Industry Observation I Montelukast oral mucosal Patch clinical Phase II trial approved
Click:121  Update time:2023-11-24  【Close

On November 14, 2023, IntelGenx Corp announced that the Swedish Medical Products Regulatory Agency (MPA), the Swedish Ethical Review Authority and the Swedish Biobank have approved a Phase II (MONTPARK) study of Montelukast Patch (VersaFilm ®) for the treatment of Parkinson's disease (PD).



IntelGenx is a leading drug delivery company focused on the development and manufacture of drug films. IntelGenx's superior film technology includes next-generation formulation products that address unmet medical needs such as VersaFilm®, DisinteQ™, VetaFilm® and VevaDerm™ (Transdermal patch).

Image credit: IntelGenx



The MONTPARK Phase II clinical study (CT No. 2023-504278-39-00) is a parallel randomized, double-blind, placebo-controlled, multicenter trial that will investigate the efficacy of high-dose oral montelumast in patients with early and middle stage PD. The study will enroll approximately 90 patients who will receive 30mg of Montelukast oral mucosal patch VersaFilm ® or placebo twice daily for 18 months before entering a three-month washout period. Eligible subjects were required to receive levodopa therapy or other dopaminergic symptomatic medication at enrollment. Recruitment for the study is expected to begin in the first quarter of 2024 and is expected to last approximately 24 to 30 months, depending on actual recruitment rates.

"We are pleased that this trial has been approved by the MPA and look forward to beginning patient enrollment as soon as possible," said Dwight Gorham, chief executive officer of IntelGenx. Professor Per Sveningsen, a PD pathologist at Karolinska University Hospital in Sweden, who led the multicentre clinical study, previously demonstrated the safety and tolerability of 40mg montelukast in patients with PD, and the Swedish Research Council awarded a 20 million Swedish kronor (about $2 million) grant to fund the clinical study. MONTPARK will evaluate the effect of receiving a daily dose of 60mg of montelukast. Montelukast oral mucosal patch VersaFilm ® Bioavailability (approximately 50% higher than tablets), Montelukast is currently available in oral dosage forms including tablets, granules, chewable tablets, in the unit size of 4mg to 10mg, oral mucosal patch can reduce the number of oral unit preparations taken.


Montelukast Treatment Protocol


Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD), with an estimated 9 million PD patients worldwide. Epidemiological studies have shown that the prevalence of Parkinson's disease in European and American countries over 60 years old reaches 1%, and over 80 years old exceeds 4%. The prevalence rate of people over 65 years old in China is 1.7%, which is similar to that of European and American countries. China is the most populous country in the world, and the number of people with Parkinson's disease in our country will rise from 1.99 million in 2005 to 5 million in 2030, accounting for almost half of the global population of Parkinson's disease. As the disease progresses, the motor and non-motor symptoms of Parkinson's disease will gradually worsen, on the one hand, it will impair the daily activities of the patient itself, on the other hand, it will also bring a huge social and medical burden. 


There are currently no specific neuroprotective or palliative treatments. The standard treatment for PD motor dysfunction is based on the use of drugs such as levodopa to increase dopaminergic transmission in patients. Evidence from multiple patient studies and animal models suggests that there are significant immune factors in the disease course of PD, highlighting immune regulation as a potential therapeutic strategy. Montelukast is a CysLT1 antagonist 2 that reduces neuroinflammation by inhibiting CysLT1. Early clinical findings suggest potential opportunities in treating various neurodegenerative diseases such as PD and AD. For example, Montelukast is the most commonly used leukotriene receptor antagonist used to treat asthma and seasonal allergies. Its leukotriene antagonism is also beneficial in reducing the harmful effects of leukotrienes on neuroinflammation, which is a signature feature of neurodegenerative diseases such as AD. The challenges of poor bioavailability and reduced absorption of Montelukast, an existing commercially available agent, reflect the insufficient effectiveness of drug delivery to the central nervous system. Targeted drug delivery, on the other hand, is a promising way to overcome such challenges. In recent years, the global drug research and development team has carried out research on new methods such as Montelukast oral mucosal patch, nano preparation, nasal gel, solid lipid preparation, nanostructured lipid carrier (NSLC), in order to achieve the ideal treatment effect of nervous system diseases. 


Montelukast drug delivery method and its mechanism of action


Lindmik View

The Phase II clinical study of the approved Montelukrest oral mucosal patch is based on IntelGenx's VersaFilm® technology platform. The company's official website describes that VersaFilm® technology can be applied on the tongue, cheek lining and under the tongue. Although the drug enters the mouth, the API release mechanism is different from common oral preparations. VersaFilm® oral mucosa patch is mainly absorbed into the circulatory system through the mucous membrane. The content of monukast in the cerebrospinal fluid and blood was measured in the previous clinical study, and the oral mucosal patch has little effect on the various organs of the entire digestive system, as shown in the figure below:

Image credit: IntelGenx


On March 4, 2020, the U.S. Food and Drug Administration (FDA) issued a drug safety alert that explicitly adds a boxed warning about the mental health side effects of Montelukast sodium and recommends limiting its use in allergic rhinitis (AR). 4



Photo credit: FDA website


Based on the FDA Adverse Event Reporting System from January 2004 to September 2020, neuropsychiatric events related to leukotriene receptor antagonists, H1 antihistamines, and inhaled glucocorticoids were analyzed. The results showed that 5201, 3226, and 1048 medical records were collected in the three groups, respectively. Leukotriene receptor antagonist-related neuropsychiatric events were more common in patients aged 4-6 years. Psychoneurotic events were more common in patients aged 18-44 years with H1 antihistamines and in patients aged 65 years with inhaled glucocorticoids. Most of the psychoneurotic symptoms after Montelukast administration occurred within 10 days of montelukast administration, and mortality due to psychoneurotic events was higher in the H1 antihistamine group. 5


Despite the FDA's black box warning, many studies have questioned the association of Montelukast with neuropsychiatric symptoms. A series analysis, published in the journal Asthma, found that Montelukast use was not associated with an increased risk of multiple neuropsychiatric symptoms after sensitivity analysis of six psychiatric drugs before and after montelukast treatment in more than 2,000 people. 6


The MONTPARK trial will evaluate the efficacy of 60mg (30mg, bid) of Montelukast per day in patients with mild to moderate Parkinson's disease and is designed to be dosed for 18 months. Montelukast oral mucosal patch VersaFilm ® bioavailability (approximately 50% higher than tablets), the Swedish regulatory approval of the MONTPARK program shows that they recognize the safety of oral mucosal patch drug delivery and promote clinical studies exploring the use of Montelukast in high doses for the treatment of neurodegenerative diseases such as PD and AD.

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