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Editors Selection IGR 21-4

Medical Treatment: Netarsudil for Glaucoma

Andrew Tatham

Comment by Andrew Tatham on:

90997 Pooled Efficacy and Safety Profile of Netarsudil Ophthalmic Solution 0.02% in Patients With Open-angle Glaucoma or Ocular Hypertension, Singh IP; Fechtner RD; Myers JS et al., Journal of Glaucoma, 2020; 29: 878-884


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The Rho kinase (ROCK) inhibitor, netarsudil 0.02%, was approved by the United States Food and Drug Administration (FDA) in December 2017 and by the European Medicines Agency (EMA) in November 2019. Netarsudil lowers intraocular pressure (IOP) by reducing actin-myosin contraction in the trabecular meshwork to decrease outflow resistance, but it also lowers episcleral venous pressure.1,2

Singh and colleagues examined pooled data from the ROCKET series of phase III clinical trials, which evaluated the efficacy and safety of once-daily netarsudil, with study durations ranging from three to 12 months.3-5 The pooled efficacy analysis included 494 participants randomized to once-daily netarsudil and 510 participants to twice-daily timolol, with baseline IOP less than 25 mmHg. Three months of study treatment were completed by 86.6% (428/494) of participants in the netarsudil group and 94.5% (482/510) in the timolol group. Once daily netarsudil met the criteria for non-inferiority at all nine time points measured (8 am, 10 am and 4 pm at weeks two and six, and month three). Mean IOP on treatment ranged from 16.4 to 18.1 mmHg in the netarsudil group, with a mean IOP reduction of 4.8 mmHg.

A secondary analysis, including 666 patients treated with once-daily netarsudil and 768 with twice-daily timolol, with baseline IOP < 30 mmHg, also showed non-inferiority of netarsudil to twice-daily timolol. Whereas the IOP-lowering effect of timolol depended on baseline IOP, the effect of netarsudil was stable across the range of IOPs. A higher proportion of patients with low baseline IOP (< 23 mmHg) achieved a ≥ 20% reduction in IOP with netarsudil than timolol (57.2% versus 45.6%), whereas timolol performed better in patients with high baseline IOP.

The pooled safety analysis included 1,678 patients, half treated with netarsudil and half with timolol. Treatment was discontinued before cessation of the studies in 31.5% (264/839) of netarsudil and 12.6% (106/839) of timolol patients. The most common ocular adverse events were conjunctival hyperemia (54.4% versus 10.4% for netarsudil and timolol respectively), cornea verticillata (20.9% versus 0.2%), instillation site pain (19.9% versus 21.6%) and conjunctival hemorrhage (17.2% versus 1.8%). Most ocular adverse events were mild and did not increase with continued dosing. Once daily netarsudil was associated with a similar pattern of systemic adverse events as timolol, but unlike timolol had no effect on heart rate.

Netarsudil was effective across IOP levels

In summary, this pooled analysis showed once-daily netarsudil had an IOP-lowering efficacy non-inferior to twice-daily timolol and that netarsudil was generally well tolerated. Whereas the efficacy of timolol varied with baseline IOP, netarsudil was effective across IOP levels. ROCK inhibitors are the first new class of glaucoma medical treatment for over two decades and provide a novel pharmacological method for IOP reduction. The ROCKET studies offer strong evidence of efficacy and safety, although the discontinuation rate may indicate problems with tolerability in some individuals.

References

  1. Lin CW, Sherman B, Moore LA, et al. Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma. J Ocul Pharmacol Ther. 2018;34(1-2):40-51.
  2. Sit AJ, Gupta D, Kazemi A, McKee H, Challa P, Liu KC, Lopez J, Kopczynski C, Heah T. Netarsudil Improves Trabecular Outflow Facility in Patients with Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 2 Study. Am J Ophthalmol. 2021 Jan 29;226:262-269.
  3. Serle J, Katz LJ, McLaurin E, et al. ROCKET-1 and ROCKET-2 Study Groups. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure. Am J Ophthalmol. 2018;186:116-127.
  4. Khouri AS, Serle JB, Bacharach J, et al. Once-daily netarsudil vs twice-daily timolol in patients with elevated intraocular pressure, the randomized phase 3 ROCKET-4 study. Am J Ophthalmol. 2019;204:97-104.
  5. Kahook MY, Serle JB, Mah FS, et al. Long-term safety and ocular hypotensive efficacy evaluation of netarsudil ophthalmic solution: Rho Kinase Elevated IOP Treatment Trial (ROCKET-2). Am J Ophthalmol. 2019;200:130-137.


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