Horizon Scanning Research April 2016 & Intelligence Centre

RGN-259 for neurotrophic keratopathy

LAY SUMMARY

Neurotrophic keratitis is a condition in which the cornea, the clear front part of the eye, becomes damaged. It is caused by nerve damage which leads to ulcers forming on the cornea. It can be very difficult to treat and some patients will need eye surgery.

This briefing is RGN-259 is a new drug for the treatment of neurotrophic keratitis that based on is given as eye drops. Some studies have suggested the RGN-259 information available at the time may be helpful for people who already have quite severe damage to of research and a their eye. limited literature search. It is not If RGN-259 is licensed for use in the UK, it could be a new treatment intended to be a option for patients with this condition, which could reduce the need for definitive statement surgery. on the safety, efficacy or effectiveness of the NIHR HSRIC ID: 11475 health technology 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

• Neurotrophic keratopathy: stage 2 and 3.

TECHNOLOGY

DESCRIPTION

RGN-259 (GBT-201; TB4; thymosin beta-4) is a synthetic version of the 43-amino-acid peptide thymosin β4 (TB4), which is a matrix metallopeptidase (MMP)-9 and MMP-1 modulator that was originally isolated from the thymus and is a wound healing agent. TB4 binds to actin and regulates its activity within cells. It promotes endothelial cell differentiation and keratinocyte migration, downregulates a number of inflammatory cytokines and chemokines, and promotes expression of laminin-5, a key component in the wound healing process. In phase III clinical trials, RGN-259 was administered as an ophthalmic 0.1% solution five times daily for four weeks1,a.

RGN-259 does not currently have Marketing Authorisation in the EU for any indication.

RGN-259 is currently in phase III clinical trials for xerophthalmia. It is also in phase II trials for unspecified ulcers, wound healing, epidermolysis bullosa and corneal ulcers.

INNOVATION and/or ADVANTAGES

If licensed, RGN-259 will offer an additional treatment option for patients with stage 2 and 3 keratopathy.

DEVELOPER

RegeneRx Biopharmaceuticals.

AVAILABILITY, LAUNCH OR MARKETING

RGN-259 is a designated orphan drug in the USA. It is in phase III clinical trials.

PATIENT GROUP

BACKGROUND

Neurotrophic keratopathy (NK) is a degenerative disease characterised by decreased corneal sensitivity and poor corneal healing resulting from impaired corneal innervation2,3. This disorder leaves the cornea susceptible to injury and decreases reflex tearing2. Epithelial breakdown can lead to ulceration, infection, melting, and perforation secondary to poor healing2,3.

The most common causes of impairment of corneal sensation are viral infection (herpes simplex and herpes zoster keratoconjunctivitis), intracranial space-occupying lesions (neuroma, meningioma and aneurysms), and neurosurgical procedures that damage the

a Company provided information.

2 Horizon Scanning Research & Intelligence Centre

trigeminal ophthalmic branch4,5. Other ocular causes include ocular surface injury (chemical or thermal burns), corneal dystrophy and contact lens wear4. Many systemic conditions are also associated with the development of corneal anaesthesia, including diabetes mellitus, multiple sclerosis and some congenital syndromes3,4,5.

NK is classified into three stages according to severity3,4: • Stage 1 – mild, non-specific signs and symptoms, characterised by corneal epithelial changes with dry and cloudy cornea. • Stage 2 – non-healing corneal epithelial defect, characterised by recurrent and/or persistent epithelial defects which are surrounded by poorly adherent opaque and oedematous epithelium. • Stage 3 – often ensues if stage 1 and 2 are not appropriately treated. Characterised by corneal ulcer with stromal involvement which may be complicated by stromal melting and progression to corneal perforation.

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 Ophthalmic Pathology Service (All Ages). D12/S(HSS)/b.

CLINICAL NEED and BURDEN OF DISEASE

NK is classified as an orphan disease with an estimated prevalence of less than 5 per 10,000 individuals worldwide4. Although the epidemiology of NK has not been accurately determined, the prevalence and incidence of the disease may be estimated from epidemiological data on conditions associated with NK4. NK develops in an average 6% of herpetic keratitis cases, which have a prevalence of 149 per 100,000 population, and in 13% of herpes zoster keratitis cases, which have a prevalence of 26 per 100,000 population2,4. In addition, 2.8% of patients who underwent surgical procedures for trigeminal neuralgia (1.5 per 10,000 population6) subsequently developed NK4. The percentage of NK cases associated with other conditions, such as diabetes mellitus, multiple sclerosis, corneal dystrophy, and congenital diseases is not known.

In 2014-15, there were 2,426 hospital admissions for keratitis (ICD-10 H16) equating to 10,437 bed days and 2,569 finished consultant episodes in England7.

The population likely to be eligible to receive RGN-259 could not be estimated from available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE interventional procedure guidance. Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for keratoconus and keratectasia (IPG466). September 2013.

3 Horizon Scanning Research & Intelligence Centre

• NICE interventional procedure guidance. Phototherapeutic laser keratectomy for corneal surface irregularities (IPG358). September 2010. • NICE interventional procedure guidance. Corneal endothelial transplantation (IPG304). June 2009. • NICE interventional procedure guidance. Corneal implants for keratoconus (IPG227). July 2007. • NICE interventional procedure guidance. Tissue-cultured limbal stem cell allograft transplant for regrowth of corneal epithelium (IPG216). April 2007. • NICE interventional procedure guidance. Insertion of hydrogel keratoprosthesis (IPG69). June 2004.

CURRENT TREATMENT OPTIONS

Current treatments for NK aim to prevent progression of corneal damage and to promote epithelial healing8. Therapy should be promptly initiated, and is based on the clinical stage of the disease3,8:

• Stage 1 o Preservative-free artificial tears. o Punctual occlusion. • Stage 2 o Prophylactic antibiotic drops and preservative-free artificial tears. o Corneal or scleral therapeutic contact lenses. o Lateral tarsorrhaphy (surgical closure of the eyelids). o Amniotic membrane transplantation over the epithelial defect. o Injection of botulinum A toxin into the upper eyelid levator muscle. • Stage 3 o Prophylactic antibiotic drops and preservative-free artificial tears. o In cases of stromal melting, topical collagenase inhibitors such as N-acetylcysteine, tetracycline or medroxyprogesterone, may be administered. o Lateral tarsorrhaphy. o Conjunctival flap surgery. o Lamellar or penetrating keratoplasty. o Amniotic membrane transplantation. o Larger defects may require lamellar or penetrating keratoplasty.

EFFICACY and SAFETY

Trial NCT02600429, RGN-NK-301; RGN-259 vs placebo; phase III. Sponsor ReGenTree, LLC. Status Ongoing. Source of Trial registry1, manufacturer. information Location USA.

Design Randomised, placebo-controlled. Participants n=46; aged 18 years and older; stage 2 or 3 neurotrophic keratopathy in at least one eye; no clinically significant slit lamp findings at visit 1 that may interfere with study parameters; no significant blepharitis, meibomian gland dysfunction, lid margin inflammation or active ocular allergy that requires treatment; no lid function abnormality (such as lagophthalmos) which in the opinion of the investigator is the primary cause of the persistent epithelial defect; no diagnosis of ongoing ocular

4 Horizon Scanning Research & Intelligence Centre

infection or active inflammation; no use of fluoroquinolone-containing antibiotic eye drops; no use of contact lenses within 14 days prior to visit 1; no use of immunosuppressive therapy; no uncontrolled systemic disease that interferes with study parameters.

Schedule Randomised to RGN-259 0.1% ophthalmic solution 5 times a day; or placebo ophthalmic solution 5 times a day. Follow-up Active treatment for 4 wks, follow-up for approximately 6 wks (2 wks post-treatment). Primary Complete healing of the persistent epithelial defect at day 29 as determined by outcome/s corneal fluorescein staining. Secondary Percentage of subjects achieving complete healing at 8, 15, 22, 36, 43 days as outcome/s determined by corneal fluorescein staining; epithelial defect measurement and classification as stage 1, 2 or 3 using Mackie Classification; tear film break-up time at 29, 36, 43 days; ocular discomfort questionnaire at 8, 15, 22, 29, 36, 43 days; visual acuity at 8, 15, 22, 29, 36, 43 days. Other outcome measures: change in biomicroscopy using slit-lamp at 8, 15, 22, 29, 36, 43 days; corneal sensitivity using an aesthesiometer (Cochet-Bonnet); safety; change in biomicroscopy using dilated fundoscopy at 29 and 43 days; intraocular pressure at 29 and 43 days. Expected Study completion date reported at Aug 2016. reporting date

ESTIMATED COST and IMPACT

COST

The cost of RGN-259 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 treatment options.

Other Issues

 Clinical uncertainty or other research question  None identified identified

5 Horizon Scanning Research & Intelligence Centre

REFERENCES

1 ClinicalTrials.gov. Assessment of the safety and efficacy study of RGN-259 ophthalmic solutions for neurotrophic keratopathy. https://clinicaltrials.gov/ct2/show/NCT02600429 Accessed 22 March 2016. 2 MedScape. Neurotrophic keratopathy. http://emedicine.medscape.com/article/1194889-overview Accessed 23 March 2016. 3 American Academy of Ophthalmology. Diagnosing and treating neurotrophic keratopathy. http://www.aao.org/eyenet/article/diagnosing-treating-neurotrophic-keratopathy?JulyAugust-2008 Accessed 23 March 2016. 4 Sacchetti M and Lambiase A. Diagnosis and management of neurotrophic keratitis. Clinical Ophthalmology 2014;8:571-579. 5 Ophthalmology Management. Neurotrophic Keratopathy: New Treatment Strategies. www.ophthalmologymanagement.com/articleviewer.aspx?articleID=107482 Accessed 23 March 2016. 6 Bhatti MT and Patel R. Neuro-ophthalmic consideration in trigeminal neuralgia and its surgical treatment. Current Opinion in Ophthalmology 2005;16;334-340. 7 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatients statistics, 2014-2015. www.hscic.gov.uk 8 Bonini S, Rama P, Olzi D et al. Neurotrophic keratitis. Eye 2003;17:989-995.

6