5HT2C- The primary receptor for advanced neuro therapies

Neurological disorders are on the rise, and the few existing drugs in the market are either not effective in healing patients or have severe side effects. This article looks at a couple of 5HT compounds approved by the FDA, their impact on patients and how the Bright Minds Biosciences’ (CSE:DRUG) 5HT2C superagonist leads the treatment race for a range of neurological problems. We also look at the various next-gen proprietary 5HT2C compounds in the pipeline and the different stages of progress in the trials.

Before we go into the drug details, here’s an overview and the functions of the 5HT2C receptors- 5HT receptors are also called 5-hydroxytryptamine, or serotonin receptors. Activated by the neurotransmitter serotonin, the receptors are primarily in the central and peripheral nervous system. Serotonin receptors activate several neurological processes such as learning, mood, sleep, nausea, anxiety, aggression, appetite and others.

5HT2C receptors are one of the 14 receptor subtypes found only in the brain. Depending on the portion of the brain they are located in, the receptors play a vital role in regulating mood, body temperature, anxiety and seizures. Activating this receptor by serotonin impedes the release of dopamine and norepinephrine in certain portions of the brain. On the other hand, overactive 5HT2C receptors generally contribute to symptoms such as depression or anxiety.

5HT2C signalling pathways

Source: Researchgate

5HT2C receptor agonists are currently in various stages of research to treat a wide range of conditions associated with neurological disorders, obesity, sexual dysfunction and several others. In the recent past, the FDA approved two drugs with the 5HT2C compound to treat obesity and epilepsy associated with the Dravet syndrome* (DS), Lennox-Gastaut syndrome (LGS) and CDKL5 disorder.

Here are the two 5HT drugs approved by the FDA and their performance- Eisai Inc’s Belviq (lorcaserin) received FDA approval as an obesity drug in 2012. The drug, developed by Arena Pharmaceuticals Inc (Nasdaq:ARNA), was a 5HT2C agonist with moderate 2A and 2B activity. The drug dramatically reduced seizure frequency and presented a low risk for cardiovascular events in a P4 study. However, another study investigating lorcaserin as an obesity drug revealed a small cancer risk in treated patients. Belviq eventually was taken off the market in 2020, although the FDA permitted Eisai to develop lorcaserin for Dravet syndrome. It is currently undergoing phase-3 clinical trials as a potential treatment for Dravet syndrome.

Zogenix Inc (Nasdaq:ZGNX) manufactures Fintepla (Fenfluramine), an FDA-approved drug to treat seizures associated with the Dravet syndrome (DS)*. The treatment is for seizures in patients who are 2+years and is available as an oral solution, CIV. The drug targets 5HT2C and 5HT2B receptors, the latter linked to cardiovascular diseases. As a result, the drug’s prescription comprises a Risk Evaluation & Mitigation Strategy (REMS) program, including regular cardiac monitoring with the dosage capped at 26mg/day.

Zogenix Inc (Nasdaq:ZGNX) manufactures Fintepla (Fenfluramine), an FDA-approved drug to treat seizures associated with the Dravet syndrome (DS)*. The treatment is for seizures in patients who are 2+years and is available as an oral solution, CIV. The drug targets 5HT2C and 5HT2B receptors, the latter linked to cardiovascular diseases. As a result, the drug’s prescription comprises a Risk Evaluation & Mitigation Strategy (REMS) program, including regular cardiac monitoring with the dosage capped at 26mg/day.

Although Fintepla and Belviq were moderately successful in patients with obesity and Dravet syndrome, the 5HT2B activity in ZGNX’s Fintepla and the potential cancer risk in Eisai’s Belviq have raised the bar for a new innovative therapy for these and other unmet psychiatric needs. This is where Bright Minds Biosciences comes in. The Vancouver-based biotech firm has developed an advanced version of Belviq’s 5HT2C anti-epilepsy drug to boost safety and eliminate the harmful side effects of the 5HB2B activity, translating into a better safety profile that allows for more effective max dosing. In cell-based assays and rats, the superagonist was more efficient in receptor activation than the endogenous ligand or Lorcaserin. This higher potency translates to superior efficacy, even with a lower dosage.

On the issues with severe side effects of Lorcaserin and Fintepla, Bright Minds’ 5HT2C compound has no affinity towards 2B, the major cause of CV events. Besides, the anti-seizure drug also avoids the 5HT2A receptor, which could cause side effects such as fatigue, headache, hypotension and insomnia.

5HT2C receptor agonists reduce locomotor activity and food intake. Testing Lorcaserin determined reduced activity in wild-type mice. However, knockout (KO) mice have hypertonic seizures identical to the Dravet syndrome, resulting in death. Injecting 5HT2C agonists (RO-60-0175) and m-chlorophenylpiperazine into substantia nigra pars reticulata increases neural activity and GABA levels in tests carried out on rats. Substantia Nigra (SN) is a midbrain dopaminergic nucleus. It plays a vital role in modulating motor movements and reward functions. Located within the midbrain, the Substantia Nigra comprises two parts

• Pars Compacta- These cells contain melanin which synthesises dopamine. According to scientists, lack of dopamine probably leads to Parkinson’s disease.
• Pars Reticulata- This region contains a large number of GABA neurons with moderate dopamine neurons. According to studies, the inhibition of substantia nigra pars reticulate reduces seizures.

The inclusion of 5HT suppresses NMDA-induced excitatory signals in humans, but that’s not the case with 5HT2C, signifying that the latter moderates the inhibitory effect. Bright Minds’ proprietary compound activates the excitatory signals, raising the inhibitory tone in the Central Nervous System (CNS).

Bright Minds Biosciences’ 5HT2C compounds are in preclinical trials to treat the Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The biotech firm’s 2C combinations are also in preclinical trials for opioid use disorder, binge eating disorder, and Alzheimer’s.

According to Netherlands-based information and analytics firm Elsevier Limited, neurological disorders are the primary reasons for disability and the second leading cause of death globally. Over the last few years, these numbers have climbed significantly in the low and middle-income countries. With a global rise in the ageing population, the advances in the management and prevention of psychiatric disorders are not sufficient. The coronavirus pandemic has also led to insistent neurological manifestations from mild symptoms like headaches, fatigue to severe conditions such as cognitive impairment, sleep disorders and pain.

In the United States, several projects supported by the National Institute of Neurological Disorders & Stroke (NINDS) aim to track the implications of COVID-19 on neurological indicators to gain insights into how the pandemic has affected the nervous system. Medical experts anticipate the global health market would reach $6 trillion by 2030, with the overwhelming side effects of the Covid-19 pandemic likely to add to the numbers. Even as patients seek more affordable treatments and governments worldwide are waking up to the seriousness of the problem, it’s time for the new class of biotech firms to urgently step up and meet the growing demand for these massive unmet psychiatric needs.

*Dravet syndrome*- is a rare, severe form of epilepsy, generally caused by SCN1A gene mutations. In most cases, it onsets at infancy and encompasses frequent treatment-resistant bouts with the risk of varying levels of developmental disability and sudden, unexpected death. The syndrome is lifelong and typically led by prolonged seizure with fever, affecting one side of the body.

#Lennox-Gastaut syndrome (LGS) - is a rare, severe form of epilepsy in children between 3-5 years, which can persist into adulthood. The progressive epilepsy syndrome could lead to intellectual development impairment, although medications, dietary therapies and surgeries can lessen seizures.

**CDKL5 disorder- is a rare neurodevelopmental condition characterised by the early-onset of epilepsy (seizures), low muscle tone and developmental challenges. Some of the other common symptoms are- disturbed sleep, impaired growth, trouble with feeding, swallowing, reflux, vision impairment, constipation, orthopaedic complications etc.