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All eyes on dry eye disease

pharmafile | May 8, 2018 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | TopiVert, dry eye disease, eye, pharma

Dr Matthew Fyfe, Head of Chemistry and Intellectual Property at TopiVert, gives an illuminating look into the latest developments in the dry eye disease market, including the biggest players, their key therapies, and the emerging treatments which may one day dethrone them.

Dry eye disease (DED) is a common, multifactorial disorder of the ocular surface characterised by loss of homeostasis of the tear film accompanied by troublesome ocular symptoms in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles. Its prevalence is growing and rises with age. It is estimated that 6.8% of the US adult population, amounting to more than 16 million individuals, have diagnosed DED. The manifold symptoms of the condition markedly reduce quality of life for its sufferers, while impairing visual and social functioning.

Clinical signs of this debilitating inflammatory disease are evaluated by the clinician through a battery of assessments. The standard diagnostic regimen includes at least one measure of tear film stability, such as tear film break-up time, a determination of ocular surface desiccation, evaluated via lissamine green or fluorescein staining, and a tear volume measurement using Schirmer’s strips. Common symptoms experienced by the DED patient include eye dryness, grittiness, itching, burning, redness, blurred vision, photophobia and pain.

For NDA approval, the FDA requires that a compound demonstrate improvements in one sign and one symptom of DED, each confirmed in a separate study. As a consequence of a low correlation between signs and symptoms, and because of the heterogeneous nature of the DED population, replication of improvements in clinical trials has proven difficult. Indeed, to date, only one agent, Shire’s Xiidra (lifitegrast ophthalmic solution), has received FDA approval for treating both signs and symptoms of DED, though this approval was granted only following demonstration and replication of results on a sign and symptom in four separate studies.

DED has traditionally been managed with artificial tears and ocular lubricants. However, to break the vicious circle of surface damage and inflammation, anti-inflammatory treatment is indicated in patients with moderate to severe DED. In this regard, although not specifically approved for DED, corticosteroid eyedrops, instilled over two to four weeks, have been shown to improve both signs and symptoms. Chronic use of topical corticosteroids is, however, associated with serious side effects, such as cataracts, ocular hypertension and opportunistic infections. As such, these agents are only used for short periods. Until 2016, only one eyedrop prescription therapy, Allergan’s blockbuster Restasis (cyclosporine ophthalmic emulsion), was approved by the FDA for improving tear production in DED, but this situation changed following Xiidra’s recent approval. Both Restasis and Xiidra produce efficacy in DED through anti-inflammatory mechanisms. Restasis’ active ingredient, cyclosporine, is an immunosuppressant which lowers the activity of T cells and their immune response by inactivating calcineurin, while lifitegrast – the active constituent in Xiidra – lessens inflammatory responses by inhibiting the recruitment and activation of T cells to the ocular surface.

Rather than eroding Allergan’s Restasis sales, Shire’s Xiidra is expanding the disease market. In the first half of 2017, Shire reported that the overall DED market expanded by 26% from the previous year, while Allergan indicated that Restasis maintained stable revenues. Trouble is brewing for the Restasis brand, however. First, Shire has filed a complaint at the New Jersey District Court alleging that Allergan is blocking competition in the area. Secondly, and more importantly, in October 2017, a Texas federal judge invalidated Allergan’s Restasis patents on the grounds of obviousness, making it possible for rival generics to enter the market this year. Allergan is now under pressure to drive switching to its Restasis MultiDose product, launched in March 2017, from the original single-use Restasis vials.

Several new formulations of cyclosporine – the active ingredient in Restasis – are in late-stage clinical development, such as Sun Pharma’s nanomicellar Seciera formulation and Novaliq’s CyclASol, wherein cyclosporine is dissolved in proprietary inert semifluorinated alkanes that offer an alternative drug delivery medium to water. In a separate development, Aurinia has planned a Phase 2a proof-of-concept (PoC) study with voclosporin, a calcineurin inhibitor claimed to have improved properties over cyclosporine, which is delivered as a nanomicellar carrier formulation. Like many of the novel cyclosporine formulations, voclosporin seeks to address the perceived limitations of Restasis, specifically: 1) slow onset of action, 2) modest efficacy, 3) effects on signs, but not symptoms, 4) and poor tolerability.

Unlike Restasis, Xiidra is approved for both signs and symptoms of DED and exhibits a somewhat faster onset of action. However, this product still suffers from limited efficacy and common toleration issues, in particular, instillation site irritation (burning), reduced visual acuity and dysgeusia (change in taste).

The limitations of Restasis and Xiidra restrict their use and, as a result, it is estimated that around only 6% of DED patients are receiving a prescription therapy. Consequently, it is clear that an unmet medical need still exists for a fast-acting, effective, safe and well-tolerated therapy to address both disease signs and symptoms. To fulfil this need, a raft of clinical candidates are in development.

Novel compounds in Phase 3 development include Mimetogen/Allergan’s tavilermide (MIM-D3), ReGenTree’s RGN-259 (thymosin β4) and Sylentis’ tivanisiran (SYL1001). The Phase 3 study with TrkA receptor agonist tavilermide completed early last year. However, no results have been forthcoming and the compound is no longer listed on Allergan’s pipeline. The Phase 3 ARISE-1/-2 trials with peptide RGN-259 failed to meet their co-primary endpoint, but demonstrated a number of statistically significant improvements versus placebo in both signs and symptoms.

Many of these significant improvements were based upon post hoc analyses and the same endpoints were not successfully duplicated in the individual trials. ReGenTree will meet with the FDA early in 2018 to determine the next regulatory steps. Blockade of TRPV1, a receptor expressed by sensory afferent fibres, by administration of siRNA tivanisiran to the ocular surface at the 1.125% dose level reduced ocular pain and hyperaemia in Phase 2.

However, a higher 2.25% dose lost efficacy, raising a potential concern that the single dose being evaluated in ongoing Phase 3 trial HELIX could miss the efficacy ‘sweet spot’. In addition to data from novel compounds, Kala Pharmaceuticals recently released topline results of its two Phase 3 DED trials with KPI-121, a short-term, non-maintenance treatment which utilises mucus-penetrating particle technology to enhance infiltration of corticosteroid loteprednol etabonate into the eye. However, only three of four primary endpoints were met, a finding received negatively by investors.

Noteworthy innovative agents in earlier development include Novartis’ ECF843, Aldeyra Therapeutics’ reproxalap (ADX-102) and TopiVert Pharma’s TOP1630. Lubricin is an endogenous glycoprotein expressed in areas of high shear stress and friction, including the tear film where it binds to and protects tissues of the ocular surface. In April 2017, Novartis in-licensed the recombinant human lubricin eyedrops ECF843 from Lubris BioPharma after demonstrating improvements on both signs and symptoms in Phase 2. Nevertheless, no clinical trials appear to be ongoing with this compound.

Five months after the ECF843 deal, Aldeyra reported statistically significant improvements across multiple sign and symptom endpoints, with a one week onset of action, in a Phase 2a trial of topical aldehyde trap reproxalap in DED patients. While the results are impressive at first glance, this trial had no placebo arm and instillation of reproxalap was associated with stinging and tolerability comparable to standard of care. Nonetheless, Aldeyra announced that its data represented the first correlation of improved DED clinical activity with a biomarker – specifically, proinflammatory aldehyde mediator malondialdehyde – and has recently opened a Phase 2b study.

Late last year, TopiVert reported that it achieved clinical PoC in a Phase 1/2a DED study of narrow spectrum kinase inhibitor TOP1630, which delivers synergistic inhibition of multiple pathways involved in innate and adaptive immunities by targeting key kinases in cellular inflammatory signalling cascades. In the study in moderate to severe DED patients, TOP1630 delivered statistically significant results compared to placebo, across multiple sign and symptom endpoints, from the first study assessment point, day 15.

In contrast to PoC studies with other agents, all analyses reported were pre-specified and no post-hoc or subgroup analyses were required. TOP1630 was shown to be safe and very well tolerated, with a placebo-like profile and no instillation site pain or discomfort. In view of the compelling PoC data attained, TopiVert believes that the consistency of effect demonstrated across a range of sign and symptom endpoints, from multiple assessment scales using pre-specified analyses, coupled with the placebo-like tolerability profile, sets a new benchmark for DED treatments. The TOP1630 programme is now ready for late stage development.