Update on Glaucoma Medical Therapy

Transcription

1 Update on Glaucoma Medical Therapy Murray Fingeret, OD Disclosures Consultant Alcon, Allergan, Bausch & Lomb, Carl Zeiss Meditec, Dyopsys, Heidelberg Engineering, Reichert, Topcon Glaucoma Therapy An Overview Chronic disease that can be difficult to control Person has the disease for the rest of their life Treatment often requires multiple medications and surgeries Treatment endpoints are poorly defined Treatment endpoints are often difficult to achieve, even when defined Medication adherence challenges are common New Developments in Glaucoma In future, similar to cardiologists we may discuss with our patients smoking cessation, altering diet, weight loss, and increased physical activity as additional therapies for glaucoma Broaden Understanding of genetic associations Understand one s risk of becoming functionally impaired Currently only limited list of genetic variations associated with glaucoma This list should increase in near future Incorporate genetic analysis into risk assessment Increased understanding of mechanisms of optic nerve damage Microcirculation Immune system Inflammatory cytokines New Developments in Glaucoma 24-hour IOP monitoring systems Better define target IOPs leading to better therapies Personalize glaucoma care Devices Triggerfish contact-lens system Currently available in Europe Measures changes in corneal curvature as surrogate for IOP Other devices in development include Implandata and AcuMEMS Today we make decisions based upon single in-office IOP but patient s IOP may vary at other times With 24 hour IOP measurement, will be able to determine our treatment target based upon IOP peak, 24-hour mean or fluctuation over 24 hours New 24-hour devices may be able to synchronize drug release with peaks of IOP 24-Hour IOP Monitoring How do we evaluate IOP if we are only measuring it briefly in office? Three approaches to measure IOP over 24 hour period Self tonometry Permanent continuous IOP monitoring Temporary continuous IOP monitoring 1

2 Habitual IOP (mmhg) hour IOP pattern (ages 40-80) glaucoma vs. non-glaucoma WAKE (sitting) glaucoma (N=28) non-glaucoma (N=28) DARK (supine) WAKE (sitting) Triggerfish Contact Lens 24-Hour IOP Monitoring Device 3:30 PM 5:30 PM 7:30 PM 9:30 PM 11:30 PM 1:30 AM 3:30 AM 5:30 AM 7:30 AM Clock Time 9:30 AM 11:30 AM 1:30 PM Leonardi M, et al. Wireless contact lens sensor for intraocular pressure monitoring: assessment on enucleated pig eyes. Acta Ophthalmol. 2009: 87: Self Tonometry Patients would monitor their IOP over time with easyto-use devices Easiest approach in regards to continuous monitoring Adapt current device such as Noncontact tonometer or Rebound tonometer May be difficult for some patients to perform Not easy to obtain 24 hour IOP New Developments in Glaucoma Modalities to assess entire visual pathway including the brain Functional magnetic resonance imaging (FMRI) Recognize that glaucoma is a neurodegenerative disease Develop new therapies around this concept Glaucoma Medical Therapy Major Events Shift from Pilocarpine dosed QID to Timolol BID Pilocarpine was the first line therapy for glaucoma for may years due to its efficacy and safety Drawbacks were frequent dosing and topical side effects 1996 Introduction of Xalatan QHS 2011 Introduction of generic latanoprost 2016 Waiting approval of several new medications including new classes of agents as well as new surgical devices 2

3 Glaucoma Therapy Update Glaucoma Pharmaceutical market world wide expected to grow from $2.4 billion USD to $3.3 billion USD by 2023 US sales from $1.7 billion USD to $2.2 billion USD by 2023 Increase due to introduction of several new products and increase in glaucoma prevalence Population aging Growth will be driven by first-in-class drugs Rhopressa/Roclatan (Aerie) Vesneo (latanoprost bunod) Bausch & Lomb Trabodenoson (Inotek) Tapcom/Taptiqom (tafluprst/timolol) - Santen Glaucoma Medical Therapy FDA Approvals since 2000 A-adrenergic agonist Brimonidine -Alphagan (Allergan) B-adrenergic antagonist Timolol -Istalol (Bausch & Lomb) Prostaglandin analogues Bimatoprost 0.01% or 0.03% Lumigan (Allergan) Tafluoprost % - Zioptan (Merck) Travoprost Travatan (preserved w Sophia Z) and Izba (preserved with Polyquad) Alcon Unoprostone isopropyl Rescula (Novartis) Muscarinic Piliocarpine (Alcon) Glaucoma Medications 2015 Usage in Dollars Prostaglandins 42% 60% generics 18% Bimatoprost (Lumigan) and 16% travatan (Travatan Z) Alpha Agonists 21% Generic brimonidine and Alphagan P Fixed Combination Agents 21% Generic and Combigan and Simbrinza Topical CAIs 9% Generic and Brinzolamide (Azopt) Beta Blockers 7% Generic timolol and Istalol Glaucoma Medical Therapies Some of the newly approved agents were reformulations of originally approved products Three were fixed-dosed combinations Dorzolamide-timolol (CoSopt, Merck) Brimonidine-timolol (Combigan, Allergan) Brinzolamide-Brimonidine (Simbrinza, Alcon) None were a new class Glaucoma Medical Therapy Issues with Therapy 50% of glaucoma patients require 2 or more drugs Today s topical therapy requires patients to instill eye drops correctly (performance) and do so at right time (adherence) These issues lead to the development of novel drug delivery devices that would reduce patient performance and adherence demands Generic Medications Currently available ophthalmic glaucoma drugs in generic form Beta blockers Timolol, levobunolol, carteolol Alpha-adrenergic agonist Brimonidine 0.15, 0.2% Topical carbonic anhydrase inhibitor Dorzolamide Fixed Combination Dorzolamide/timolol Oral carbonic anhydrase inhibitors Acetazolamide Methazolamide Prostaglandins Latanoprost Bimatoprost 0.03 Travaprost 3

4 Generic Timeline Bimatoprost 0.03% - New Generic Travoprost Generic March 2013 Par Pharmaceuticals Not Travatan Z Azopt Generic April 2013 No company making this Lumigan 0.03% - Generic August 2014 Not Lumigan 0.01% Latanoprost PF 2014 Alphagan P Generic January 2022 Combigan Generic April 2022 Lumigan 0.01% - June 2027 Travatan Z October A patient suggested that he did better on Lumigan when it was 0.03% rather than the current formula With the introduction of 0.03 generic bimatoprost, we tried it and he was better by 3 points and will continue it Lesson If need additional few points, going to this generic is a consideration Problem is that this drug is not inexpensive Adherence New Drugs Different methods to improve patient adherence Reduce side effects of medications by selecting best agent for patient Keep treatment regimen simple No more than two bottles Fixed combinations Educate patients about glaucoma and why they need to use medications as well as how to instill medications Use generic medications as noted by Stein paper Use 90 day fill Latanoprost bunod Nitric oxide donating Prostaglandin F2a Bausch & Lomb Rho Kinase Inhibitors Rhopressa and Roclatan With and Without Latanoprost Aerie Lumigan SR Sustained release bimatoprost implant Trabodenoson Selective adenosine mimetic acting at A1 receptor subtype Inotek OTX-TP Sustained release travoprost punctal plug Ocular Therapeutix Latanoprostone bunod 0.024% used once daily to reduced IOP Bausch & Lomb Hopes to launch in the U.S. by July 2016 Metabolized to latanoprost acid plus butanediol mononitrate Butanediol mononitrate is a nitric-oxide donating moiety that can dilate blood vessels and also reduce IOP Works over 24 hour period with >35% IOP reduction One molecule leads to IOP reduction via the uveoscleral and trabecular meshwork paths Latanoprostene bunod Acts on both the Uveoscleral outflow pathway by altering the extracellular matrix in the ciliary muscle and the sclera Trabecular meshwork outflow by inhibiting actomyosin contractility in trabecular meshwork cells thereby relaxing the meshwork 4

5 Latanoprostene bunod Latanoprostene bunod The pivotal Phase 3 program includes two separate randomized, multicenter, double-masked, parallel-group clinical studies, APOLLO and LUNAR Designed to compare the efficacy and safety administered once daily (QD) against timolol maleate 0.5% administered twice daily (BID) in lowering IOP in patients with open-angle glaucoma or ocular hypertension The primary endpoint of both studies, which include a combined total of 840 patients, was the reduction in mean IOP measured at specified time points during three months of treatment The Phase 3 studies are pivotal for U.S. registration and are being conducted in North America and Europe. The primary endpoint of non-inferiority to timolol maleate 0.5% was achieved in both Phase 3 studies. Additionally, showed a reduction in mean IOP of 7.5 to 9.1 mmhg from baseline between 2 and 12 weeks of treatment in the two Phase 3 studies This IOP effect was statistically superior (p < 0.05) to timolol in both studies. Also showed positive results on a number of secondary endpoints There were no significant safety findings in either study The collection of patient safety data for a total of up to 12 months is still ongoing New Medication Rho Kinase Inhibitors Rho kinase inhibitors with norepinephrine transporter inhibition Reduce cellular stiffness in trabecular meshwork Target trabecular meshwork cells to enhance outflow May offer neuroprotective as well as anti inflammatory effects Aerie and Altheos New Glaucoma Medications Aerie Pharmaceuticals Two compounds Dual action Rho kinase (ROCK) + norepinephrine transport (NET) inhibitor AR lowers IOP by enhance outflow through TM (ROCK) and inhibit aqueous production (NET) Also believed to reduce episcleral venous pressure which may allow it to better reduce IOP when it is below 21 mm Hg Triple action ROCK + NET + latanoprost PG324 fixed combination of AR and latanoprost Additional IOP reduction through uveoscleral outflow Both agents are once per day dosage Hyperemia is most common side effect found in studies to date 5

6 Rhopressa Rhopressa Rocket person phase 3 study Rhopressa efficacy study done over 3 months Non-inferiority to Timolol Results 2 nd quarter 2015 Rocket 2 3 month efficacy along with 12 month safety study Results mid-late 2015 Rocket 3 12 month safety study only Phase 3 of Roclatan expected to start in mid 2015 The research found that the drug suppressed the activity of the profibrotic proteins transforming growth factor beta-2 and connective tissue growth factor on human trabecular meshwork cells in an in vitro model This is the first study to show that Rhopressa, a novel once-daily, triple-action eye drop that lowers IOP in glaucoma patients, has the potential to modify the course of glaucoma by arresting fibrosis Rhopressa Another recent preclinical study by Aerie indicated that Rhopressa may increase the perfusion of the trabecular meshwork with aqueous humor, which has the potential to positively affect the overall health of the tissue. New Glaucoma Medications Altheos Has rights to Asahi Kasei Pharma Corp.'s preclinical AK138 series of selective Rho kinase inhibitors that is now called ATS907 Amakem Therapuetics ROCK inhibitor AMA0076 Aim is for reduced hyperemia due to its quick penetration into TM Mean IOP reduction 20% in phase I trials 3-5 years away Trabodenoson Inotek Pharmaceuticals Selective adenosine mimetic that targets one of four known receptors of naturally occurring adenosine A1 receptor When stimulated this receptor upregulates proteases in TM such as matrix metalloprotease which digests and removes hydrolyzed proteins that clog TM Dosage either once or twice daily Still being determined but probably will be QD dosing Few side effects, well tolerated Phase 2 trials completed, starting phase 3 this fall Bimatoprost SR Allergan Sustained release prostamide-loaded bioerodible implant that will last 4-6 months with similar efficacy to eyedrops Injected into the anterior chamber Can be performed in the office Ensures patient compliance 6

7 Sustained-release Travoprost Travoprost Punctum Plug OTX-TP, Ocular Therapeutix Intracanalicular depot composed of polyethylene glycol hydrogel and drugcontaining micro particles Once drug placed in tear drainage system, the hydrogel expands to conform to surrounding tissue The drug is then released into the tear film in a controlled fashion to lower IOP over an extended period To date, studies show a 3 month effect Reduces need of patient to take a medication Compares to punctal plug delivery systems and injectable depots currently in development Sustained release prostaglandin analogs for the treatment of glaucoma and ocular hypertension. Inserted non-invasively through the punctum The plug resides within the canaliculus, delivering travoprost to the ocular surface for up to 90 days Reduce or eliminate the need for daily dosing Travoprost encapsulated in microparticles which are suspended in a dried polyethlene glycol resorbable hydrogel rod Hydrolysis of the microparticles mediates sustained release The product also contains a visualization aid (fluorescein) to monitor retention over the treatment period. After therapy is complete, the hydrogel resorbs and exits the nasolacrimal system, so there is no need for removal. New Glaucoma Medications Ono Pharmaceuticals ONO mg and 30 mg/ml dose groups Developing novel FP/EP-3 prostaglandin Dual receptor agonist to lower IOP Phase I safety and tolerability studies complete Phase I showed 35% IOP reduction with up to 33 hour IOP drop 3-5 years away Ocular Therapy Update Prostaglandin analogues (PGAs) reduce IOP by targeting the prostaglandin F (FP) receptor to increase outflow of aqueous humor, primarily through the uveo-scleral pathway In the U.S., latanoprost, bimatoprost and travaprost are the most commonly prescribed PGAs used to target the FP receptor New Class of Prostaglandins New classes of PGA molecules with enhanced tolerability and additional therapeutic benefits are being evaluated One area is prostaglandin E (EP) receptor agonists The EP3 receptor is found in the trabecular meshwork and ciliary muscle demonstrated to augment IOP reduction in monkeys Ocular Therapy Update Prodrug ONO-9054 is an isopropyl ester derivative of the biologically active free acid ONO-AG-367 A highly selective and potent agonist of both prostaglandin EP3 and FP receptors in vitro Due to its dual receptor activity, the drug has potential to produce a more potent reduction of IOP than drugs that target the FP receptor 7

8 Neuroprotection Drug Delivery Systems for Glaucoma Refers to mechanisms that protect neurons from apoptosis arising from insult or progressive neurodegenerative diseases Parkinson, Alzheimers Only a few medications are FDA approved for neuroprotection Some glaucoma patients progress despite reduced IOP Pressure independent factors Neuroprotection offers hope of protecting vision via a different means than reducing IOP Currently according to clinical trials.gov, there are 9 clinical trials for neuroprotection in glaucoma Allergan s Memantine study which was completed several years ago Amorphex Therapeutics A polymer, similar to a contact lens, that contains the drug and sits under the upper eyelid Releases the drug over several months Envisa Therapeutics Implantable extended-release device psivida and SKS Ocular Delivery devices Kala Pharmaceuticals Drops that can get into the eye more easily Ocular Therapeutix Tear duct plugs containing medication Mati Therapeutics Inc. Punctal plug device Graybug Sustained release Objectives for Drug Delivery Ensure drug delivered to the site of action in the eye Reduce side effects of topical medications Improve compliance Improve clinical outcomes Ocular Delivery Devices Ocular Surface Contact lens, punctal plug Sclera Anterior chamber Intravitreal Subconjunctival/subchoroidal Drug-Loaded Contact Lenses Approximately 35 million individuals in US wear contact lenses If a person requires glaucoma therapy and wear CLs, request individual to discontinue CL wear, at least while administering drug This may impact on adherence of medication If CL is to contain medication, this combination must be as safe and effective as CL and drug is used singly Cannot impact upon refractive properties of lens Concern for preservatives concentrating in CL or concentrating in tear layer between CL and cornea Drug-Loaded Contact Lenses Drug Loading Strategies Use colloidal nanoparticles or molecular imprinting Sub-micron size particles either coated with or encapsulating drug Liposomes Colloidal gold or silver Once CL is placed on eye, drug diffuses into tear layer Packing of drug in colloidal allows for more sustained delivery Drug imprinting Modifies contact lens material to allow drug molecule to sit within hydrogel complex Allows higher drug load than simple diffusion 8

9 Drug-Loaded Contact Lenses Drug Loading Strategies Soak CL in lens storage solution with drug Hydrophilic matrix of soft CL absorbs drug and then releases it by simple diffusion Limited by drug kinetics which leads to rapid diffusion Diffusion varies drug to drug, often in under one hour Medication with preservatives may cloud CL or effect oxygen permability Issues with both forms Want linear release which is difficult to achieve Mati Therapeutics Silicone Punctal Plug Device Used with Latanoprost w 5-6 mm Hg reduction Concern with plugs is retention, patient comfort and ease of insertion 92% retention rate over 90 days Easily removable if need be Long term efficacy also a concern Lifestyle Choices and Glaucoma Exercise Aerobic exercise reduces IOP approx 15-20% effect lists for weeks Body mass index (BMI) Not clear but probably positive Cigarette smoking Linked with cataracts, macula degeneration with mild association with glaucoma and elevated IOP Yoga Body inversion may elevate IOP High resistance instruments IOP rose briefly in relation to force of blowing and total life hours of playing Wearing neckties Associated with elevated IOP Lifestyle Choices and Glaucoma Dietary choices Omega fats No evidence of positive effect Alcohol consumption Drinking modest amounts may lower IOP Caffeine consumption Mild amount fine Association with caffeinated coffee and open angle glaucoma from Blue Mtns Study Positive association with heavier coffee consumption and development of exfoliation Magnesium May be associated with glaucoma development in high doses Ginkgo Biloba Some studies report positive effect such as neuroprotection, blood flow Lifestyle Choices and Glaucoma Other factors Antihypertensive drugs at bedtime May be a problem in causing blood pressure to dip Individual should talk with their doctor Sleep apnea Moderate to severe sleep apnea may be linked with glaucoma development Migraines Associated with low tension glaucoma Marijuana Lowers IOP for short duration Lifestyle Choices and Glaucoma Also ask if they play a wind instrument wear a necktie take antihypertensive medications have symptoms of sleep apnea have migraines Giving your patients some lifestyle choices may empower them and feel better about the condition 9

10 Lifestyle Choices and Glaucoma Summary Do some aerobic exercise Limit cigarette smoking Try to eat diet high in antioxidants and low in fat Lose weight Avoid excessive caffeine Avoid head-down positions, such as in yoga 10