Dr. Mark H.N. Corrigan, MD

Dr. Corrigan is Chairman of the Board of Epirus Biopharmaceuticals, Inc. a public biopharmaceutical company, and from 2010 to 2014, he previously served as a director, president and chief executive officer of Zalicus Inc. prior to its merger with Epirus Biopharmaceuticals in July 2014. Prior to Zalicus, Dr. Corrigan joined the specialty pharmaceutical company Sepracor Inc. in 2003 (now known as Sunovion Pharmaceuticals, Inc.) where he served as Executive Vice President of Research and Development until December 2009. Prior to joining Sepracor, Dr. Corrigan spent 10 years with Pharmacia & Upjohn, where he served most recently as Group Vice President of Global Clinical Research and Experimental Medicine.
Before entering pharmaceutical industry, Dr. Corrigan spent five years in academic research at the University of North Carolina, School of Medicine, focusing on psychoneuroendocrinology; he maintains a faculty appointment as Adjunct Professor in the Psychiatry Dept. He is a Distinguished Fellow of the American Psychiatric Association. Dr. Corrigan has also chaired the Scientific Committee of the boards of directors of Avanir Pharmaceuticals and of Cubist Pharmaceuticals, Inc. Dr. Corrigan holds a B.A. and an M.D. from the University of Virginia and received specialty training in psychiatry at Maine Medical Center and Cornell University.


Rett Syndrome

DNARett syndrome (RTT) is a genetically-encoded neurodevelopmental disorder that occurs almost exclusively in females and arises from deficiencies in the function of the methyl-CpG binding protein 2 gene (MeCP2). Rett syndrome (RTT) was first described by Austrian paediatrician Andreas Rett in 1966. RTT is characterized by arrested development at about 1 year of age, regression of acquired skills and mental retardation. The clinical features include small hands and feet and a deceleration of the rate of head growth. Repetitive stereotyped hand movements, such as wringing, are also noted. Females with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures. They typically have no verbal skills, and many individuals affected do not walk. Scoliosis, growth failure, and constipation are common and can be problematic. Along with the core symptoms of RTT, disturbances in breathing are particularly troublesome (see below). RTT is severely debilitating and patients require constant and life-long care from family members and medical institutions.


Breathing irregularities in Rett syndrome

Among the symptoms of RTT, breathing difficulties, including hyperventilation, forced expulsion of air and saliva, and apneas, can be most troubling and disrupt patients' condition. Breathing difficulties occur in most RTT patients to varying degrees and predominate during daytime wakefulness, although they are also present during sleep. Breathing disturbance is associated with chronic deficits in blood oxygen levels that may accentuate cognitive deficits and are a risk factor for the seizures which are observed in RTT patients. Breathing irregularity is also associated with feeding difficulties, notably because of dysfunctional coordination between breathing and swallowing. RTT patients also suffer from accentuated aerophagia (air swallowing) which causes digestive disturbance. Finally, irregular breathing can be distressing for patients and their families, accentuating heightened anxiety levels. A pharmacotherapeutic, such as NLX-101, that is able to improve breathing difficulties (as well as, potentially, cognitive function and movement) could ameliorate the quality of life of patients and their carers.


For additional background information on Rett syndrome, see curated articles here.

NLX-101 : a novel treatment for Rett syndrome (RTT), an orphan disorder

NLX-101 (previously known as F15599) is a novel compound that activates serotonin 5-HT1A receptors [1] with exceptional selectivity, having over 1000-fold higher affinity for this target over other receptors. In addition, NLX-101 is a 'biased agonist' at 5-HT1A receptors, preferentially activating 5-HT1A receptors in those brain regions that control mood and cognition. In animal models, NLX-101 is very active in a rat test of antidepressant activity following a single administration, whereas currently used antidepressants require repeated administration to show activity. NLX-101 also robustly restores memory deficits. These pronounced antidepressant and cognitive enhancing properties are not seen with older 5-HT1A agonists.


Treatment of breathing deficits in Rett syndrome using NLX-101

A dysfunction of the serotonergic system has been described for Rett syndrome (RTT), with supporting data coming from Rett patients and from transgenic mouse models [2]. Taken together, these data suggest that a selective 5-HT1A receptor agonist would be of therapeutic benefit for Rett syndrome patients.

The effects of NLX-101 were investigated in a transgenic mouse model of Rett syndrome. These mice exhibit severe breathing difficulties, including apneas and respiratory irregularity, similar to those seen in girls with Rett syndrome. Notably, the administration of NLX-101 in Rett mice robustly reduced the occurrence of apneas and normalized the irregular breathing patterns [3] without interfering with other behaviors. These data suggest that NLX-101 may represent a promising strategy for treating breathing disturbances in Rett syndrome: a cardiorespiratory study of NLX-101 in Rett mice is being supported by a grant from the International Rett Syndrome Foundation. Rett syndrome patients also exhibit high levels of mood deficits and are cognitively impaired: NLX-101 treatment may bring additional benefit in these areas.


[1] Newman-Tancredi A. (2011) Neuropsychiatry, 1(2):149-164.

[2] Abdala et al. (2014) Front Physiology, 5:205.

[3] Levitt et al. (2013) J Appl Physiol, 115(11):1626-33.

Parkinson's Disease

Parkinson's disease (PD) is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. Early in the course of the disease, the most obvious symptoms are movement-related; these include shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems. Parkinson's disease is more common in older people, with most cases occurring after the age of 50. Some of these non-motor symptoms are often present at the time of diagnosis and can precede motor symptoms.



Treatment of Parkinson's Disease motor symptoms with L-DOPA

Levodopa (L-DOPA; L-3,4-dihydroxyphenylalanine) has been the most widely used PD treatment for over 30 years. It is converted into dopamine by an enzyme called dopa decarboxylase in dopaminergic neurons. Since motor symptoms are produced by a lack of dopamine, the administration of levodopa temporarily diminishes them. However, upon long-term administration, levodopa leads to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication. When this occurs, a person with PD can experience phases with good response to medication and few symptoms ("on" state), and phases with no response to medication and significant motor symptoms ("off" state). Delaying initiation of levodopa therapy by using alternatives (dopamine agonists and MAO-B inhibitors) is common practice. Nevertheless, most people with PD will eventually need levodopa and later develop motor side effects.


Serotonin mechanisms in L-DOPA-induced dyskinesia

Although PD is primarily caused by dysfunctional dopamine neurotransmission, serotonin levels are also reduced in the brain of post-mortem PD patients. This is likely a consequence of deficits in serotonergic innervation from a brain region called the Raphe, as observed by labeling of serotonin transporter sites and confirmed in immunohistological studies. The dyskinesia observed in PD patients upon prolonged treatment with levodopa arises from serotonin neurons which synthesize dopamine in an unregulated manner as a "false transmitter" from levodopa. Thus, when serotonin neurons are inactivated, the dyskinesia elicited in rat by repeated levodopa administration is reduced, suggesting that inappropriate activity of serotonergic neurons underlies motor fluctuations. Thus, inhibiting serotonergic transmission by targeting Raphe 5-HT1A receptors with drugs such as NLX-112 offers the means to reduce dyskinesias.


For additional background information on Parkinson's disease, see curated articles here.

NLX-112 : a Phase 2 drug for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease

NLX-112 (also known as befiradol or F13640) is a novel compound that activates serotonin 5-HT1A receptors. NLX-112 has two main advantages over older compounds: 1. NLX-112 is extremely selective for the 5-HT1A receptor, with over 1000-fold selectivity compared to other types of receptor types, and 2. NLX-112 is a full agonist at 5-HT1A receptors, maximally activating the receptor.

NLX-112 strongly reduces L-DOPA-induced abnormal movements ('dyskinesias') in animal models of Parkinson's disease (PD). Based on these observations, Neurolixis conducted a Phase 2 clinical study in Parkinson's disease patients with L-DOPA-induced dyskinesias. This study, completed in March 2023, was a success: NLX-112 was well tolerated in patients and significantly reduced their dyskinesias (see press release). Neurolixis is now looking to advance the development of NLX-112 in larger clinical trials.


Treatment of L-DOPA-induced dyskinesia with NLX-112: mechanism of action

L-DOPA is the most effective drug for treating Parkinson's disease. However, its long-term use is often complicated by significantly disabling fluctuations and dyskinesias, reducing the beneficial effect of L-DOPA. Dyskinesia consists of involuntary, rapid, irregular, purposeless, and unsustained movement that seems to flow from one body part to another. The risk of developing LID depends on age of onset and severity of PD, with up to 80% of patients suffering from LID as the disease progresses.

The onset of LID is related to dysfunction in serotonergic systems. Indeed, recent research shows that L-DOPA can be taken up by serotonin neurons and converted to dopamine in an unregulated manner, thus eliciting the uncontrolled motor functions that typify dyskinesia. Inhibition of serotonergic neurons is therefore a promising strategy to diminish dyskinesia in PD and can be achieved by targeting serotonin 5-HT1A receptors, which inhibit serotonergic function.


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