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A proof-of-concept clinical trial of a non-benzodiazepine drug, a version of a naturally occurring neuroactive steroid, has shown that it’s as effective as alprazolam, better known as Xanax, at reducing anxiety. Critical to the trial’s success was technology that converted the neurosteroid into an oral form.
Gamma-aminobutyric acid (GABA) is the chief inhibitor neurotransmitter in the central nervous system, reducing neuronal excitability. Benzodiazepines diffuse quickly through the blood-brain barrier to work primarily on type A (GABA-A) receptors, allowing GABA to exert a more significant effect.
However, the long-term use of benzodiazepines such as alprazolam (Xanax) to treat anxiety can lead to significant health problems, including psychological and physical dependence, impaired thinking, and memory loss.
Now, researchers at Monash University, in partnership with Boston-based biotherapeutics company PureTech Health, have completed a Phase 2a clinical trial involving the non-benzodiazepine drug LYT-300, an oral version allopregnanolone, a naturally occurring metabolite of the sex hormone progesterone, finding that it’s just as effective at reducing anxiety as alprazolam.
Allopregnanolone is considered a neuroactive steroid or neurosteroid and, like benzodiazepines, acts on GABA-A receptors to modulate the action of GABA.
“Allopregnanolone has been recognized for its potential to treat a range of neurological and neuropsychiatric indications and has a well-established rapid onset of action in mood disorders,” said Chris Porter, Director of the Monash Institute of Pharmaceutical Sciences (MIPS). “However, historically, there have been major hurdles associated with the development of endogenous neurosteroids as medicines. Most notably, a lack of oral bioavailability and a need to administer intravenously. This makes convenient dosing to patients over an extended period of time in chronic diseases extremely difficult.”
Porter overcame these difficulties by developing the Glyph platform, which reversibly links a drug to a dietary fat molecule, creating a prodrug that re-routes the drug’s normal path to the systemic circulation, bypassing the liver and instead moving from the gut into the lymphatic vessels. MIPS exclusively licensed the Glyph platform to PureTech in 2017.
“The Glyph platform harnesses the body’s natural lipid absorption and transport process to enable the oral administration of therapeutics like allopregnanolone that otherwise cannot be administered orally,” Porter said. “These data validate that LYT-300 has the potential to become a simple oral capsule for people living with anxiety, a condition where there’s been a dearth of innovation.”
The researchers recruited 80 healthy trial participants, randomized to receive either LYT-300 or a placebo. The participants were subjected to the Trier Social Stress Test (TSST), the human experimental gold standard for evaluating acute stress, and their salivary cortisol levels measured. Cortisol is a biomarker of stress.
Oral administration of LYT-300 achieved the trial’s primary goal of a statistically significant reduction in peak levels of the stress hormone and achieved a similar effect size to previously seen results for alprazolam using the TSST.
“Anxiety disorders are an area of significant unmet medical need, and current standard-of-care treatments leave much room for improvement due to inconsistent efficacy and adverse events,” said Murray Stein, Distinguished Professor of Psychiatry and Public Health at the University of California San Diego and advisor to PureTech. “We know that benzodiazepines, like alprazolam, can reduce the salivary cortisol response to stress in the TSST. Cortisol is an important marker of the physiological response to stress, and reduction of stress overreactivity may be an important mechanism for treating anxiety and stress-related disorders. LYT-300, a non-benzodiazepine neurosteroid, blunts this stress response, highlighting its novel pharmacology and potential for helping patients in serious need of new treatment options.”
LYT-300 was well-tolerated, with all adverse events transient, mild or moderate and in keeping with the known pharmacology profile of allopregnanolone.
The results of the clinical trial have not yet been published.
Source: Monash University