Sleeper Diseases:
Forecast and Assessment of Neglected Disease Market Opportunities
Hermann A.M. Mucke, Ph.D.
 |
It is debatable whether still more such disorders are real medical conditions at all or, as many allege, are mere fictions created by special interest groups, often for litigious or other self-serving purposes. Several of these emerging sleeper diseases share key properties that make them highly interesting for the pharmaceutical industry:
• They are well defined and “real” beyond any reasonable doubt, although their etiology might be unknown or scientists’ understanding of them might be highly incomplete.
• They affect a considerable number of otherwise healthy individuals in ways that significantly compromise their quality of life, social functioning and professional accomplishments, yet they are rarely recognized as disorders (or are dismissed as personality quirks) by family, friends, colleagues, or even medical professionals, frequently because they do not manifest constantly or pervasively.
• They respond to treatment with currently available medications (or at least some of their constituent aspects do to a limited degree), and novel drugs (frequently based on genetic insights that reveal possible targets) are being investigated on the basis of scientifically defendable working hypotheses.
Five syndromes, described here, will develop into significant pharmaceutical markets by 2015.
Restless Legs Syndrome
Restless legs syndrome (RLS) is a recently recognized but vastly under-diagnosed movement disorder characterized by involuntary muscle contractions in the lower extremities that typically commence during sleep. In most cases the legs are affected, but RLS must be regarded as a manifestation of a broader syndrome, periodic limb movement disorder. Sleep quality––and, correspondingly, daytime wakefulness and attentiveness—are significantly impaired. In severe cases, uncontrollable limb movements can disrupt patients’ sleep every few minutes, effectively abolishing their ability to regenerate at night. Selective dopamine agonists that are already approved for treating Parkinson’s disease are the current treatment standard, and all major pharmaceutical companies have some sort of ongoing development program for this most “established” sleeper disease.
RLS is a new market, but it is associated with Parkinson’s disease, a mature therapy field that has been served for decades by neurologists prescribing dopaminergic drugs to essentially every diagnosed patient. Because RLS also is a movement disorder with a dopaminergic deficiency background that draws on the same class of drugs, there is solid ground on which to build this new market.
The RLS market, which so far has been very small in terms of sales and started to take off only when GlaxoSmithKline secured additional RLS approval for its selective dopamine D2/D3 receptor agonist Requip (ropinirole) in May 2005, will see a 10-fold expansion of its potential treatment population until 2015. The degree to which physicians are trained to recognize RLS in patients, who in most cases do not complain about repetitive limb movements but only about sleep disturbances or daytime sleepiness, will determine the dynamics of this emerging market during the next decade.
Eating Disorders
Comprising bulimia nervosa, binge eating disorder and anorexia nervosa, eating disorders have recently gained a certain public notoriety because of the numerous celebrities who have described themselves as sufferers. These purely mental syndromes, which mostly affect young women but are also found in some men, are characterized by excessive eating/purging cycles or alimentary rejection accompanied by delusions and obsessions about body shape and weight.
Only a minority of people who meet stringent diagnostic criteria for eating disorders are seen in mental health care. The average prevalence rate for anorexia nervosa, for which the predominant symptom is excessive weight loss through self-starvation, is 0.3% in young Western girls; it hardly seems to exist in adolescent boys.
The prevalence rate for bulimia nervosa (characterized by periods of compulsive consumption of large amounts of food, followed by self-induced immediate purging) is 1% and 0.1% for young women and young men, respectively. The estimated prevalence of binge eating disorder (essentially bulimia without the purging component) is at least 1%. Some researchers believe that, although bulimia might essentially be a culture-bound syndrome, this might not be the case for anorexia nervosa. Because of their significant physical, psychological, and social consequences, eating disorders deserve aggressive intervention. Typically, their successful management currently requires a multidisciplinary team approach, which is expensive. The costs of therapy for anorexia nervosa are higher than those for schizophrenia, and the binge-related types are at least as costly to treat as obsessive/compulsive disorder (OCD). While clinicians treat quantitative and qualitative malnutrition and gastroenterologic complications, psychotherapy and treatment with several classes of psychopharmacologic agents have brought only limited success so far.
Because of the significant degree of psychiatric comorbidity, especially with bipolar disorders, pharmacotherapy of these potentially underlying disorders is mandated. Mood stabilizers used in bipolar disorders and high doses of selective serotonin reuptake inhibitor antidepressants are the most frequently prescribed drugs. The important challenge for the future is to develop drugs that reduce the strong obsessive elements in eating disorders while not interfering with weight, as do virtually all current antidepressants and most antipsychotics.
Chronic Fatigue Syndrome and Fibromyalgia
Chronic fatigue syndrome (CFS; characterized by disabling fatigue that persists for at least 6 months) is a controversial midlife disorder, with its issues further obscured and complicated by different case definitions, etiologic models, and proposed treatments. It is distinguished from simple tiredness by its incapacitating intensity and pervasiveness, which severely interfere not only with occupation and daily chores but with virtually every aspect of life, including most types of recreational activity.
Importantly, although complaints about fatigue are generally very common in medical practice, CFS is understood to be relatively rare: Its prevalence is estimated at less than 3% in the general population and is markedly higher in women than in men. The significant association with certain types of occupation that is sometimes reported usually disappears after accounting for gender. Although many immune parameters have been evaluated in CFS, no specific biomarkers have been identified. Increasing evidence has shown that persistent, CFS-like symptoms and the fibromyalgia syndrome (FMS; characterized by chronic and mostly localized muscular tenderness with or without joint pain, recurrent sore throat, and “functional somatic syndromes,” including irritable bowel syndrome, subsets of chronic low-back pain, sleep disturbances and malaise after minor exertions) share common underlying causes.
The concept of “continuum” or “spectrum” disorders is pivotal in understanding these interactions. The neuroendocrine system, the immune system, and the limbic areas of the brain appear to play major pathogenetic roles in both syndromes. Symptoms are often exacerbated by stress, lack of sleep, and weather changes. A wide variety of medications are used to manage the eclectic symptomatology of FMS patients, although relatively few have been rigorously tested.
Estimates are that 2% to 6% of American adults have symptoms that fit either CFS or FMS diagnoses, with a significant overlap. However, many of the epidemiologic associations seen in specialist clinics are not found in community samples, and the extent and importance of the interactions between psyche and soma are unknown. A special case is the “Gulf War syndrome,” a set of heterogeneous ailments consisting mainly of chronic pain, fatigue, and depression, for which approximately 16% of all U.S. and U.K. veterans of the 1991 Gulf War have been seeking public healthcare–related support. Pain medications and antidepressants show limited effects in these syndromes, which cause a significant amount of economic damage because they affect mostly the young and middle-aged. New interdisciplinary concepts that involve addressing the stress hormone cascades and the immune system might open new approaches that are based on the interplay between neurohormonal shifts and pain processing.
Compulsions, Phobias and Panic Attacks
OCD and specific, directed phobias that impair quality of life through avoidance of anxiety-causing situations (and can cause isolated panic attacks if such situations cannot be avoided) seem to be part of a psychiatric spectrum. Although these conditions can involve a high degree of anxiety, they must not be confused with general anxiety disorder, because symptoms occur in a highly focused fashion. Characteristically, affected persons can lead outwardly normal lives and can even be professional overachievers; their disorder is either regarded as merely peculiar (as in OCD patients, who have to follow minor compulsive rituals) or manifests only in specific situations, as do phobias that can render a person unable to board an airplane, attend social events or give presentations.
 |
Social phobia (the pathologic fear of doing or saying something embarrassing in social situations) and panic disorders are more clearly within the spectrum of anxiety disorders than is OCD. Younger individuals show the highest rates, and once again women are more frequently affected than men. Often without prior warning, and without apparent and adequate cause, patients with panic disorder experience attacks with all the physiologic and psychological symptoms that would normally only be triggered in immediately life-threatening situations. Concern about having attacks in public directly leads to social phobia as an avoidance behavior. Prevalence is approximately 3% for panic disorder and 13% for social anxiety disorder in the United States, but both conditions are vastly underreported because of social stigmatization. Reported rates are much lower (around 2% for social anxiety disorder) in Europe, where their degree of acceptance as diagnostic psychiatric entities is lower. Although cognitive behavioral therapy can be very useful in mild cases of social anxiety disorder, more severe manifestations require additional pharmacotherapy, which usually comprises antidepressants and anxiolytics. Panic disorder is treated much in the same way, but with higher doses and with more emphasis on sedation; even so, it is frequently not possible to suppress panic attacks completely. Both conditions might require long-term therapy to prevent relapse. Again, molecular life science and genetic research suggests novel treatment approaches, but much of the pharmacotherapeutic success expected for the years until 2015 will have to be based on a reconceptualization of these disorders, a required change of paradigms that also extends to OCD.
Autism
Rain Man, the Oscar-winning 1988 film in which the actor Dustin Hoffman embodies an autistic man who slowly opens up to his brother, was most influential in raising public awareness of the pervasive development disorder that constitutes the broadly varying spectrum of autism. From the earliest ages, affected persons exhibit significant difficulty in social interactions and communicating with others and inflexible adherence to unusual stereotyped routines. Intellectual retardation and motor clumsiness manifest at later stages. Adults with autism can suffer from epilepsy and from a wide array of psychiatric disturbances, including affective disorder, anxiety disorders, schizophrenia-like psychosis, aggression, antisocial behavior and Tourette disorder. Asperger’s syndrome also falls into the autistic spectrum, but, because delayed language development is not among its characteristics, it usually manifests itself only at preschool age. Its incidence and prevalence might be higher than those of autism, but it is believed to be more underreported. The current rational consensus for the incidence of autistic spectrum disorders (ASD) of any severity in the major pharmaceutical markets is 300 to 600 cases per 100,000 births (which in this case equals prevalence, i.e., 0.3–0.6%), dramatically more than the 20 to 40 cases per 100,000 figure that had been estimated in the 1960s. It is not yet clear how much of this reported rise is attributable to actual epidemiologic changes, since the definition of ASDs has been considerably broadened during this period. The much higher figures (up to one-digit percent levels) that are also circulating in the literature do not pertain to ASDs that meet medical definitions. Although much of this increase can be explained by improved assessment methods and a considerable broadening of the diagnostic concept, environmental factors and damages from mercury-containing preservatives in vaccines have also been invoked, especially in the United States. If such environmental influences exist, the high degree of heritability of ASD would suggest that these factors may interact with genetic predispositions during vulnerable periods of development; this is a concept not unlike the one that has been proposed for susceptibility to schizophrenia and multiple sclerosis. In any case, this proliferation of diagnosed cases could create a significant market for the pharmaceutical industry if targeted drug therapies could be developed that have some effectiveness. Because ASDs are lifelong chronic disorders and patients are expected to have a normal lifespan, a market of very considerable size—probably comparable to the dementia market—could be created. This market would have a large pediatric segment, especially as it emerges, but it would span all age groups from its inception. A wide array of brain pathologies and neurotransmitter systems have been studied to establish neurochemical correlates, but the heterogeneity of ASDs has mostly prevented firm conclusions. None of the current treatments for ASD core symptoms are curative, and most pharmacologic treatments, such as antidepressants and anticonvulsants (none of them approved for ASD), are directed at treating specific troubling symptoms. The peculiar association between autism and certain intestinal problems has led to extensive trials with the neuropeptide secretin, but they now finally seem to have failed. New pharmacotherapies are desperately needed, and research is intense but has to deal with equations that have many unknowns. Although ASDs will most certainly not be curable by 2015, significant progress in achieving self-reliance for the milder cases will be made until this time.
Summary
Sleeper diseases comprise a broad spectrum with various degrees of neuropsychiatric involvement, and their clear definitions are earning them increasing acceptance as real disorders that can and should be addressed by pharmacotherapy. The estimate that approximately 10% of all adults with diseases in the major pharmaceutical markets could profit from such therapy does not seem exaggerated, given the known prevalence data. Impairments from sleeper diseases can range from the marginal to very severe, even if they are not deadly. The pharmaceutical industry has already begun to create markets for RLS and OCD, it is gearing up to tackle eating disorders and CFS/fibromyalgia, and it is pushing for more insights into the other syndromes. Treatment of all these now-emerging disorders will be an accepted, if not already integral, part of healthcare by 2015.
About the Author
Hermann A.M. Mucke, Ph.D. is founder and principal of H.M. Pharma Consultancy (www.hmpharmacon.com <http://www.hmpharmacon.com> ). He is an independent pharmaceutical consultant, analyst and science author.
More info:
Sleeper Diseases: Forecast and Assessment of Neglected Disease Market Opportunities is an Advances Report published by Cambridge Healthtech Associates, Waltham, MA. www.advancesreports.com.
