Tavilermide (MIM-D3)

An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and demonstrates therapeutic efficacy in a rat model of dry eye

The aim of this study was to evaluate the efficacy of MIM-D3, a small molecule nerve growth factor (NGF) peptidomimetic, as a therapeutic agent in rats with scopolamine induced dry eye. NGF plays an important role in ocular surface maintenance and corneal wound healing and was recently shown to have mucin secretagogue activity in conjunctival cells. We investigated whether MIM-D3 increased glycoconjugate secretion in conjunctival cells in vitro and in rat tear fluids in vivo. Primary rat conjunctival cell cultures were treated with increasing concentrations of MIM-D3 and evaluated for glycoconjugate secretion, proliferation and MAPK1/2 activation. Glycoconjugates were quantitated in tear fluids from normal rats treated topically with increasing doses of MIM-D3 (0.4%, 1% and 2.5%). Dry eye was induced in rats by subcutaneous scopolamine treatment, administered by surgically implanted osmotic pumps for 14 or 28 days. Aqueous tear production, tear clearance, fluorescein corneal staining and tear break-up time (tBUT) were evaluated. Glycoconjugates and NGF were quantitated in the tear fluids by enzyme-linked lectin assay (ELLA) and enzyme-linked immunosorbant assay (ELISA), respectively. We found that 50 μM MIM-D3 statistically significantly induced a 1.3-fold increase in glycoconjugate secretion and a 2.3-fold increase in MAPK1/2 activation without increasing proliferation from conjunctival cell cultures. Application of 2.5% MIM-D3 in normal rat eyes statistically significantly increased tear glycoconjugate concentration by 2.3-fold. In the experimental dry eye model, application of 1% MIM-D3 to rat eyes for either 1 or 17 consecutive days, followed by 1 week of no dosing produced a statistically significant decrease in corneal staining (p < 0.001), a slight increase in tBUT, and increases in tear glycoconjugates (p < 0.05) compared to vehicle. Scopolamine treatment also caused a statistically significant increase of endogenous NGF in tears (p < 0.005). We concluded that the increase in glycoconjugate concentration by the 1% MIM-D3 dose may have improved the quality and stability of the tear film, and thereby improved healing on the ocular surface in dry eye. Therefore, MIM-D3 may have therapeutic potential as a topical agent for the treatment of dry eye.

Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye

Purpose: To evaluate the safety and efficacy of ophthalmic MIM-D3, a tyrosine kinase TrkA receptor agonist, in patients with dry eye.
Design: A prospective, two-center, randomized, double-masked, placebo-controlled Phase 2 study.
Methods: A total of 150 dry eye patients were randomized 1:1:1 to study medication (1% MIM-D3, 5% MIM-D3, or placebo) and dosed twice daily (BID) for 28 days. Key eligibility criteria included exacerbation in corneal staining and ocular discomfort in the Controlled Adverse Environment (CAE(SM)) on two visits, separated by 1 week of BID dosing with artificial tears. Safety and efficacy were evaluated at baseline, throughout treatment, and for 2 weeks post-treatment. The pre-specified primary outcome measures were fluorescein corneal staining post-CAE at day 28 and diary worst symptom scores over 28 days. Secondary outcomes included the pre-, post-, and the change from pre- to post-CAE fluorescein and lissamine green staining in both corneal and conjunctival regions, as well as individual diary symptoms.
Results: The prespecified primary endpoints were not met. Compared with placebo, fluorescein corneal staining at day 28 was significantly improved (P < 0.05) in the 1% MIM-D3 group for the assessment of change from pre-CAE to post-CAE. In addition, following CAE exposure, patients in the 1% MIM-D3 group showed significant improvements versus placebo (P < 0.05) in inferior fluorescein and lissamine green staining after 14 and 28 days. Compared with placebo, patients in the 5% MIM-D3 group reported significantly lower daily diary scores for ocular dryness (P < 0.05). In a subgroup defined by higher symptom scores during the run-in period, significant treatment effects (P < 0.05) were observed for diary symptoms for both MIM-D3 doses. Ocular adverse events were mild and not considered to be treatment-related.
Conclusion: Treatment with topical ophthalmic MIM-D3 demonstrated protection against the effects of a CAE challenge on dry eye signs, reduced patient-reported diary symptoms, with a favorable safety profile.

Controlled Adverse Environment Chambers in Dry Eye Research

Dry eye disease (DED) is a common condition with signs and symptoms that vary depending on a wide range of environmental factors to which people are exposed in their daily lives. Factors such as variable temperature, airflow velocity, relative humidity, seasonality, and pollutants can alter the rate of tear film evaporation, improving or exacerbating symptoms of DED. Results from currently available clinical tests do not always correlate well with patient-reported symptoms, and the continually changing environment and variability in DED symptoms present challenges for the design and conduct of clinical trials. Controlled adverse environment chambers allow standardization of temperature, humidity, and airflow and may minimize potential confounding factors in clinical investigations. Their use can promote accurate study of the pathophysiology of DED, discovery of disease biomarkers, and assessment of the effect of various therapeutic approaches on patients' symptoms. Controlled adverse environment chambers have been used to simulate indoor surroundings such as airplane cabins and to test their effects on contact lens wearers. This review summarizes how these chambers may be useful for the development, approval, and differentiation of potential new treatments for DED.