Netarsudil for Open-Angle Glaucoma Or Ocular Hypertension

Horizon Scanning Research March 2016 & Intelligence Centre

Netarsudil for open-angle glaucoma or ocular hypertension

LAY SUMMARY

Glaucoma is a serious condition caused by abnormal pressure within the eye leading to blindness. All glaucoma treatments aim to prevent further damage to sight, but any damage to vision that has already been caused by glaucoma cannot be repaired. Glaucoma can be treated with eye drops, tablets, laser surgery, eye surgery or a combination of these methods. This briefing is based on information Netarsudil is a new eye drop to treat patients with glaucoma. It works available at the time by reducing the pressure and increasing fluid removal from the eye to of research and a prevent further damage to the eye. Netarsudil is taken as an eye drop limited literature once a day. search. It is not intended to be a If licensed for use in the UK, it could be a new treatment option for definitive statement patients with glaucoma which works differently compared to other on the safety, glaucoma eye drops. efficacy or effectiveness of the health technology NIHR HSRIC ID: 9615 covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Glaucoma or ocular hypertension ─ open-angle.

TECHNOLOGY

DESCRIPTION

Netarsudil (Rhopressa; AR-13224) inhibits both Rho kinase and the norepinephrine transport protein. The company considers the drug to be a triple-action product, affecting the major pathways involved in the control of intraocular pressure, leading to reduced aqueous humour production, decreased episcleral venous pressure and increased fluid outflow through the trabecular meshwork and the uveoscleral pathway. In phase 3 clinical trials, netarsudil was administered as a 0.02% ophthalmic solution once daily1.

Netarsudil does not currently have Marketing Authorisation in the EU for any indication.

Netarsudil is not in clinical trials for any other indication.

INNOVATION and/or ADVANTAGES

If licensed, netarsudil will offer an additional topical treatment option for patients with ocular hypertension or glaucoma, with a different mechanism of action from current available preparations.

DEVELOPER

Aerie Pharmaceuticals.

AVAILABILITY, LAUNCH OR MARKETING

Phase III clinical trials.

PATIENT GROUP

BACKGROUND

The glaucomas are a group of optic neuropathies characterised by progressive degeneration of retinal ganglion cells, resulting in a distinct appearance of the optic disc and retinal nerve fibre layer and a concomitant pattern of visual loss2,3. Without adequate treatment, glaucoma can progress to visual disability and eventual blindness3. Glaucoma is usually associated with an increase in intraocular pressure (IOP) above the normal value, usually estimated at 21 mmHg; however, surveys show that 20-52% of patients with glaucoma have IOP within the normal range4. Ocular hypertension is a term used to describe any situation in which IOP is greater than 21 mmHg, with absence of glaucomatous defects on visual-field testing; and it can last for many years without development of glaucoma5,6.

The overall risk of developing glaucoma increases with the number and strength of risk factors. It increases substantially with the level of IOP elevation and with increasing age. Other strong risk factors include high myopia, diabetes, black ethnicity and a family history of

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glaucoma in a first degree relative3,4. Identifiable gene mutations are implicated but account for only about 5% of cases of adult onset glaucoma4.

Glaucoma is classified into two major categories according to the appearance and obstruction of the drainage pathway at the iridocorneal angle4. Primary open angle glaucoma is the most common type of glaucoma, accounting for over 70% of cases. It is an IOP related optic neuropathy that gives rise to characteristic optic disc changes and visual field loss. In its early stages it affects peripheral visual field only, but as it advances it results in loss of visual acuity and can cause blindness4.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • NHS England. 2013/14 NHS Standard Contract for Specialised Ophthalmology (Adult). D12/S/a. • NHS England. 2013/14 NHS Standard Contract for Specialised Ophthalmology (Paediatrics). D12/S/b.

CLINICAL NEED and BURDEN OF DISEASE

Glaucoma is one of the most common ophthalmic conditions encountered in primary and secondary care6. The World Health Organization estimated that in 2010, glaucoma accounted for 2% of visual impairment and 8% of blindness worldwide4. Disability adjusted life years attributable to glaucoma more than doubled between 1990 and 2010 due to a global increase in the number of older people4,6. Glaucoma is the leading cause of irreversible blindness in the world and the social and economic burden is likely to increase in the future because of longer life expectancy and an ageing population2,6. In the UK, glaucoma is the second most common cause for registration of visual impairment, accounting for 9-12% of registrations in people over the age of 65 years4. Open-angle glaucoma is the most common type of glaucoma; it has an overall prevalence of approximately 2% of people over the age of 40 years and 5% of people over the age of 80 years7.

Ocular hypertension has an overall prevalence of 3-5% of people over the age of 40 years8. Approximately 10% of people with untreated ocular hypertension go on to develop glaucoma8.

In England and Wales, it is estimated that more than 500,000 people have glaucoma9. In 2014-15, there were 21,792 hospital admissions for glaucoma (ICD-10 H40) in England, resulting in 4,804 bed days and 21,964 finished consultant episodes10.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE clinical guideline. Glaucoma: diagnosis and management (CG85). April 2009. • NICE quality standard. Glaucoma in adults (QS7). March 2011. • NICE interventional procedure guidance. Trabeculotomy ab interno for open-angle glaucoma (IPG397). May 2011.

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• NICE interventional procedure guidance. Trabecular stent bypass microsurgery for open- angle glaucoma (IPG396). May 2011. • NICE interventional procedure guidance. Canaloplasty for primary open-angle glaucoma (IPG260). May 2009.

Other Guidance

• Scottish Intercollegiate Guidelines Network. Glaucoma referral and safe discharge. (SIGN publication no. 144). 201511.

CURRENT TREATMENT OPTIONS

The management of glaucoma focusses on early recognition and treatments to reduce IOP. Medical, laser, and surgical options are available for lowering IOP. Typically, the patient is started on glaucoma eye drop monotherapy, with extra drops being added as required, so that two or more different types of drug can be used in cases that are difficult to control. If the maximum tolerated treatment regimen is unsuccessful, a laser intervention may be advised or the patient may proceed directly to surgery4.

Current treatment options include4,12: • Topical drug therapies (eye drops): • Prostaglandin analogues to increase outflow—latanoprost; bimatoprost; tafluprost; travoprost. • Beta-adrenergic receptor blockers to decrease aqueous production— betaxolo; levobunolol; timolol; carteolol. • Alpha-agonists to increase outflow and decrease aqueous production— apraclonidine; brinonidine. • Carbonic anhydrase inhibitors to decrease aqueous production— brinzolamide; dorzolamide. • Parasympathomimetic to increase outflow—pilocarpine. • Oral therapy—carbonic anhydrase inhibitors. Patients may experience tingling in their fingers and toes, lethargy, and loss of appetite; making it unsuitable for long term treatment but useful for controlling acute increases in pressure or managing raised IOP in the short term while awaiting surgery4. • Laser treatment—laser trabeculoplasty is used to open up blocked drainage tubes. Cyclodiode and endocyclodiode laser of the ciliary body are used for severe glaucoma if standard surgery is not effective. • Surgical treatment—trabeculectomy, which creates a guarded fistula into the wall of the eye to allow a slow egression of aqueous humour into the subconjunctival space.

EFFICACY and SAFETY

Trial NCT02207491, AR-13324- NCT02207621, AR-13324- NCT02246764, AR-13324- CS301; AR-13324 vs CS302; AR-13324 vs CS303; AR-13324 vs timolol maleate; phase III. timolol maleate; phase III. timolol maleate; phase III. Sponsor Aerie Pharmaceuticals. Aerie Pharmaceuticals. Aerie Pharmaceuticals. Status Complete. Ongoing. Ongoing. Source of Trial registry1. Trial registry13. Trial registry14. information Location USA. USA. USA. Design Randomised, active- Randomised, active- Randomised, active- controlled. controlled. controlled.

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Participants n=411; 0-2 years of age n=690 (planned); 0-2 years n=240 (planned); 19-99 and 18 years or older; of age and 18 years or years of age; diagnosis of diagnosis of open-angle older; diagnosis of open- open-angle glaucoma or glaucoma or ocular angle glaucoma or ocular ocular hypertension; hypertension; unmedicated hypertension; unmedicated unmedicated IOP>20mmHg and <27mm IOP>20mmHg and <27mm IOP>20mmHg and <27mm Hg in the study eye at 2 Hg in the study eye at 2 Hg in the study eye at 2 qualification visits, 2-7days qualification visits; qualification visits, 2-7days apart, with an IOP corrected visual acuity in apart, with an IOP >17mmHg and <27mmHg each eye equivalent to >17mmHg and <27mmHg in the same eye at the 20/200; no in the same eye at the second visit; corrected pseudoexfoliation or second visit; corrected visual acuity in each eye pigment dispersion visual acuity in each eye +1.0 logMAR or better by component of glaucoma; +1.0 logMAR or better by Early Treatment Diabetic no history of angle closure ETDRS; no Retinopathy Study or narrow angles; no pseudoexfoliation or (ETDRS); no previous laser peripheral pigment dispersion pseudoexfoliation or iridotomy; no IOP component of glaucoma; pigment dispersion ≥27mmHg in either eye; no no history of angle closure component of glaucoma; more than 2 ocular or narrow angles; no no history of angle closure hypotensive medications previous laser peripheral or narrow angles; no IOP within 30 days of iridotomy; no IOP ≥27mmHg in both eyes; no screening; no ≥27mmHg in either eye; no use of more than 2 ocular contraindications to beta- more than 2 ocular hypotensive medications adrenoceptor antagonists; hypotensive medications within 30 days of screening no previous glaucoma within 30 days of no contraindications to intraocular surgery or screening; no beta-adrenoceptor glaucoma laser procedures contraindications to beta- antagonists; no previous in either eye; no refractive adrenoceptor antagonists; glaucoma intraocular surgery; no ocular trauma no previous glaucoma surgery or glaucoma laser within 6 months prior to intraocular surgery or procedures in either eye screening; no ocular glaucoma laser procedures (including laser peripheral surgery or non-refractive in either eye; no refractive iridotomy); no refractive laser treatment within 3 surgery; no ocular trauma surgery; no ocular trauma months prior to screening; within 6 months prior to within 6 months prior to no recent or current ocular screening; no ocular screening; no ocular infection, inflammation surgery or non-refractive surgery or non-refractive blepharitis, conjunctivitis, laser treatment within 3 laser treatment within 3 and no history of herpes months prior to screening; months prior to screening; simplex or zoster keratitis; no recent or current ocular no recent or current ocular no clinically significant infection, inflammation infection, inflammation ocular disease in either blepharitis, conjunctivitis, blepharitis, conjunctivitis, eye including severe and no history of herpes and no history of herpes glaucomatous damage; no simplex or zoster keratitis; simplex or zoster keratitis; central corneal thickness no clinically significant no clinically significant >600µm at screening. ocular disease in either ocular disease in either eye including severe eye including severe glaucomatous damage; no glaucomatous damage; no central corneal thickness central corneal thickness >600µm at screening. >600µm at screening. Schedule Randomised to AR-13324 Randomised to AR-13324 Randomised to AR-13324 0.02% ophthalmic solution ophthalmic solution once ophthalmic solution once once daily; or timolol daily; or AR-13324 twice daily; or AR-13324 twice maleate 0.5% ophthalmic daily; or timolol maleate daily; or timolol maleate solution once daily. The ophthalmic solution twice ophthalmic solution twice duration of treatment has daily. The dosage and daily. The dosage and not been reported. duration of treatment have duration of treatment have not been reported. not been reported.

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Follow-up Not reported. Not reported. Not reported. Primary IOP. IOP. Safety; visual acuity using outcome/s ETDRS; evaluation of anterior and posterior segment. Secondary Ocular safety. Ocular safety. None reported. outcome/s Key results Not reported. - - Adverse Not reported. - - effects (AEs) Expected Not reported. Estimated study Estimated study reporting completion date is reported completion date is reported date as June 2016. as May 2016.

Trial NCT02558374, AR-13324- NCT01731002, AR-13324- NCT01528787; AR-13324- CS304; AR-13324 vs CS202; AR-13324 vs CS201; AR-13324 vs timolol maleate; phase III. latanoprost; phase II. placebo; phase II. Sponsor Aerie Pharmaceuticals. Aerie Pharmaceuticals. Aerie Pharmaceuticals. Status Ongoing. Complete. Complete. Source of Trial registry15. Publication16, trial Trial registry18. information registry17. Location USA. USA. USA. Design Randomised, active- Randomised, active- Randomised, placebo- controlled. controlled. controlled.

Participants n=700 (planned); 18 years n=224; 18 years and older; n=85; 18 years and older; and older; diagnosis of diagnosis of open-angle diagnosis of open-angle open-angle glaucoma or glaucoma or ocular glaucoma or ocular ocular hypertension; hypertension; unmedicated hypertension; unmedicated unmedicated IOP≥24mmHg in the study IOP≥24mmHg in the study IOP>20mmHg and <30mm eye at 2 qualification visits, eye at 2 qualification visits, Hg in the study eye at 2 2-7days apart, with an IOP 2-7days apart, with an IOP qualification visits; ≥22mmHg in the same eye ≥21mmHg in the same eye corrected visual acuity in at the second visit; at the second visit; each eye equivalent to corrected visual acuity in corrected visual acuity in 20/200; no each eye +1.0 logMAR or each eye +1.0 logMAR or pseudoexfoliation or better by ETDRS; no better by ETDRS; no pigment dispersion pseudoexfoliation or pseudoexfoliation or component of glaucoma; pigment dispersion pigment dispersion no history of angle closure component of glaucoma; component of glaucoma; or narrow angles; no IOP no history of angle closure no history of angle closure ≥30mmHg in both eyes; no or narrow angles; no IOP or narrow angles; no IOP more than 2 hypotensive >36mmHg in both eyes; no >36mmHg in both eyes; no ocular medications within more than 2 ocular more than 2 ocular 30 days of screening; no hypotensive medications hypotensive medications contraindications to beta- within 30 days of within 30 days of adrenoceptor antagonists; screening; no previous screening; no previous no previous glaucoma glaucoma intraocular glaucoma intraocular intraocular surgery or surgery or glaucoma laser surgery or glaucoma laser glaucoma laser procedures procedures in either eye procedures in either eye in either eye (including (including laser peripheral (including laser peripheral laser peripheral iridotomy); iridotomy); no refractive iridotomy); no refractive no refractive surgery; no surgery; no ocular trauma surgery; no ocular trauma ocular trauma within 6 within 6 months prior to within 6 months prior to months prior to screening; screening; no ocular screening; no ocular no ocular surgery or non- surgery or non-refractive surgery or non-refractive refractive laser treatment laser treatment within 3 laser treatment within 3

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within 3 months prior to months prior to screening; months prior to screening; screening; no recent or no recent or current ocular no recent or current ocular current ocular infection or infection, inflammation infection, inflammation inflammation; no mean blepharitis, conjunctivitis, blepharitis, conjunctivitis, corneal thickness >620µm and no history of herpes and no history of herpes at screening. simplex or zoster keratitis; simplex or zoster keratitis; no clinically significant no clinically significant ocular disease in either ocular disease in either eye including severe eye including severe glaucomatous damage; no glaucomatous damage; no central corneal thickness central corneal thickness >600µm at screening. >600µm at screening.

Schedule Randomised to AR-13324 Randomised to AR-13324 Randomised to AR-13324 ophthalmic solution once 0.01% ophthalmic solution, ophthalmic solution at, daily in the evening with a or AR-13324 0.02% 0.01%, 0.02% or 0.04%, placebo ophthalmic ophthalmic solution; or once daily; or placebo solution drop in the 0.005% latanoprost vehicle ophthalmic solution morning; or timolol maleate ophthalmic solution; all once daily. The duration of ophthalmic solution twice once daily for 28 days. treatment has not been daily. The dosage and reported. duration of treatment have not been reported. Follow-up Not reported. Not reported. Not reported. Primary IOP. IOP. IOP. outcome/s Secondary Ocular safety and None reported. None reported. outcome/s tolerability; visual acuity; visual field test; pupil size. Key results - For AR-13324 0.01%, Not reported. 0.02% and latanoprost groups, respectively: mean diurnal IOP on day 28, 20.1, 20.0 and 18.7 mmHg; decrease in IOP from unmedicated baseline, 5.5, 5.7, and 6.8 mmHg (p<0.001). Reduction in IOP by AR- 13324 0.02% did not meet the criterion for noninferiority to latanoprost.

Adverse - The most frequently Not reported. effects (AEs) reported AEs in all groups were conjunctival/ocular hyperaemia, with a combined incidence of 52%, 57%, and 16% in the AR-13324 0.01%, 0.02% and latanoprost groups, respectively. On day 28, the incidence of mild to moderate hyperaemia by biomicroscopy was 18%, 24%, and 11% in these groups, respectively.

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Expected Estimated study - Not reported. reporting completion date is reported date as November 2016.

ESTIMATED COST and IMPACT

COST

The cost of netarsudil is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs

 Other: uncertain unit cost compared to  None identified existing alternative medications.

Other Issues

 Clinical uncertainty or other research question  None identified identified

REFERENCES

1 ClinicalTrials.gov. Double-masked study if AR-13324 ophthalmic solution in patients with glaucoma or ocular hypertension (Rocket 1). www.clinicaltrials.gov/ct2/show/NCT02207491 Accessed 11 February. 2 Weinreb RN, Aung T and Medeiros FA. The pathophysiology and treatment of glaucoma. The Journal of the American Medical Association 2014; 311(18):1901-1911. 3 Michelessi M, Lucenteforte E, Oddone F et al. Optic nerve head and fibre layer imaging for diagnosing glaucoma (review). The Cochrane Collaboration 2015; issue 11. 4 King A, Azuara-Blanco A, and Tuulonen A. Glaucoma. The British Medical Journal 2013; 346:f3518. 5 MedScape. Ocular hypertension. www.emedicine.medscape.com/article/1207470-overview Accessed 9 February 2016. 6 Patient.info. Glaucoma and ocular hypertension. www.patient.info/doctor/glaucoma-and-ocular- hypertension Accessed 9 February 2016.

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7 National Institute of Health and Clinical Excellence. Glaucoma: diagnosis and management of chronic open angle glaucoma and ocular hypertension. Clinical guideline CG85. London: NICE; April 2009. 8 WebMD. Ocular hypertension. www.webmd.boots.com/eye-health/guide/ocular-hypertension Accessed 9 February 2016. 9 NHS Choices. Glaucoma. www.nhs.uk/conditions/Glaucoma/Pages/Introduction.aspx Accessed 9 February 2016. 10 Health and Social Care Information Centre. Hospital episode statistic for England. Inpatient statistics, 2014-15. www.hscic.gov.uk 11 Scottish Intercollegiate Guidelines Network. Glaucoma referral and safe discharge. National clinical guideline 144. Edinburgh: SIGN; March 2015. 12 McKinnon SJ, Goldberg LD, Peeples P et al. Current management of glaucoma and the need for complete therapy. The American Journal of Managed Care 2008;14(1 Suppl):S20-27. 13 ClinicalTrials.gov. Evaluation of netarsudil (AR-13324) ophthalmic solution in patients with glaucoma and ocular hypertension. www.clinicaltrials.gov/ct2/show/NCT02207621 Accessed 11 February. 14 ClinicalTrials.gov. Study of netarsudil (AR-13324) ophthalmic solution in patients with glaucoma or ocular hypertension. www.clinicaltrials.gov/ct2/show/NCT02246764 Accessed 11 February. 15 ClinicalTrials.gov. Double-masked study of netarsudil (AR-13324) ophthalmic solution in subjects with glaucoma or ocular hypertension. www.clinicaltrials.gov/ct2/show/NCT02558374 Accessed 11 February. 16 Bacharach J, Dubiner HV, Levy B et al. Double-masked, randomised, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. American Academy of Ophthalmology 2015; 122(2): 302-307. 17 ClinicalTrials.gov. A phase 2, double-masked, randomised, multi-center, active-controlled, dose- response parallel group study comparing trhe safety and ocular hypotensive efficacy of AR-13324 to latanoprost in patients with elevated intraocular pressure. www.clinicaltrials.gov/ct2/show/NCT01731002 Accessed 11 February. 18 ClinicalTrials.gov. Study of AR-13324 in patients with elevated intraocular pressure. www.clinicaltrials.gov/ct2/show/NCT01528787 Accessed 11 February.