OSD Pipeline Update: Etiology-Specific Treatments for MGD, Demodex Getting Closer

First-in-class drugs are being investigated to treat two etiologies of dry eye disease (DED)—meibomian gland dysfunction (MGD) and Demodex blepharitis—both highly prevalent conditions for which no approved treatments exist. Here’s a quick look at those two candidates

NOV03 (Bausch + Lomb)
B+L recently announced the second of two Phase III studies evaluating the investigational compound perfluorohexyloctane, or NOV03, a novel mechanism-of-action drop for treating the signs and symptoms of DED associated with MGD. If approved, NOV03 would be the first prescription pharmaceutical indicated for the most common cause of dry eye. MGD is present in 86% of patients, according to a study in the journal Cornea.1 The company expects to submit a New Drug Application (NDA) to the Food and Drug Administration next year, said Joseph C. Papa, chairman and CEO, Bausch Health.

The Phase III program for NOV03 also includes a previous multicenter, randomized, double-masked, saline-controlled trial known as GOBI. Earlier this year B+L reported statistically significant topline results from the trial as well as an ongoing multicenter, open-label, single-arm 12-month safety extension trial, KALAHARI. The company expects the data from the fully enrolled MOJAVE study (622 patients) to be consistent with those from GOBI. Previous results from the Phase 2 SEECASE Study were published in Cornea in January.2

What is It?
Perfluorohexyloctane ophthalmic solution is a high-molecular weight hydrocarbon based on the previously patented EyeSol technology created by Novaliq. The oil-like organic material is said to be an effective lubricant that coats the eye quickly, allowing for increased absorption and minimal spillover without blurring vision. Bausch Health acquired exclusive commercialization rights for NOV03 in the United States and Canada.

B+L said the low viscosity and surface tension result in a dispensed drop that’s about four times smaller than aqueous-based formulations. Although the clear solution has a refractive index similar to water, it doesn’t contain water, making it unfriendly to bacteria or fungi and potentially obviating the need for preservatives.

“NOV03 is a very promising agent, as the studies have hit all of their endpoints and the solution is now on to the confirmatory Phase III investigations,” Paul Karpecki, OD, FAAO, clinical director of corneal services and advanced ocular surface disease at Kentucky Eye Institute, and a clinician for Gaddie Eye Centers, told OIS Weekly. “To date we have not had a drug that targets the glands and can actually solubilize the oils in the meibum. NOV03’s water-free formula is lipophilic, allowing it to penetrate to the site of the problem.”

Dr. Karpecki said he sees the agent being used as an adjunct to in-office, device-based treatments for practitioners who are using them and as first-line treatments for providers who aren’t. “Once available, NOV03 can move us closer to the true dental model of dry eye care,” Dr. Karpecki said.

GOBI Topline data
Among the topline data from GOBI, which included 597 participants dosed with NOV03 or placebo four times daily, researchers reported a statistically significant change from baseline in total corneal fluorescein staining at day 15, with results persisting through day 57 compared with control.

The change from baseline in dryness score achieved statistical significance at day 15, with continued results through day 57 compared with control as rated on a visual analogue scale ranging from 0-100 (0 = no discomfort; 100 = maximum discomfort). The GOBI trial met all of its secondary endpoints, showing statistically significant improvements in both the signs and symptoms of DED associated with MGD.

TP-03 Anti-Parasitic Agent
Tarsus Pharmaceuticals’ lead candidate TP-03 (lotilaner ophthalmic solution, 0.25%) is a novel, anti-parasitic agent designed to target and eradicate Demodex mites. The company reported that its pivotal Saturn-1 Phase IIb/III trial met all primary and secondary endpoints, showing significant, clinically meaningful outcomes with no serious treatment-related adverse events and no treatment-related discontinuations.

There is no currently approved pharmaceutical for Demodex blepharitis, which the company estimates affects as many as 25 million Americans.

“Our current methods for treating recalcitrant Demodex do not eradicate the infestation,” Dr. Karpecki said. “We can debride the area with BlephEx or kill the mites with IPL [intense pulsed light], but they do come back. Tea tree oil is somewhat effective, but it’s often a little too strong for patients. There is a very large need for a drug that targets Demodex blepharitis and is actually curative.”

Collarette Cure
The Saturn-1 trial demonstrated a statistically significant complete collarette cure—the primary endpoint— at day 43 in Demodex blepharitis patients treated with TP-03 compared with vehicle. Collarettes on the lashes are pathognomic for Demodex infestation, and are composed of partially digested epithelial cells, mite waste products and eggs.

The trial also met the secondary endpoints of mite eradication at day 43 and composite cure based on complete collarette and erythema cures at day 43.Clinically meaningful improvements were observed within two weeks across multiple endpoints, Tarsus reported, and TP-03 was well tolerated with a safety profile similar to vehicle.

President and CEO Bobak Azamian, MD, PhD, said that Tarsus expects to provide topline results for Saturn-2, the second pivotal trial of TP-03, in the first quarter of next year. If positive, the company plans to submit an NDA soon afterward. Saturn-2 has the same endpoints as Saturn-1, and patient enrollment commenced in May.

Saturn-1 Details
In Saturn-1, 81% of patients achieved a significant, clinically meaningful collarette cure defined by a collarette grade of 0 or 1 at day 43 compared with 23% of those assigned to vehicle. A significant, clinically meaningful collarette cure was seen in 23% of patients on TP-03 compared with 11% assigned to vehicle as early as day 8. Data also revealed that 43% of patients assigned to TP-03 treatment achieved the primary endpoint of complete collarette cure (grade 0) at day 43, defined as 0 to 2 collarettes per lid vs. 7% of vehicle participants.

The secondary endpoint of complete mite eradication met statistically significant results by day 15, and 68% of patients assigned the treatment achieved mite eradication compared with 18% in the vehicle group at day 43. Mite eradication is defined as a mite density of 0 mites per lash.

“Data on both NOV03 and TP-03 are compelling, showing a highly statistical separation between the vehicle groups and the drug for the two agents,” Dr. Karpecki said. “It is very exciting to see the level of evidence we have for these promising new first-in-class therapies.”

References
1. Lemp MA, Crews LA, Bron AJ, et al. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea. 2012;31:472-478. doi: 10.1097/ICO.0b013e318225415a.
2. Tauber J, Wirta DL, Sall K, et al, for the SEECASE study group. A randomized clinical study (SEECASE) to assess efficacy, safety, and tolerability of NOV03 for treatment of dry eye disease. Cornea. 2021;40:1132-1140. doi: 10.1097/ICO.0000000000002622.

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