Has Promising Cannabinoid-Based Drug Development Finally Come to Ophthalmology?
Before Tetra Bio-Pharma‘s recent announcement of US Food and Drug Administration Orphan Drug Designation for its ophthalmic clinical program, ophthalmology was one of the few medical specialties lacking in cannabinoid-based (CBD) drug development.
The long-held belief that marijuana has beneficial intraocular pressure-lowering effects, for example, has gained little mainstream clinical traction. Not only has the notion of cannabis as an ocular therapy been met with skepticism by many in the ophthalmic community, the idea also has often been the butt of jokes about stoned patients and copious amounts of snack consumption.
But CBD science and medicine researchers at Tetra Bio-Pharma’s wholly owned subsidiary Panag Pharma are not laughing – quite the opposite. The four founders of Panag, all of whom are members of the International Cannabinoid Research Society, account for more than 100 years of experience in the CBD research space.
Canada-based Tetra wanted Panag largely to gain access to this expertise and the vast amount of ophthalmic drug discovery that the move would add to the former’s pipeline. The year-old acquisition is bearing fruit of the orphan variety with the investigation of the synthetic cannabinoid PPP003 (HU308) in the prevention of proliferative vitreoretinopathy (PVR). If found successful in clinical trials, PPP003 would be the first drug approved for the prevention of proliferative vitreoretinopathy.
Indications for painful dry eye and uveitis are also in the works for the agent, which activates the cannabinoid type 2 (CB2) receptor. Tetra also last week said it has obtained a patent in Australia for CBD compositions to treat ocular inflammation and pain.
How It Works
“In the presence of trauma or inflammation, recruited immune cells express large amounts of CB2, making it advantageous as a drug target,” said Tetra Chief Scientific Officer and Panag founder and director Melanie Kelly, PhD. “When CB2 is activated, pro-inflammatory responses in the eye are very effectively dampened. Further, inflammation drives pain, and many ocular conditions result in both.”
CB2 receptor-activating drugs represent a nonsteroidal alternative for treating inflammatory conditions. Dr. Kelly noted that there hasn’t been any innovation whatsoever in this space. “Currently, most ophthalmologists reach for a steroid to reduce inflammation, but there are lots of people who are not always the best candidates for steroid use,” she said.
As a small company, Tetra has needed to prioritize its ophthalmic pipeline, so receiving an orphan designation clearly helped in the decision to advance PPP003 for a PVR indication. Responsible for about 75% of the complications following retinal detachment surgery, PVR is the result of an inflammatory response that ultimately leads to vision loss. It can also be recurrent, causing a subsequent retinal detachment requiring additional surgery with further associated risk.
“The market for our anti-inflammatory CBD compound will be the population of people with retinal detachment that requires surgery to reattach the retina, especially those who are at high risk of developing PVR,” explained PPP003 researcher Anna-Maria Szczesniak, PhD. “PPP003 would be used as prophylaxis treatment administered at the time of the surgery allowing a reduction in the inflammatory state, thereby preventing the pathological changes within the retina that cause PVR.”
In the US, retinal detachment occurs in approximately 10 individuals per 100,000 annually. In this population, the prevalence of PVR ranges from 5% to 12%, translating to 1,700 to 3,800 patients a year.1
Dr. Szczesniak, from the department of pharmacology at Dalhousie University in Halifax, Nova Scotia, has published the preclinical efficacy data on CB2 agonists and CB2 receptors as a target in experimental PVR.2-4 PPP003 is well on its way toward the final stages of safety and toxicology study. “We continue to work on an expanded program as we stay in touch with and get feedback from the FDA,” said Dr. Kelly. “We also have to fully develop our delivery platform and do the necessary preclinical testing on that, particularly if it’s novel.”
Tetra has targeted 2021 for a Phase II trial. However, the COVID-19 crisis has led to significant delays. “We are still going to continue to work toward that goal, and we hope that we can file our CTA [Clinical Trial Application] in Canada as well as an IND [Investigational New Drug application] to the FDA by the very end of this year,” she said.
1. Charteris DG, Sethi CS, Lewis GP, Fisher SK. Proliferative vitreoretinopathy—developments in adjunctive treatment and retinal pathology. Eye. 2002;16:369-374.
2. Thapa D, Cairns EA, Szczesniak, AM, et al. The cannabinoids Δ8THC, CBD, and HU-308 act via distinct receptors to reduce corneal pain and inflammation. Cannabis Cannabinoid Res. 2018;3:11-20.
3. Thapa D, Cairns EA, Szczesniak AM, et al. Allosteric cannabinoid receptor 1 (CB1) ligands reduce ocular pain and inflammation. Molecules. 2020;25:417.
4. Thapa D, Toguri JT, Szczesniak AM, Kelly MEM. The non-psychoactive phytocannabinoid, cannabidiol (CBD), and the synthetic derivatives, HU308 and CBD-DMH, reduces hyperalgesia and inflammation in a mouse model of corneal injury. Fed Am Soc Exp Bio J. Published online April 1, 2017.
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