Before prescription drugs can be marketed, they must undergo a thorough and complete research and development process. During this time, the drug is extensively studied in the laboratory, in healthy human volunteers, and in patients who suffer from the targeted condition. This process is imperative to ensure that prescription drugs are safe and effective.
Chelsea currently has drug candidates at various stages of development and has initiated research of droxidopa in multiple indications in which norepinephrine may play a role, including:
These areas of research and development have not been reviewed or approved by the FDA.
Symptomatic Neurogenic Orthostatic Hypotension
Orthostatic hypotension (OH) is a prolonged drop in blood pressure when a person assumes a standing position from a sitting or lying down position, which compromises
blood flow to the brain and other parts of the body. Causes for OH can be cardiovascular, endocrine or neurological in nature.1
Symptoms of OH are a result of hypoperfusion of vital organs and can occur frequently and may include: dizziness, lightheadedness, blurred vision, fatigue and poor concentration.1,2 In more serious cases, patients may faint, a disorder known as syncope, which can lead to injury and disability.2,3 OH, whether or not it is related to a neurologic disease, is defined as a reduction of systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 minutes of standing.4
Symptomatic neurogenic orthostatic hypotension (Neurogenic OH or NOH) is a subtype of OH that results from an attenuated norepinephrine response to standing. Norepinephrine is the neurotransmitter used by autonomic nerves to send signals to the blood vessels and the heart to regulate blood pressure.5 The symptoms of Neurogenic OH present similarly to the aforementioned symptoms of OH.4 Neurogenic OH occurs in patients with underlying neurodegenerative disorders, including Parkinson's disease, multiple system atrophy, pure autonomic failure, non-diabetic autonomic neuropathy and dopamine beta hydroxylase deficiency.6
There are few options currently available to treat the symptoms of neurogenic orthostatic hypotension (Neurogenic OH or NOH). These treatments encompass both non-pharmacologic and pharmacologic strategies.7
Non-pharmacologic treatments are generally used initially to treat Neurogenic OH and may include:
If non-pharmacologic treatments are unsuccessful, practitioners may add a pharmacologic agent. The most common pharmacologic treatments, available from other manufacturers, include midodrine, a vasoconstrictor, that works directly on the vasculature to increase blood pressure, and fludrocortisone, a mineralcorticoid, that increases blood plasma volume which can also increase blood pressure.
Midodrine (ProAmatine®), an alpha agonist, is the only drug approved by the FDA for the treatment of symptomatic OH.7
- Has been shown to increase standing systolic blood pressure
- Side effects include hypertension, gastrointestinal distress, parasthesia, pruritis and piloerections
- Carries a black box warning regarding supine blood pressure elevation and lack of demonstrated clinical benefit, principally in improving the ability of patients to carry out activities of daily living
Fludrocortisone (Florinef®), approved for treatment of adrenocortical insufficiency in Addison’s disease patients, is widely used off-label to treat OH.
- Side effects include edema, hypokalemia, hypertension, headache and congestive heart failure
In September of 2011, Chelsea submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval to market droxidopa in the United States for the treatment of symptomatic Neurogenic OH. The clinical portion of the NDA filing comprises pooled safety and efficacy data from two finalized Phase III studies in Neurogenic OH, studies 301 and 302, two long-term open-label extension studies, a comprehensive QTc study, and a 24-hour ambulatory blood pressure monitoring safety study. The NDA was accepted for review by the FDA in November of 2011. (top)
Intradialytic hypotension (IDH) is a common adverse event during routine hemodialysis. Yet at this point in time, there are no FDA approved therapeutic agents for the treatment of IDH in the US. IDH is often defined as a decrease in systolic blood pressure by greater than or equal to 20 mmHg upon standing after hemodialysis.8 IDH has been reported in approximately 25% of all hemodialysis patients, with elderly patients reporting higher incidences.9 Many adverse hemodialysis events, including abdominal discomfort; yawning; sighing; nausea; vomiting; muscle cramps; restlessness; dizziness or fainting; and anxiety, are associated with IDH.9 These complications can routinely interrupt dialysis sessions, necessitating repetition of the procedure.9,10 Interruptions due to IDH increase the costs of both the dialysis treatment sessions and the long-term care of less healthy hemodialysis patients.
In March of 2009, Chelsea reported results from a Phase II trial investigating droxidopa compared to placebo in patients with IDH. The pertinent press release describing the study can be viewed here. (top)
Fibromyalgia is characterized by chronic, widespread musculoskeletal pain, multiple tender points, abnormal pain sensitivity, and is often accompanied by severe fatigue, insomnia and mood symptoms.11 Fibromyalgia is one of the most commonly diagnosed rheumatologic conditions and is estimated to affect two to four percent of people, mostly women.12 While the precise etiology of fibromyalgia remains unknown, current research indicates that norepinephrine reuptake and availability in the central nervous system plays a significant role in this disease.13 Norepinephrine deficiency has long been linked to both chronic pain and depression. While norepinephrine does not penetrate the blood-brain barrier, droxidopa, due to its unique mechanism of action, is able to do so thus providing both a peripheral and central effect on circulating norepinephrine levels.14 Currently, there are very few viable pharmacotherapeutic options available for fibromyalgia patients, necessitating novel treatments for this under-recognized and undertreated disease state.
In December of 2011, Chelsea completed a Phase II trial of droxidopa, both alone and in combination with carbidopa for the treatment of fibromyalgia. The primary endpoint of the study was the average reduction in pain as measured by the Short Form McGill Pain Questionnaire (SF-MPQ). Topline results indicate average improvements in baseline SF-MPQ scores of those receiving droxidopa of 3.2 units over placebo, at the end of the nine-week treatment period. Furthermore, there were fewer discontinuations in the droxidopa monotherapy treatment group (29.2%) compared to placebo (46.7%) and no serious adverse events were associated with droxidopa as either monotherapy or in combination with carbidopa. The pertinent press release describing the study can be viewed here. (top)
In addition to the research and development areas for which Chelsea has established active clinical programs, there are a number of other prospective therapeutic areas in which norepinephrine function may play a significant role and for which droxidopa may provide clinical benefit. To facilitate research in additional therapeutic areas and maximize the long-term development potential, Chelsea has initiated an extra-mural development program that enables independent investigators to conduct clinical trials in their respective fields of expertise. Specifically, Chelsea is exploring clinical studies, under investigator-sponsored investigational new drug applications (INDs), intended to evaluate the safety and efficacy of droxidopa for norepinephrine related disorders
In July of 2011, droxidopa completed an investigator-led Phase II clinical study in ADHD, initiated by the Narrows Institute for Biomedical Research in New York. The pertinent press release describing the study can be viewed here.
Chelsea plans to continue working with key opinion leaders to identify and evaluate additional research and development areas for droxidopa and may provide droxidopa for future studies when deemed appropriate and as funding and availability of drug substance permits. (top)
Figueroa JJ, Basford JR, Low PA. Preventing and treating orthostatic hypotension: As easy as A, B, C. Cleveland Clinic Journal of Medicine 2010; 77(5):298-306.
Olshansky, B. (1998). Chapter 1- Syncope: Overview and Approach to Management. In Syncope: Mechanisms and Management (pp. 1-46). Wiley-Blackwell.
4. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neutrallymediated syncope and the postural tachycardia syndrome. Auton Neurosci. 2011 Apr 26;161(1-2):46-8.
5. McCorry LK. Physiology of the Autonomic Nervous System. Am J Pharm Educ. 2007 Aug 15; 71(4): 78.
6. Goldstein DS, Sharabi Y. Circulation. 2009 Jan; 119(1):139-46.
7. Low PA, Singer W. Update on Management of Nuerogenic Orthostatic Hypotension. Lancet Neurol. 2008 May; 7(5):451-458.
8. Fujisaki K, Kanai H, Hirakata H, Nakamura S, Koga Y, Hattori F, Iida M. Midodrine hydrochloride and L-threo-3,4-dihydroxy-phenylserine preserve cerebral blood flow in hemodialysis patients with orthostatic hypotension. Ther Apher Dial. 2007 Feb; 11(1):49-55.
9. KDOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients. National Kidney Foundation 2005.
10. Hayes W, Hothi, DK. Intradialytic hypotension. Pediatr Nephrol 2011; 26:867–879
11. Fibromyalgia. 14 Feb 2011. ADAM Medical Encyclopedia. 20 Jan 2012
12.Fibromyalgia. Feb 2012. American College of Rheumatology. 15 Feb 2012.
Mease PJ. Further strategies for treating fibromyalgia: the role of serotonin and norepinephrine reuptake inhibitors. Am J Med. 2009 Dec;122(12 Suppl):S44-55.
14. Kaufmann H. L-dihydroxyphenylserine (Droxidopa): a new therapy for neurogenic orthostatic hypotension. Clin Auton Res 2008; 18(Suppl 1):19–24