Glaucoma Update.Fall 2019 Update.pdf · Rocklatan(Aerie Pharmaceuticals) • Netarsudil+...
Transcript of Glaucoma Update.Fall 2019 Update.pdf · Rocklatan(Aerie Pharmaceuticals) • Netarsudil+...
Glaucoma Update: What’s New in Glaucoma
Richard J. Madonna, MA, OD, FAAOSUNY College of [email protected]
Disclosures
• Aerie Pharmaceuticals• Allergan, Inc.• Bausch and Lomb• Carl Zeiss Meditec• Heidelberg Engineering• Novartis
Outline
• IOP‐lowering– Medical– Drug Delivery– MIGS
• IOP Measurement– iCare Home– Triggerfish
• Recent Studies– EAGLE– ZAP– LiGHT
• OCTA
1. New Medications
• Elevated IOP is primarily caused by increased aqueous outflow resistance at the trabecular meshwork
JuxtacanalicularTissue
The Problem – Commonly Prescribed Glaucoma Drops Have Not Targeted the Trabecular Outflow Pathway
IOP‐Lowering Drugs: Sites of Action
2016. Used with permission of Elsevier. All rights reserved.
Aqueous suppression
Beta blockersCarbonic anhydrase inhibitorsAlpha-receptor Adrenergic agonists
Netarsudil
Open angle by mechanical tension
Miotics
Decrease trabecular outflow resistanceLBN (NO)Netarsudil
Increase uveoscleral outflow
Prostaglandins
Alpha-receptor adrenergic agonists
LBN (PGA)
Lower Episcleral Venous Pressure
Netarsudil
1.
3.
2.
4.
Nitric Oxide (NO)
Mededicus CE Monograph, 2017
Nitric Oxide in the Eye
• NO increases trabecular outflow by inhibiting actin‐myosin interaction, which relaxes TM
• NO causes vasodilation and increased blood flow to the optic nerve
• Evidence exists of dysregulation of the NO pathway in glaucoma
Vyzulta (Bausch and Lomb)
• Latanoprostene bunod (LBN) 0.024%
• Nitric oxide donating prostaglandin F2 alpha analog– Latanoprostene is metabolized in situ to latanoprost acid– Bunod modification (butanediol mononitrate) is a nitric oxide donator
• NOT a new class of medication nor a fixed combination –PGA with DUAL MECHANISM OF ACTION
• Additive effect to lower IOP by:– Increasing uveoscleral outflow – latanoprost– Increasing trabecular outflow – NO
• Also? ‐ Speculative– NO dilates blood vessels – increase blood flow to ONH?– Neuroprotection?
Mean IOP Reduction of 7.5 to 9.1 mmHg from Baseline1
‐7.5
‐9.1
1. VYZULTA Prescribing Information. Bausch & Lomb, Inc. 2017 2.Weinreb RN, Sforzolini BS, Vittitow J, Liebmann J. Ophthalmology. 2016;123(5):965‐973. 3. Medeiros FA, Martin KR, Peace J, Sforzolini BS, Vittitow JL, Weinreb RN.. Am J Ophthalmol. 2016;168:250‐259. 4. Data on File. Bausch & Lomb Incorporated.
VYZULTA Demonstrated Superior IOP Reduction vs Timolol 0.5% at 3 Months1
MEAN IOP REDUCTION AT MONTH 31
1. Data on File. Bausch & Lomb Incorporated.
*Pooled data from all tested time points in the APOLLO and LUNAR studies.
Adverse Reactions (AR) in APOLLO and LUNAR1
APOLLO1 LUNAR2
Adverse Reactions (%)
VYZULTA TIMOLOL 0.5 % VYZULTA TIMOLOL 0.5 %
Eye Irritation 3.9 2.2 7.2 4.4
Conjunctival Hyperemia 2.8 1.5 9.0 0.7
Eye Pain 1.4 2.2 5.8 3.7
Instillation Site Pain 1.1 1.5 1.4 –
MOST COMMON OCULAR ADVERSE REACTIONS IN THE APOLLO AND LUNAR STUDIES
• Approximately 0.6% of patients discontinued therapy due to ocular adverse reactions1,2
– These included ocular hyperemia, conjunctival irritation, eye irritation, eye pain, conjunctival edema, vision blurred, punctate keratitis, and foreign body sensation
Low rate of discontinuation due to ocular AR 1,2
1. Weinreb RN, Sforzolini BS, Vittitow J, Liebmann J Ophthalmology. 2016;123(5):965‐973. 2. Medeiros FA, Martin KR, Peace J, Sforzolini BS, Vittitow JL, Weinreb RN. Am J Ophthalmol. 2016;168:250‐259.
1. Weinreb RN, et al. Br J Ophthalmol. 2015;99:738‐45.
Reduction in mean diurnal IOP on Days 7, 14, and 28
VYZULTA (LBN 0.024%) Demonstrated Statistically Significant Greater Mean IOP Reductions as Compared to Latanoprost 0.005%1
VYZULTA (LBN 0.024%) lowered mean diurnal IOP by 1.23 mmHg more than latanoprost 0.005% at day 281
Study design: JUPITER study1
Primary Objective:> Evaluate the long-term safety and IOP-lowering efficacy of VYZULTA over one year in Japanese patients with OAG or OHT
Primary Endpoints:> Absolute IOP> CFB in IOP> Safety over a 1-year treatment period
Study Baselines: > IOP ranged from 15.0 mmHg to 30.0 mmHg> Most patients had baseline IOP ≤21.0 mmHg
A single-arm, multicenter, open-label, long-term study in Japanese patients with open-angle glaucoma (OAG) or ocular hypertension (OHT)
1. Kawase K, Vittitow JL, Weinreb RN, Araie M. Adv Ther. 2016;33(9):1612‐1627.
VYZULTA Treatment Resulted in a Reduced Mean IOP of 14.4 mmHg at 12 Months1
In the long-term JUPITER study, treatment with VYZULTA resulted in a reduced mean IOP of 14.4 mmHg at 12 months
1. Kawase K, Vittitow JL, Weinreb RN, Araie M. Adv Ther. 2016;33(9):1612‐1627.
Constellation Study – LBN and 24‐Hour IOP
Constellation Study – LBN and 24‐Hour IOP
Vyzulta – Summary • Package label: VYZULTA™ (latanoprostene bunod ophthalmic solution), 0.024%, is used to lower intraocular (eye)
pressure in patients with open‐angle glaucoma or ocular hypertension.
• QD dosing
• Efficacy– On average, 1.23 mm greater efficacy than latanoprost in high‐pressure patients (Voyager Study)– 32% IOP lowering in high‐pressure patients (Apollo and Lunar Studies)– Excellent IOP‐lowering in patients with lower starting pressures (Jupiter Study)
• Adverse Reactions– Similar side effect prolife as latanoprost– Same concentration of BAK as latanoprost (0.02%)
• Cost– Like other new medications, out‐of‐pocket is high– Increasing number of plans
Rhopressa (Aerie Pharmaceuticals)
• Netarsudil 0.02%– Inhibits Rho kinase– Also inhibits norepinephrine transporter (increases adrenergic activity)
• (May) Lower IOP by 3 mechanisms– Increase TM outflow (ROCK)– Decrease EVP (ROCK)– Decrease aqueous production (NET inhibition)
Rhopressa MOA
Rocket 4 Study
Rhopressa
Rhopressa• Package Label: RHOPRESSA® (netarsudil ophthalmic solution) 0.02% is a Rho kinase inhibitor
indicated for the reduction of elevated intraocular pressure in patients with open‐angle glaucoma or ocular hypertension
• Once per day in the evening dosing
• Adjunctive therapy typically
• Excellent systemic profile but concern about its local side effect profile
• Cost– Like other new medications, out‐of‐pocket is high– Increasing number of plans
Rocklatan (Aerie Pharmaceuticals)
• Netarsudil + latanoprost – first fixed combination with a PGA in the US– Netarsudil 0.024%
1. Increase TM ouflow2. (Decrease aqueous production)3. (Decrease EVP)
– Latanoprost 0.004%4. Increase uveoscleral outflow
Mercury 1 Trial
Mercury 1 Trial
Mercury 1 Trial
Rocklatan• Package Label: ROCKLATAN™ 0.02%/0.005% is a fixed dose combination of a Rho kinase inhibitor and
a prostaglandin F2α analogue indicated for the reduction of elevated intraocular pressure (IOP) in patients with open‐angle glaucoma or ocular hypertension
• Once per day in the evening dosing
• Most potent topical glaucoma medication we’ve seen
• Excellent systemic profile but concern about its local side effect profile
• Cost– Like other new medications, out‐of‐pocket is high– Increasing number of plans
• Latanoprost 0.005% ophth. emulsion
• BAK‐free (preservative is potassium sorbate)
• IOP‐lowering and adverse reactions similar to latanoprost
2. Drug Delivery
Bimatoprost SR (Allergan)
• Depot injection into AC
• Phase 2 – mean IOP reduction of 7.2 – 9.5 mm four months after injection vs. 8.4 mm in fellow eye using once daily bimatoprost
• No serious adverse effects
Bimatoprost SR (Allergan)
• Phase 3 comparison of SR vs. timolol 0.5% BID
• At 12 weeks, 30% IOP lowering
• A paradigm shift in treatment upcoming?
Other Drug Delivery Approaches
• Other types of injection into the AC
• Helios ring
• Punctal plugs
• Contact lenses
• Other devices
3. MIGS
MicroInvasiveGlaucomaSurgery (MIGS)
• Ab interno microincisional approach
• Minimal trauma to target tissue
• Effective
• Positive safety profile
• Rapid recovery
MIGS
• Increasing Trabecular Outflow– iStent Inject– Trabectome– Kahook Dual Blade– Hydrus Microstent– ABiC– GATT– Omni 360
• Increasing Uveoscleral Outflow– Cypass – removed from market– iStent Supra – not yet approved
• Reducing Aqueous Production– ECP
• Subconjunctival Filtration (Trabab interno)– Xen Gel Stent
MIGS – Which One?• How much IOP lowering?
• Which tissue do you want to target?
• When in the course of the disease?
• +/‐ Cataract surgery
• Surgeon preference
• Cost/Insurance coverage/FDA approval
4. IOP Measurement
IOP Fluctuation Matters
Research suggests that short‐term IOP fluctuation may be an independent risk factor for the incidence, prevalence and progression of glaucoma.
Boland MV, Quigley HA. J Glaucoma. 2007;16:406‐418. Asrani S, Zeimer R, Wilensky J, et al. J Glaucoma. 2000;9:134‐142.
Not only is an ideal mean target IOP needed, but also a target for IOP fluctuation. Asrani S, Zeimer R, Wilensky J, et al. J Glaucoma. 2000;9:134‐142.
Home Tonometer
Asrani S, Zeimer R, Wilensky J, et al. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma. 2000;9:134‐142.
Self‐Monitoring Makes a Difference
Asrani S, Zeimer R, Wilensky J, et al. Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma. 2000;9:134‐142.
1
5.76
01234567
Diurnal IOP Range 3.11 mm Hg Diurnal IOP Range 5.4 mm HG
Relative Risk of Disease
Progression
Icare Tonometer
What is it?• The Icare® HOME tonometer is a handheld, battery operated device that measures intraocular pressure (IOP) without the need for topical anesthetic.
• The device is intended as an adjunct for monitoring IOP of adult patients (self‐use). The HOME tonometer is designed for use at home or on the go.
Icare HOME tonometer• IOP, date, time, eye recognition
(right/left) and measurement quality are all stored in the internal memory.
• Data is transferred to a PC for further analysis by the prescribing physician.
• New features: positioning light, automatic eye recognition system, series or single measurements, new user interface panel.
Results of Icare Home Study
• 171 patients– 7 dropped out because of time concerns– 10 couldn’t be trained to use it– 27 couldn’t be certified based on IOP (5mm Hg difference between HOME and GAT)
• Of the other 127– 116 (91.3%) HOME and GAT agreed within 5mm Hg– Mean difference between HOME and GAT was ‐0.33mm Hg– R = 0.92
Questions???
• How many times per day and for how long should it be utilized?
• How can practitioners use it in their offices?
• As it cannot be used when the patient is supine, can it tell us anything about nighttime IOP?
What is Triggerfish?
Smart Contact Lens ‐ A soft, disposable silicone contact lens with an embedded micro‐sensor that captures circumferential changes near the corneoscleral junction
pressure
strain gauge
contact lens
tissue biomechanicsTriggerfish is measuring ocular volume change over a 24 hour period. Ocular volume change is associated with the eyes ability to handle increases in pressure as they are related to tissue elasticity
Data is wirelessly transmitted from the lens to the antenna, that is applied adhesively around the eye (2)
The data is transmitted through a wire to a recorder (3) that the patient wears (4)
The data is then downloaded to the practitioners computer for analysis
Patients maintain their regular routine and wear the lens for 24 hours, capturing the most sensitive night time activity
The lens is applied just like a contact lens (1)
Why is this important?
• The data has been shown that elements of the TF curve are highly correlated to glaucoma progression
• Initiation of therapy may be effectively monitored with TF application
• Data has shown that the curve that is produced may also be indicative of glaucoma even with normal IOP (NTG)
• Healthy eyes versus diseased eyes may also be determined (screening application)
• Records changes during critical times such as sleep
Questions???
• What information is it actually giving us?
• How do we use this information?
• What will be the cost?
5. Recent Studies
The Lancet, Oct 1, 2016
EAGLE Study
• Inclusion– PACG with IOP > 21– PAC with IOP > 30 (1/3 of the patients)
• Compared clear lens extraction vs. LPI
• CE performed better across all clinical (IOP) and patient‐reported outcomes (QOL, cost‐effectiveness ratio per quality‐adjusted life‐year gained) at 36 months
The Lancet, March 13, 2019
ZAP Study
• Compared prophylactic LPI versus no treatment in bilateral angle closure suspects to determine risk of primary angle closure
• Very low risk of AAC in eyes that don’t get LPI
• Most AAC after dilation
• Results indicate that widespread prophylactic LPI for PACS is not indicated
The Lancet, March 9, 2019
LiGHT Study• Performed in the UK (National Health Service)
• Compared SLT to medicine as first‐line treatment over 36 months– N = 718
• Outcomes– HRQoL the same between groups– 74.2% of patients in the SLT group required no drops to maintain target IOP– SLT more cost‐effective
• MAJOR RECOMMENDATION: SLT should be offered as a first‐line treatment for OAG and OHT, supporting a change in clinical practice
6. The macula in glaucoma
There is ample evidence that the macula is affected in early glaucoma
Hood, et al. IOVS, 2014
Hood, et al. Prog Ret Eye Res, 2013.
Questions
Should we be doing 10‐2 on all of our glaucoma suspects or glaucoma patients?
Should we be doing 10‐2 on our glaucoma suspects who have ganglion cell changes in the macula?
Can we modify current visual field protocols i.e. 24‐2 so that we can easily test the central 10?
Octopus “G” Program
24-2C Pattern - HFA
The 24-2C test pattern combines all 24-2 points + ten selected 10-2 points (shown in OD orientation)
Large Gray 24‐2 pattern
Large Orange Ten additional 24‐2C points
Small Gray 10‐2 pattern
SITA Faster – tests in 2 minutes or less without compromise to test results
Two minute test for near normal patients ~50% faster than SITA Standard; ~30% faster than SITA Fast
Clinically equivalent to SITA Fast and Standard
Same SITA algorithm and normative data as Standard and Fast
Removes unnecessary “dead time” during the test
No Blind Spot or False Negatives‐ Uses Gaze Monitoring and False Positives for test quality monitoring
Mixed SITA GPA Reports Allows mixing all SITA test strategies for GPA reports
Helps immediately adopt SITA Faster
Clinical equivalence of tests allows intermixing
24-2C SITA FasterFlagged points detected centrally in OD
24‐2 SITA Standard 24‐2C SITA Faster
7. OCT‐A in Glaucoma?
Chicken or Egg?
• Are vascular changes in glaucoma the cause of glaucoma damage or do they result from glaucoma damage?
My Patient
OCT‐A and Glaucoma
• As compared to normals, glaucoma suspects and patients have– Attenuated vascular density– Enlarged FAZ– Reduced blood flow index
• Reduction in vessel density in glaucomatous eyes is found in both superficial and deep vascular plexi
• Eyes with hemifield field defects have reduced vessel density in both hemifields – is this predictive of future damage?
THANK YOU!