official to receive studies, but the drug’s efficacy was not com- treatment algorithms, especially if the efficacy of their medication, a policy that hinders drug pared with that of psychostimulant formula- Concerta is demonstrated to be superior to that compliance. Although the introduction of tions in clinical trials. Additionally, many of atomoxetine in the FOCUS study. We fore- long-acting psychostimulant formulations experts interviewed by Decision Resources cast the continued uptake of atomoxetine and such as Concerta and Adderall XR to the question whether the efficacy of atomoxetine the continued success of current psychostimu- ADHD market has helped ease the burden of can match or surpass that of currently avail- lant market leaders Concerta and Adderall XR mid-day dosing at school, the abuse potential able psychostimulants, whose effect on ADHD will help increase the ADHD market in the associated with psychostimulant drugs has symptoms have been well documented in seven major pharmaceutical markets from US left many physicians and concerned parents numerous trials. In an effort to elucidate dif- $1.4 billion in 2002 to nearly US $3.3 billion in wishing for effective alternative therapies. ferences in treatment outcomes between 2012 (FIG. 2a).In 2012, we believe atomoxetine Concerta and atomoxetine, McNeil Consumer has the potential to capture a 45% share of the Enter atomoxetine & Specialty Pharmaceuticals initiated the ADHD market, with sales totalling just under Nonstimulant therapies (for example, anti- Formal Observation of Concerta versus US $1.5 billion. depressants, α adrenoceptor agonists, anti-epi- Strattera (FOCUS) study in October 2003. 2 Peter Kirkpatrick is at Nature Reviews Drug leptics and ) have been used The results of this open-label, randomized, Discovery.Melissa Garland is at Decision Resources off-label as second-line agents to treat ADHD community-based study will have a significant Inc., 260 Charles Street, Waltham,Massachusetts for years, but the effectiveness of these agents in impact on whether physicians turn to atom- 02453, USA. Correspondence to M. G. treating ADHD symptoms has not been con- oxetine or established psychostimulant ther- e-mail: [email protected] clusively demonstrated in multiple large-scale apies for first-line use in ADHD patients. doi:10.1038/nrd1387 clinical trials. In January 2003, Eli Lilly launched Even if results of the FOCUS study indicate 1. Elia, J. et al. Treatment of attention-deficit–hyperactivity disorder. N. Engl. J. Med. 340, 780–788 (1999). atomoxetine hydrochloride (Strattera) in the that atomoxetine is less efficacious than 2. Zametkin, A. J. & Ernst, M. Problems in the management of United States as the first nonstimulant therapy Concerta, we believe atomoxetine has the poten- attention-deficit–hyperactivity disorder. N. Engl. J. Med. 340, 40–46 (1999). specifically indicated for the treatment of tial to become the sales leader in the ADHD 3. Wilens, T. E. et al. Attention deficit/hyperactivity disorder across the lifespan. Annu. Rev. Med. 53, 113–131 (2002). 4. Solanto, M. V. dysfunction in AD/HD: integrating a 83 b clinical and basic neuroscience research. Behav. Brain Res. 107 130, 65–71 (2002). 110 816 5. Biederman, J. & Spencer, T. Attention-deficit/hyperactivity 387 Methylphenidate disorder (ADHD) as a noradrenergic disorder. Biol. Pyschiatry 806 formulations 46, 1234–1242 (1999). 6. Wong, D. T. et al. A new inhibitor of uptake 2002 2012 2003 Amphetamine 680 1,484 formulations devoid of affinity for receptors in rat brain. J. Pharmacol. 613 Atomoxetine Exp. Ther. 222, 61–65 (1982). Other drugs 7. Zerbe, R. L. et al. Clinical pharmacology of tomoxetine, a potential . J. Pharmacol. Exp. Ther. 232, 900 771 139–143 (1985). 8. Spencer, T. et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity Figure 2 | Market for drugs used to treat ADHD in US $ millions. a | Sales in the seven major pharmaceutical disorder. Am. J. Psychiatry 155, 693–695 (1998). 9. FDA Drug Approvals List [online], (cited 6 Mar 2004). markets (United States, France, Germany, Italy, Spain, United Kingdom, and Japan). b | Impact of atomoxetine in (2002).

386 | MAY 2004 | VOLUME 3 www.nature.com/reviews/drugdisc