Directly targeting pathology: A novel approach to treating glaucoma

Take-home message: Rho kinase inhibitors are intriguing in that they work directly on the pathogenic mechanism of abnormally elevated IOP, increased resistance to trabecular outflow.

Glaucoma Angle By Mark Packer, MD, FACS, CPI

It is a sad irony that not a single glaucoma medication in use today primarily targets the pathogenic cause of increased IOP: impaired function of the conventional trabecular outflow pathway.

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As Kopczynski and Epstein noted in an editorial last year: “The trabecular outflow pathway is the primary draining tissue for the aqueous humor in the eye. It consists of 3 structures, the trabecular meshwork, juxtacanalicular tissue, and Schlemm’s canal. In a healthy eye, IOP is maintained within a narrow range through dynamic regulation of trabecular outflow resistance. In a glaucomatous eye, elevated IOP is due to an abnormally high resistance to outflow in the trabecular outflow pathway. The causes of increased outflow resistance are not fully understood, but it has been hypothesized to involve an increase in the contractile tone and stiffness of the trabecular meshwork and changes in extracellular matrix composition and/or a change in the conductance of Schlemm’s canal.”¹

The most commonly prescribed class of ocular hypotensive drugs-the prostaglandin analogues-reduces IOP by increasing uveoscleral outflow. While this pharmacologic activity remains relatively consistent over time, IOP still tends to increase, and patients tend to require additional adjunctive medications, because the outflow resistance of the trabecular meshwork continues to increase as the disease progresses.

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Similarly, drugs that decrease aqueous production-such as carbonic anhydrase inhibitors, alpha agonists, and beta-blockers-may actually serve to reduce trabecular outflow in a counterproductive fashion by increasing trabecular resistance indirectly through feedback mechanisms that attempt to regulate IOP.

In fact, the addition of second and third medications to the regimen of patients with glaucoma yields progressively less satisfactory results in terms of IOP reduction.²

However, in a recent fortunate development, a novel class of glaucoma medications, the rho kinase inhibitors, have been found to actually increase trabecular outflow by acting directly on the contractile tone of the trabecular meshwork.³

Increasing outflow facility

Rho kinase is a serine/threonine kinase whose activity increases actomyosin contraction in smooth muscle cells, including the smooth muscle-like cells of the trabecular meshwork. Bacharach et al. have recently published results of a phase II clinical trial of AR-13324 (Rhopressa, Aerie Pharmaceuticals), the first of a new class of ocular hypotensive compounds that inhibits both rho kinase and the norepinephrine transporter.

Next: Comparison trial

The authors note: “Consistent with its inhibition of rho kinase, AR-13324 seems to reduce IOP in part by increasing outflow facility. In addition, AR-13324 seems to lower IOP by decreasing the production of aqueous humor. This latter activity may be related to the inhibition of norepinephrine transporter, although this relationship has not been directly demonstrated.”⁴

Perhaps most interesting of their results, Bacharach et al. demonstrated that AR-13324 effects a more consistent reduction in IOP irrespective of baseline. This result is in contradistinction to the effect of prostaglandin analogues, which tend to demonstrate a smaller reduction in IOP in subjects with lower baseline IOPs. For the prostaglandin analogues, patients with mild to moderately elevated IOP generally realize a smaller absolute reduction in pressure. Not so for rho kinase inhibitors.

Comparison trial

In their randomized, double-masked, 28-day trial, the authors compared two concentrations of AR-13324, 0.01% and 0.02%, with latanoprost in subjects with ocular hypertension or open-angle glaucoma (pseudoexfoliation and pigmentary glaucoma were excluded).

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The primary effectiveness endpoint was the mean diurnal IOP at day 28. A pre-specified analysis of the endpoint stratified by baseline IOP ≤ 26 mm Hg or > 26 mm Hg was performed because of the suggestion from an earlier study that the hypotensive effect of AR-13324 may not vary with baseline IOP, which, in fact, is what the study showed.

Two hundred thirteen subjects (95.1%) completed the trial. Mean unmedicated baseline diurnal IOP was 25.8, 25.6, and 25.5 mm Hg in the AR-13324 0.01%, AR-13324 0.02%, and latanoprost groups, respectively (p = 0.805).

On day 28, mean diurnal IOP was 20.1, 20.0, and 18.7 mm Hg, respectively, representing a decrease from unmedicated baseline of 5.5, 5.7, and 6.8 mm Hg. Latanoprost and AR-13324 0.02% were similarly effective at all time points in the subset of patients with baseline IOPs ≤ 26 mm Hg, producing decreases in mean diurnal IOP of 6.0 and 5.7 mm Hg.

The authors reported: “Although AR-13324 0.02% was less effective in ocular hypotensive efficacy than latanoprost by 1 mm Hg in the (intent-to-treat) population, it showed similar efficacy to latanoprost in a pre-specified patient subgroup that excluded patients with baseline IOPs of > 26 mm Hg.”4

Next: Mechanism of action

The improved relative efficacy of AR-13324 0.02% in the subset of patients with baseline IOP ≤ 26 mm Hg was due to the decline in absolute IOP reduction with latanoprost (from 6.8 mm Hg in the intent-to-treat population to 6.0 mm Hg in the subset with baseline IOP ≤ 26 mm Hg), compared with the more consistent absolute IOP reduction with AR-13324 0.02% (5.7 mm Hg in the intent-to-treat population and 5.7 mm Hg in the subset with baseline IOP ≤ 26 mm Hg).

The most common adverse event experience by subjects was conjunctival hyperemia. However, the redness was generally transient (i.e., less noticeable in the morning than immediately after the evening dose) and gradually diminished during the course of the study.

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“By the first morning visit on day 28, the incidences of mild to moderate conjunctival hyperemia were 18% and 24% in the AR-13324 0.01% and 0.02% treatment groups, respectively, compared with 11% in the latanoprost group.”4

Despite these promising results, phase III registration trial (Rocket 1) results for Rhopressa announced in April 2015, did not meet the primary efficacy endpoint of demonstrating non-inferiority of IOP lowering for once-daily Rhopressa compared with twice-daily timolol.⁵

However, in a pre-specified secondary analysis for patients in the study with baseline IOPs below 24 mm Hg, Rhopressa did demonstrate statistical non-inferiority to timolol at all nine measured time points and numerical superiority over timolol at the majority of measured time points. Results from a second phase III trial are expected in the third quarter of this year.

Mechanism of action

In a compelling study of mechanism of action, Pattabiraman et al. treated human trabecular meshwork cells with AR-13324 alone or in combination with fibrinogenic mediators TGFβ2 and CTGF to test induced expression of fibrogenic and myofibroblast specific markers.⁶

They found that AR-13324 induces cell shape changes, loss of actin stress fibers, and loss of focal adhesions in human trabecular meshwork cells, and that AR-13324 significantly suppresses TGFβ2- and CTGF-induced levels of α-SMA, collagen1A, and FSP1in HTM cells. These cell-based observations revealed anti-fibrogenic activity of AR-13324 in cultured human trabecular meshwork cells.

In further elucidation of the mechanism of action and consistent absolute IOP reduction with AR-13324, Kiel and Kopczynski have shown that this compound reduces episcleral venous pressure (EVP) in an animal model (Figure 1).⁷

Next: Combo product results

The trabecular outflow pathway drains into downstream episcleral veins in the eye, and pressure in the veins contributes significantly to IOP. Using Dutch Belted Rabbits, the protocol involved once-per-day topical application of AR-13324 0.04% for 2 days. On the morning of the third day, the animals were anesthetized and surgically prepared, and then measurements were obtained before and for 3 hours after dosing with AR-13324 or vehicle (3 to 5 days of dosing were determined to be necessary to measure peak effectiveness).

The authors concluded: “Consistent with the study hypothesis, AR-13324 lowered the EVP significantly. At baseline, half of the measured IOP in the AR-13324 treated group (34 mm Hg) was attributable to EVP (17 mm Hg), assuming the 1:1 correspondence between IOP and EVP in the Goldmann equation. At 3 hours post-dosing, the reduction in EVP caused by AR-13324 treatment accounted for 42% of the measured reduction in IOP. The remaining reduction in IOP achieved by AR-13324 is presumed to occur through 1 or more additional mechanisms of action, most likely increased outflow facility and decreased aqueous production, as occurred in a previous primate study.”

Three distinct likely mechanisms of action characterize Rhopressa:

• relaxation of trabecular outflow tissue,

• suppression of aqueous secretion by norepinephrine transport inhibition, and

• reduction of episcleral venous pressure.

Results with combination product

A new combination product (Roclatan, Aerie Pharmaceuticals) links these mechanisms with the proven enhancement of uveoscleral outflow associated with latanoprost. In phase IIb trial results released in June 2014, Roclatan achieved its primary efficacy endpoint of statistically significant superiority over each of its components (Rhopressa and latanoprost) on day 29.⁸

The phase IIb 28-day clinical trial included 297 patients. The baseline IOPs tested in the study ranged from 22 to 36 mm Hg. Roclatan lowered mean diurnal IOP on day 29 from 25.1 mm Hg at baseline to 16.5 mm Hg, a 34% decrease in IOP. Roclatan mean diurnal IOP reduction on day 29 was about 2 mm Hg greater than latanoprost. Roclatan efficacy exceeded that of latanoprost by 1.6 to 3.2 mm Hg across each time point evaluated during the study (8 a.m., 10 a.m., 4 p.m. on days 8, 15 and 29).

Next: Impact of therapies

These results were statistically significant at all time points with p values less than 0.05. The most common adverse event was hyperemia, which was reported in 40% of patients and was scored as mild for the large majority.

The emerging picture of the clinical efficacy, safety, and mechanisms of action of these agents suggest that new, powerful therapeutic tools will soon be available for reduction of IOP in patients with ocular hypertension and glaucoma. Most intriguing is the fact that these agents work directly on the pathogenic mechanism of abnormally elevated IOP, increased resistance to trabecular outflow.

In addition, the consistent absolute reduction of IOP regardless of baseline suggests increased effectiveness among the vast majority of patients who have mild to moderately elevated IOP. The impact of these therapies on patients with normal tension glaucoma will be an important topic for future investigation.

Mark Packer, MD, FACS, CPI, is in private practice in Boulder, CO. Dr. Packer is a consultant to Aerie Pharmaceuticals.

References

1. Kopczynski CC, Epstein DL. Emerging trabecular outflow drugs. J Ocul Pharmacol Ther. 2014;30:85-87. doi: 10.1089/jop.2013.0197. Epub 2013 Dec 4.

2. Jampel HD, Chon BH, Stamper R, Packer M, Han Y, Nguyen QH, Ianchulev T. Effectiveness of intraocular pressure-lowering medication determined by washout. (2014) JAMA Ophthalmol. Jan 30. doi: 10.1001/jamaophthalmol.2013.7677. [Epub ahead of print]

3. Stamer WD, Acott TS. Current understanding of conventional outflow dysfunction in glaucoma. Curr Opin Ophthalmol. 2012;23:135-143. doi: 10.1097/ICU.0b013e32834ff23e.

4. Bacharach J, Dubiner HB, Levy B, Kopczynski CC, Novack GD; AR-13324-CS202 Study Group. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology. 2015;122:302-307. doi: 10.1016/j.ophtha.2014.08.022. Epub 2014 Sep 27.

5. Aerie Pharmaceuticals Reports Initial Rhopressa Phase 3 Efficacy Results. http://investors.aeriepharma.com/releases.cfm (Accessed May 1, 2015).

6. Pattabiraman PP. Effects of Rho kinase inhibitor AR-13324 on the actin cytoskeleton and on TGFβ2- and CTGF-induced fibrogenic activity in Human Trabecular Meshwork Cells. AOPT 2015. Poster 43.

7. Kiel JW, Kopczynski C. Effect of AR-13324 on episcleral venous pressure (EVP) in Dutch Belted rabbits. ARVO 2014. Abstract 2900

8. Aerie Pharmaceuticals Reports Roclatan Phase 2b Results Achieve All Clinical Endpoints. http://investors.aeriepharma.com/releases.cfm?Year=&ReleasesType=&PageNum=2 (Accessed May 1, 2015).