Dry eye treatment recently received a publicity boost when Allergan announced a licensing agreement with Mimetogen Pharmaceuticals to develop and commercialize MIM-D3 in November 2015.1 MIM-D3 is an ophthalmic solution of tavilermide that is currently in Phase III trials for treatment of ocular surface disease.
This stable, cyclic peptide that mimics part of the structure of nerve growth factor (NGF) and is mechanistically classified as a partial TrkA receptor agonist.2 Like the recent column on lifitegrast (Nov. 2015), discussion of this drug marks another encounter with a novel mechanism that warrants an examination.
NGF belongs to the neurotrophin family and is an essential protein in the differentiation and survival of neurons. Signaling of NGF is mediated by the activation of a tyrosine kinase receptor (TrkA) and p75 neurotrophin receptor (p75NTR). When NGF binds to TrkA, numerous pathways are activated including the phospholipase C-1 cascade. Activation of P75NTR, which belongs to the tumor necrosis factor receptor family, often results in effects that oppose the TrkA receptors, including apoptosis. This also stimulates growth of projections from a neuron cell body (i.e., neurite outgrowth).2,3 NGF and TrkA are present on the ocular surface suggesting a role in homeostasis, corneal healing and nerve function.3
Topically, NGF has demonstrated corneal healing in subjects with a variety of corneal diseases; however, despite these benefits, it has poor bioavailability, is costly to manufacture and stimulates pain due to neurite sprouting, making it a poor therapeutic option. MIM-D3 is a partial TrkA receptor agonist with similar effects to NGF at the TrkA receptors, with one difference: it does not bind to the p75NTR receptor, thereby minimizing the associated stimulated pain.2,3
In cell culture experiments, researchers found NGF-stimulated secretion of mucin. Animal models have also shown that topical NGF increases goblet cell density. Therefore, interest in MIM-D3 as a novel mimicker of NGF is attractive. Using a rat model of dry eye, MIM-D3 showed a significant improvement in corneal staining.2
A Phase II study randomized 150 dry eye patients to one of three groups: tavilermide 1%, tavilermide 5% or placebo. Study participants used the medication twice a day for 28 days, while a controlled adverse environment (CAE) was incorporated to exacerbate and standardize dry eye presentations. Primary outcomes included one objective (i.e., fluorescein corneal staining) and one subjective (i.e., diary worst symptom score over 28 days) measure. Patients rated symptoms of burning, dryness, grittiness and stinging on a scale of zero to five.
No serious ocular adverse events occurred in any treatment group, but the primary endpoints were not met. There was, however, an improvement in corneal staining. Additionally, in a subset of participants with higher symptom scores at the time of randomization, there was a significant treatment effect noted in both treatment groups.3,4,5
Recently, a Phase III trial enrolling 403 dry eye patients to receive MIM-D3 1% or placebo concluded. The patients used the study medication twice a day for 56 days and were stratified into patients with cataracts and those with a normal crystalline lens. There was significantly less fluorescein corneal staining in the treatment groups after 56 days, and improvements in symptoms were also noted. A dramatic difference in treatment response was noted in the cataract group compared with those with no lenticular opacities. Patients with cataracts had significant improvement in staining and the ocular surface disease index questionnaire (OSDI). Those with normal lenses had improvement in the ocular discomfort symptom scores compared with the placebo.5,6
A second multi-center Phase III study is currently recruiting patients with an estimated enrollment of 400 to be randomized to either receive MIM-D3 1% or placebo twice a day for 56 days. Primary outcome measures are corneal staining and ocular discomfort. The estimated completion is July 2016.5
A decrease in conjunctival goblet cell density along with a corresponding reduction in the secretion of ocular surface mucins may be noted in patients with dry eye. Although therapies rarely target this specific mechanism or these deficiencies, MIM-D3 appears to be an exciting drug in the pipeline that may provide us with a new mechanism to establish a normal, healthy ocular surface.
1. PR Newswire. Allergan Enters Into Licensing Agreement with Mimetogen Pharmaceuticals to Develop and Commercialize Tavilermide (MIM-D3) Topical Dry Eye Treatment. Available at: www.prnewswire.com/news-releases/allergan-enters-into-licensing-agreement-with-mimetogen-pharmaceuticals-to-develop-and-commercialize-tavilermide-mim-d3-topical-dry-eye-treatment-300171929.html. Accessed Dec 30, 2015.
2. Jain P, Ruihong L, Lama T, et al. An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and demonstrates therapeutic efficacy in a rat model of dry eye. Exp Eye Res. 2011 Oct;93(4):503-12.
3. Meerovitch K, Torkildsen G, Lonsdale J, et al. Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye. Clin Ophthalmol. 2013;7:1275-85.
4. Ousler G, Meerovitch K. High CAE Responders show greater improvement in signs and symptoms of dry eye after treatment with MIM-D3. IOVS 2013; 54; E-Abstract 4343.
5. Clinical Trials.gov. A safety and efficacy study of tavilermide (MIM-D3) ophthalmic solution for the treatment of dry eye. Available at: clinicaltrials.gov/ct2/show/NCT02634853. Accessed Dec 30, 2015.
6. Meerovitch K, Brazzell K, Ousler GW, Cumberlidge G. Improvements in signs and symptoms of dry eye with MIM-D3 1% ophthalmic solution compared to placebo in different patient populations. IOVS 2015; 56: E-Abstract 4460.