New Topical Medications

Sunita Radhakrishnan, M.D. Glaucoma Center of San Francisco, Glaucoma Research and Education Group

Financial Disclosure Consultant: Netra Systems, Inc Latanoprostene bunod Netarsudil

FDA approval Nov 2017 Dec 2017

Trabecular outflow • Pilocarpine • Latanoprostene NEW bunod • Netarsudil

Uveoscleral outflow • Prostaglandins • Alpha agonists Rudkin et al. Recognizing congenital glaucoma. Med J Aust 2009; 191: 466-467

Aqueous inflow • Beta blockers • Alpha agonists • CAIs New Medications

Latanoprost with potassium Netarsudil and latanoprost sorbate (non BAK) fixed combination

FDA approval Sept 2018 Mar 2019

Latanoprostene bunod

• Latanoprost + Nitric oxide donating component (butanediol mononitrate) • Dual mechanism of action – Latanoprost increases uveoscleral flow – NO relaxes TM and increases trabecular outflow Latanoprostene bunod

• Efficacy: – IOP reduction of 8-9 mm Hg (30 to 33%) in OAG/OHTN with mean baseline IOP of ~27mm Hg. (pooled phase-3 studies APOLLO, LUNAR; Weinreb et al. J Glaucoma 2018) – IOP reduction of at least 22% (4.3 mm Hg) in Japanese patients with mean baseline IOP of 19.6 mm

Hg (JUPITER study, Kawase et al. Adv Ther. 2016; 12 month follow-up)

Latanoprostene bunod

• Side effects – Similar to latanoprost – Stinging Netarsudil

• RhoKinase inhibitor • Multiple mechanisms of action – Increases trabecular outflow by relaxing TM – Reduces episcleral venous pressure – Reduces aqueous production

Netarsudil

• Efficacy: – IOP reduction of 3.3 to 5.1 mm Hg (15 to 22%) in 3

phase 3 trials (ROCKET-1, 2, 4) with mean baseline IOP 20.7 to 23.4) – In ROCKET-4, netarsudil demonstrated non-inferiority to timolol across various IOP ranges (<25, <27, <30)

Serle et al, ROCKET 1,2 AJO 2018, Khour et al. ROCKET 4, AJO Aug 2019 Netarsudil

• Side effects reported in ROCKET -4 study with 6 month follow-up – Hyperemia: 48%, mostly mild – Subconjunctival hemorrhages: 16% www.aeriepharma.com – Instillation site pain: 24% – Cornea verticillata: 25% • Onset at ~ 3 months • Mild, no visual consequence • Resolved upon discontinuation in 60%

Netarsudil

• Discontinuation rate: – From all adverse events (mostly ocular): 19% – Due to conjunctival hyperemia: 4%

ROCKET-4, Khouri et al. AJO, Aug 2019 Latanoprost emulsion with potassium sorbate (Xelpros) • Efficacy: – In one Phase 3 trial, IOP reduction was 5.0 – 6.2 mm Hg (22 – 25%) in Xelpros group versus 5.7 – 6.6 m Hg (25- 26%) in Xalatan group. • Side effects: – 67% reported eye pain with Xelpros versus 47% with Xalatan • Storage: – No refrigeration required

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/206185Orig1s000MedR.pdf

Netarsudil and latanoprost fixed combination (Rocklatan) • Efficacy: – IOP reduction of 6.8 to 9.2 mm Hg (31 to 37%) from mean baseline IOP of 22.4 to 24.7 mm HG – Additional IOP lowering IOP of • 1.8–3.3 mmHg vs netarsudil • 1.3–2.5 mm Hg vs latanoprost

Asrani et al, MERCURY-1, AJO June 2019; Walters et al, MERCURY – 2, Ophthalmolog Glaucoma 2019, In Press Netarsudil and latanoprost fixed combination (Rocklatan) • Side effects:

– 53 to 55% conjunctival hyperemia (similar to netarsudil)

– 2.5 to 7% discontinuation rate (lower than netarsudil)

Asrani et al, MERCURY-1, AJO June 2019; Walters et al, MERCURY – 2, Ophthalmolog Glaucoma 2019, In Press

Frequency of administration

PGA

PGA+NO RhoK- β- α2+ α2+ α2+

CAI- CAI- CAI-

AM PM PGA

CAI-

PGA+NO RhoK-

Choosing first line therapy

• Effective • Good side effect profile • Inexpensive • Once a day dosing • 24 hour IOP control Van der Walk R, et al. IOP lowering effects of all commonly used glaucoma drugs: a meta-analysis of RCTs. Ophthalmology. 2005;112:1177-85

Newer options for first line therapy

• Latanoprostene bunod and Netarsudil – Advantages: • May help maintain the physiological aqueous outflow pathways • Convenient dosing – Disadvantages • Cost/Access • Netarsudil: Side effects Adjunctive treatment

• Many glaucoma patients require more than one medication to adequately lower IOP – OHTS, 40% required 2 or more meds by year 5 – CIGTS, 75% required 2 or more meds after 2 years of treatment • With PGA monotherapy, consider trying a different PGA before adding another medication

Choosing adjunctive therapy

• Additional IOP lowering • Other factors – Side effects – Impact on adherence • Dosing schedule • Cost Adjunctive therapy to PGAs

• Beta blockers • Topical CAIs – Easy once daily dosing – At least BID schedule – Diurnal and nocturnal IOP – Poor nocturnal IOP control control • Brimonidine • Rho Kinase inhibitor – At least BID – Easy qd dosing – Poor nocturnal IOP control – Diurnal and nocturnal IOP control

New medications versus latanoprost

• Netarsudil/latanoprost fixed dose combination – Additional IOP lowering of 1.8mm – 2.5 mm Hg – Higher proportion of patients achieving IOP ≤ 15 mm Hg • 42 to 44% with netarsudil/latanoprost FDC versus 18- 25% with latanoprost alone First line and adjunctive therapy

• No one-size-fits-all algorithm • Treatment has to be individualized for each patient

Clinical experience - Early

• Initially tried both Latanoprostene bunod and Netarsudil in patients who were already on multiple medications Early experience

• Cost: • Access: – Prior authorization for almost every prescription – Created template statement about mechanism of action of new meds • Side effects: – Warned patients of hyperemia from netarsudil; tends to get better after first few days of use

Early experience

• Efficacy of netarsudil: – Greater than expected in some patients – Able to achieve single digit IOPs even in patients on multiple medications Early experience

• Side effects with netarsudil – Follicular conjunctivitis and eyelid dermatitis similar to brimonidine induced reaction • Takes longer to resolve? Brimonidine induced follicular conjunctivitis. Eyerounds.org – Discontinuation rate higher than reported in trials

Initial survey

• 64 patients started on netarsudil treatment • 25% discontinued due to side effects: – Conjunctival hyperemia (n=6) – Follicular conjunctivitis (n=5) – Eyelid dermatitis (n=3) – Tearing, discomfort, or severe itching (n=2) New medications in 2019

• More likely to consider latanoprostene bunod as first line agent, especially in younger patients – Good efficacy – Tolerated well – Potential advantage of maintaining trabecular pathways open

New medications in 2019

• Netarsudil can be a good adjunct to PGA • Side effects are relatively more common but has several advantages over other agents – Once daily dosing – Night-time efficacy – May keep trabecular pathways open – May achieve very low IOPs in some patients New medications in 2019

• Cost is still an issue for many patients – Competing against very cheap generics

New medications in 2019

• Access is improving Summary

• New medications with novel mechanisms of action are a welcome addition to our treatment portfolio • Cost and access is not optimal • Side effects/discontinuation rate with Rho Kinase inhibitors is high but they can be very effective in some patients