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Daniel Keller PhD in Oklahoma, US

PIRENZEPINE, a potent antimuscarinic drug, appears to reduce the progression of myopia in children, new clinical trial results suggest.
The drug slowed the progression of myopia by 50% over 12 months in a Phase II clinical trial. Researchers applied a 2% gel of pirenzepine or a placebo gel twice daily for one year to the eyes of 174 children ranging in age from eight to 12 years, according to R Michael Siatkowski MD.

Researchers at 13 centres used standardised equipment to measure the children's prescriptions by cycloplegic auto-refraction at baseline and at one year. At baseline, the subjects had mild to moderate myopia of - 0.75 to - 4.0 D, with a BCVA of 20/25.

“At 12 months, we found that children of both groups had become more myopic, but the amount of increased myopia was twice as much in the placebo group as it was in the pirenzepine group. Our safety profile was what we felt to be acceptable. No serious adverse events related to the study medication occurred,” Dr Siatkowski said.

The most common adverse effect was a residue of gel on the eyelid, which occurred with the placebo as well as the active medication. Adverse events specific to the active drug included blurred reading vision and some mild allergic reactions of the conjunctiva.
Many patients have continued in the trial in an open-label fashion, with no long-term significant adverse effects.

Other measures in the study showed that the axial length of the eyes in the placebo group was slightly, but not significantly, larger compared to the drug group. There were no significant changes in IOPs.

Pirenzepine is a muscarinic antagonist which is relatively selective for the M1 muscarinic receptor. The exact mechanism of action of the drug is unknown. Researchers believe it can decrease the axial growth of the eye, although there is no evidence of this from the present study

The drug has been used systemically in Europe for several years for gastrointestinal disorders. Dr Siatkowski said the oral safety profile is quite high, so even if there were any slight systemic absorption from the eye, he would not expect any problems.
US specialist Josh Wallman PhD works on animal models of myopia and mechanisms of eye growth. He explains that muscarinic receptors are “strewn” throughout the eye “in the sclera, the choroid, everywhere”.

“It's a sort of a funny situation to have a drug which is a very specific drug, and yet you don't know where it is acting,” Dr Wallman said.
Some of his animal studies have shown that muscarinic antagonists can inhibit proteoglycan synthesis in the sclera, but he is not ready to attribute the action of pirenzepine to this effect because of its other widespread actions. Good evidence also shows that it probably does not exert its anti-myopia effect at the retina.

Atropine, a nonselective muscarinic antagonist, has been known for decades to reduce the progression of myopia. The original hypothesis was that myopia resulted from over-accommodation and that atropine moderated this effect.

However, researchers found that atropine affected eye growth even in animals in which it had no effect on accommodation. The was shown to be the case in birds, for example, in which the muscles of accommodation are not muscarinic.

Since the clinical usefulness of atropine is limited by its effect on accommodation and pupil size, researchers turned to more selective compounds that would not affect the ciliary muscles.

Dr Siatkowski explained that in comparison to atropine, pirenzepine is much more selective for the M1 receptor. Among the muscarinic receptors, of which there are at least five types, M1, M2, and M3 are the most common in the eye.

Pirenzepine has M1 and some M2 activity. But atropine is not selective and its action on M3 receptors is largely responsible for the significant side-effects of dilated pupils and blurred near vision.

While Dr Wallman said he would not call myopia “a disease” that needs treatment, he said he felt certain “people with kids who have rapidly progressing myopia would really like to be able to do something”.
Dr Siatkowski noted a number of negative effects associated with myopia. Among them are a higher incidence of retinal detachment or peripheral retinal degeneration and glaucoma. Other factors include comfort, lifestyle and social-psychological issues, convenience, performance in school, visual learning and athletic performance.

“Certainly there's a very high demand for refractive surgery among myopic adults. So I think the potential usefulness for a compound like this is quite high,” Dr Siatkowski said.
He expects a reduction in myopic complications if patients receive a drug that can retard progression.

“Someone who is -5.0 D has a higher incidence of peripheral retinal degeneration than someone who is -1.0 D. So even within that range, there's a difference,” he said.
The Phase II trial used only a fixed dose of the drug. The US FDA will meet soon to decide on a Phase III trial design, which could examine dosage effects. Optimal dosages, ages for treatment and degrees of myopia may be determined only after it has been used in the marketplace for a number of years, he said.

Valley Forge Pharmaceuticals in Irvine, California, US is the developer of pirenzepine for this indication and is now conducting Phase II trials. Novartis Ophthalmics in Basel, Switzerland has acquired the rights to market the drug.

R Michael Siatkowski MD
University of Oklahoma, Oklahoma City, US
Email: rmichael-siatkowski@ouhsc.edu

Josh Wallman PhD
City University of New York, US
Email: wallman@sci.ccny.cuny.edu

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