5/25/2018 1 Advances in Ocular Drug Delivery COPE#54896-PH Walter O. Whitley, OD, MBA, FAAO Director of Optometric Services Virginia Eye Consultants Residency Program Supervisor PCO at Salus University Virginia Eye Consultants Tertiary Referral Eye Care Since 1963 • John D. Sheppard, MD, MMSc • Stephen V. Scoper, MD • David Salib, MD • Elizabeth Yeu, MD • Thomas J. Joly, MD, PhD • Dayna M. Lago, MD • Constance Okeke, MD, MSCE • Jay Starling, MD • Samantha Dewundara, MD • Rohit Adyanthaya, MD • Albert Cheung, MD • Walter O. Whitley, OD, MBA, FAAO • Cecelia Koetting, OD, FAAO • Christopher Kruthoff, OD, FAAO • Jessica Schiffbauer, OD • Mark Enochs, OD • Kelsey Butler, OD Disclosures - Walter O. Whitley, OD, MBA, FAAO has received consulting fees, honorarium or research funding from: • Alcon • Allergan • Bausch and Lomb • Biotissue • Beaver-Visitec • Carl Zeiss Meditec • Glaukos • Advanced Ocular Care…..Collaborative Eye – Co-Chief Medical Editor • Review of Optometry – Contributing Editor • Optometry Times – Editorial Advisory Board • J&J Vision • Ocusoft • Science Based Health • Shire • Sun Pharmaceuticals • TearLab Corporation • Tearscience Compliance: Areas of Concern http://www.allaboutvision.com/contacts/contact_lenses.htm Current Drug Delivery https://www.openpr.com/images/articles/Q/5/Q53063449_g.jpg http://www.naturalherbalmedizine.com/diabetes-type-1-oral-medication/ http://www.allaboutvision.com/buysmart/eye-drops.htm http://www.retina-specialist.com/article/an-update-on-the-intravitreal-injection-procedure
Transcript
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Advances in Ocular Drug Delivery
COPE#54896-PH
Walter O. Whitley, OD, MBA, FAAO Director of Optometric Services
Virginia Eye Consultants Residency Program Supervisor
PCO at Salus University
Virginia Eye Consultants Tertiary Referral Eye Care Since 1963
• John D. Sheppard, MD, MMSc
• Stephen V. Scoper, MD
• David Salib, MD
• Elizabeth Yeu, MD
• Thomas J. Joly, MD, PhD
• Dayna M. Lago, MD
• Constance Okeke, MD, MSCE
• Jay Starling, MD
• Samantha Dewundara, MD
• Rohit Adyanthaya, MD
• Albert Cheung, MD
• Walter O. Whitley, OD, MBA, FAAO
• Cecelia Koetting, OD, FAAO
• Christopher Kruthoff, OD, FAAO
• Jessica Schiffbauer, OD
• Mark Enochs, OD
• Kelsey Butler, OD
Disclosures - Walter O. Whitley, OD, MBA, FAAO has received consulting fees, honorarium or research funding from:
• Alcon
• Allergan
• Bausch and Lomb
• Biotissue
• Beaver-Visitec
• Carl Zeiss Meditec
• Glaukos
• Advanced Ocular Care…..Collaborative Eye – Co-Chief Medical Editor
• Literature review of 76 studies show • Compliance increases
with decreased dosage regimen and complexity1
• 79% compliance with QD regimen vs 51% for QID regimens (p=0.001)1
• Simpler, less-frequent dosing results in better compliance in a variety of therapeutic classes1
Co
mp
lian
ce
Dosing (Times/day)
1. Claxton et al. Clinical Therapeutics. 2001; 23:1296-1310.
Barriers to Compliance
Topical Drug Delivery Considerations
1. Ghate D, Edelhauser HF. Ocular drug delivery. Expert Opin Drug Deliv. 2006;3(2):275-287. 2. Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010;12(3):348-360. 3. Coffey MJ, Decory HH, Lane SS. Development of a non-settling gel of 0.5% loteprednol etabonate for anti-inflammatory use as an ophthalmic drop. Manuscript in preparation. 4. McGhee CN. An overview of topical ophthalmic drugs and the therapeutics of ocular infection. http://www.fmhs.auckland.ac.nz/som/ophthalmology/teaching/_docs/optometry-355-05-pharmacokinetics.pdf. Accessed October 25, 2012. 5. Kaur IP, Kanwar M. Ocular preparations: the formulation approach. Drug Dev Ind Pharm. 2002;28(5):473-493.
Strategies to Improve Topical Ocular Drug Delivery
1. Ghate D, Edelhauser HF. Expert Opin Drug Deliv. 2006;3(2):275-287. 2. Shirasaki Y. J Pharm Sci. 2008;97(7):2462-2496 3. Kaur IP, Kanwar M. Drug Dev Ind Pharm. 2002;28(5):473-493. 4. Barar J, et al. Expert Opin Drug Deliv. 2008;5(5):567-581
Key Approaches to Improve Ocular Bioavailability • Prodrug strategies
• Excipients • Cyclodextrins
• Penetration enhancers
• Dosage forms • Polymeric gels
• Bioadhesive hydrogels
• Temperature induced gelation
• pH induced gelation
• Osmotically induced gelation
• Combination of polymers
• Microneedling
• Colloidal systems • Liposomes
• Niosomes
• Cubosomes
• Microemulsions
• Nanoemulsions
• Nanoparticles
Achouri D., Alhanout, K., Piccerelle, P. Recent advances in ocular drug delivery. Drug Development and Industrial Pharmacy, 2012.
1. Data on file. Inspire Pharmaceuticals Inc, Study report I 04U0207 2. Data on file. Inspire Pharmaceuticals Inc, NDA Study Report 01-401-003 3. Data on file. Inspire Pharmaceuticals Inc, NDA Study Report 01-401-004
Use of DuraSite® Results in Increased Aqueous Humor Concentrations
US National Institutes of Health. Aqueous humor concentration of InSite Vision (ISV) 303 (bromfenac in DuraSite) to Bromday once daily (QD) prior to cataract surgery. https://clinicaltrials.gov.
49.33
23.64
0
10
20
30
40
50
60
70
80
90
100
BromSite™ Bromfenac OphthalmicSolution 0.09%
Me
an P
eak
Aq
ue
ou
s H
um
or
Co
nce
ntr
atio
n (n
g/m
L)
(Bromday®)
(N=29)
(N=29)
Δ2.1X
P=0.0040
Mucoadhesive Adaptive Viscosity: Polycarbophil Gel Matrix
Gel at Rest; Viscous Liquid in the Eye
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CMHA-S Crosslinked Hyaluronic Acid • HA occurs naturally in the human body with qualities ideal for the
ocular surface • Promotion of wound healing and lubrication
• Native HA has a relatively short half-life
• Crosslinking HA creates a 3D structure that stabilized the molecule • Adheres longer to the ocular surface (up to 90 min)
• Higher viscosity that thins with blinking and is non blurring
• Matrix protects the ocular surface
CMHA-s: Animal studies
Commercially available as a veterinary device;
Manufactured by SentrX Animal Care
Sold in the U.S. by Bayer Animal Health as Remend® Corneal Repair1
Sold world wide with 5 years experience in thousands of dogs, cats and horses, with an excellent safety profile
Efficacy has been demonstrated in masked, randomized clinical studies of corneal defects in dogs and cats
1. EyeGate (NASDAQ: EYEG) has human ophthalmic rights only. Visit http://www.bayerdvm.com/show.aspx/remend-cross-linking-video
M O L L Y A 1 2 Y E A R O L D
C A T W I T H A N O N -
H E A L I N G C O R N E A L
D E F E C T A T 4 2 D A Y S
( A )
H E A L I N G U L C E R A F T E R 1 2
D A Y S W I T H 0 . 7 5 % C M H A - S
G E L D R O P S
C M H A - s : O c u l a r b a n d a g e G e l
A clear hydrogel (or liquid-gel) eye drop with a 0.75% concentration of CMHA-S
Crosslinked to provide reduced degradation on the eye
Exhibits significant shear thinning properties
Enables better residence time with no optical blur
Forms a thin layer over the ocular surface, protecting the eye
May accelerate re-epithelialization of corneal epithelial defects
PRK, superficial keratectomy, PKP
Corneal abrasions and ulcers
Neurotrophic keratitis
Severe SPK
Iontophoresis Platform: A Non-Invasive Method of Propelling Charged Active Compounds Into Ocular Tissues
Conclusions
• EGP-437 is safe and effective in reducing inflammation and preventing pain as early as Day 1 with 2 different iontophoretic doses.
• Best responses observed with 4.5 mA-min and 14.0 mA-min doses
• Percentage of patients with ACC count of zero greater than Durezol historical data at Day 7 and Day 28
• Percentage of patients with zero pain better than Durezol historical data at Day 4, 7, and 14
• Phase 2b trial initiation targeted for 1H 2017 EGP-437 effectively controls post operative pain and inflammation without the need for drop therapy
VersiDoser / VRx2
• Disposable/reloadable multi-dose ophthalmic delivery systems • VersiDoser – Liquid
An injection of an antibiotic & steroid combination in the eye at the time of surgery.
Preparation:
1. triamcinolone or dexamethasone
2. moxifloxacin One intravitreal injection
Pars plana injection into the vitreous cavity.
Medicine is injected after the IOL placement.
Patients are still under anesthesia so it is mostly painless
What Will the Doctor See???
View of the injected medication 2 hours after injection
Benefits…
Compliance Convenience Cost
https://en.wikipedia.org/wiki/Endophthalmitis
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Safety?
A-no antibiotic 0.23%
B-intracameralcefuroxime
0.05%
C-topical levofloxacin 0.17%
D-intracameral & topical 0.03%
0.00%
0.05%
0.10%
0.15%
0.20%
0.25%
Rat
es o
f En
do
ph
thal
mit
is
5-fold decrease in endophthalmitis with intracameral cefuroxime
Braga-Mele, R., Chang, D., Henderson, B., Mamalis, N., Talley-Rostov, A., & Vasavada, A. (2014, December). Intracameral antibiotics: Safety, efficacy, and preparation. Journal of Cataract & Refractive Surgery, 40, 2134-2141.
Kaiser Study
0
0.5
1
1.5
2
2.5
3
3.5
2007 2008 2009 2010 2011
Endophthalmitis cases per1000
Percent of patients receivinginjections of post-op meds
22 (2100%) fold
decrease in
endophthalmitis
from 2007-2011.
Topical Only
Some injections Topical and Injection
Shorstein, N., Winthrop, K., & Herrinton, L. (2013, January). Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a Northern California eye department. Journal of Cataract & Refractive Surgery, 39, 8-14.
Concerns with Injections
1. Cystoid Macular Edema 1. This study measured
macular thickness in both arms at both 1 week and 1 month post-op
2. No statistically significant difference in macular thickness
Fisher, B. L., & Potvin, R. (2016). Transzonular Vitreous Injection vs. a Single Drop Compounded
Topical Pharmaceutical Regimen After Cataract Surgery. Clinical Ophthalmology, 10, 1297-1303.
Concerns with Injections
• Cystoid Macular Edema
• Steroid response/ IOP spikes • Compared at Baseline, 1 day PO, 1
week PO, and 1 month PO
• No statistically significant difference in IOP, no significant drift over time.
Fisher, B. L., & Potvin, R. (2016). Transzonular Vitreous Injection vs. a Single Drop Compounded
Topical Pharmaceutical Regimen After Cataract Surgery. Clinical Ophthalmology, 10, 1297-1303.
Concerns with Injections
1. Cystoid Macular Edema
2. Steroid response/ IOP spikes
3. HORV
Fisher, B. L., & Potvin, R. (2016). Transzonular Vitreous Injection vs. a Single Drop Compounded
Topical Pharmaceutical Regimen After Cataract Surgery. Clinical Ophthalmology, 10, 1297-1303.
Concerns with Injections
1. Overall experience
Fisher, B. L., & Potvin, R. (2016). Transzonular Vitreous Injection vs. a Single Drop Compounded
Topical Pharmaceutical Regimen After Cataract Surgery. Clinical Ophthalmology, 10, 1297-1303.
92% 88%
0%
20%
40%
60%
80%
100%
TM vs. Drops
Patient Experience Drops vs. TM
Overall Experience Vision Post-Op.
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Dextenza – Dexamethasone 0.4mg Insert
• Currently under FDA Review for post-surgical ocular inflammation and pain • Intracanalicular Plug • Drug released over 30 days
• DEXTENZA successfully met the trial’s two primary efficacy endpoints, absence of ocular pain on day 8 and absence of ocular inflammation on day 14 when compared to placebo
• A topical twice-a-day product candidate for the treatment of inflammation and pain in patients who have undergone ocular surgery.
• Utilizes Mucus Penetrating Particles (MMP) which binds to mucin in the eye and slowly release loteprednol etabonate
KPI-121 Cataract Prevention Drug?
Gemini Refractive Capsule Omega Ophthalmics • Drug delivery
• Biometric sensors
• Lens technology
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TRUETEAR™: PRODUCT INNOVATION
• First-ever neurostimulation device in eye care
•An easy-to-use and drug-free option to temporarily increase tear production during neurostimulation in adult patients
• Provides small electrical pulses to stimulate production of your own natural tears
• First “smart” device in eye care with Bluetooth® enabled and connected application
LFU REGULATES TEAR PRODUCTION1-4
• Lacrimal Functional Unit (LFU) maintains a healthy environment for the eye by regulating tear production
• In response to any external and internal stimuli, LFU communicates with Central Nervous System (CNS)
• Sensory signals are carried via afferent neurons from LFU to CNS
• Parasympathetic and sympathetic signals are carried via efferent neurons from CNS to LFU
• This afferent and efferent signaling and communication occurs via the trigeminal nerve
• Neurostimulation in the nasal cavity targets the trigeminal nerve to trigger the nasolacrimal reflex to emulate the normal neural signals to create a natural tear
BY COMMUNICATING WITH CENTRAL NERVOUS SYSTEM (CNS)
1. Kossler et al. Ophthal Plast Reconstr Surg. 2015; 2. Beuerman et al. In: Pflugfelder et al, eds. Dry Eye and Ocular Surface Disorders. 2004; 3. Dartt. Ocul Surf. 2004. 4. Freidman et al. A nonrandomized, open-label study to evaluatethe effects of nasal stimulation on tear production in subjects with dry eye disease. 2016
CLINICAL DATA • In Study 1, patients saw an approximate 2.5x greater increase in tear production with intranasal
stimulation on study day compared to sham or external stimulation1
1. Data on file, Allergan; OCUN-009
Results of a randomized, controlled, double-masked, cross-over clinical trial conducted at two sites in patients with Aqueous Deficient Dry Eye (≥22 yo; baseline OSDI score ≥ 13 with no more than three responses of N/A; At least one eye: baseline Jones Schirmer test with anesthetic of ≤ 10 mm/5 min and cotton swab nasal stimulation Jones Schirmer test ≥ 7 mm higher in the same eye). Participants underwent 3 applications in random order: active intranasal, active extranasal (control), and sham device intranasal (control). Primary endpoint was the difference between the Schirmer test score during active stimulation and the 2 control applications in the study eye. The direct clinical benefit of temporarily increasing tear production as a therapy for Dry Eye Disease patients was not assessed as part of the clinical trial.1
• In Study 2, clinically and statistically significant increase in tear production was seen at 180 days1
Results of a 6-month single-arm, open-label clinical trial conducted at three sites in patients with Aqueous Deficient Dry Eye (≥ 22 yo; baseline OSDI score ≥ 23 with no more than three responses of N/A; At least one eye: baseline Jones Schirmer test with anesthetic of ≤ 10 mm/5 min and cotton swab nasal stimulation Jones Schirmer test ≥ 7 mm higher in the same eye; corneal fluorescein staining score of ≥ 2 in at least one corneal region and sum of ≥ 4 for all corneal regions in the same eye; no contact lens wear for 7 days prior to screening and during the study). Participants used the TrueTear™ device at least 2 times/day, and no more than 3 minutes/use. The primary endpoint was tear production increase in the study eye during the TrueTear™ device use compared to unstimulated tear production as assessed by the Schirmer test at day 180. The analysis used a one-sided paired t-test. The direct clinical benefit of temporarily increasing tear production as a therapy for Dry Eye Disease patients was not assessed as part of the clinical trial.1
1. Data on file, Allergan; OCUN-010
CLINICAL DATA (CONTINUED)
OTX-101 – Sun Pharmaceuticals
• A nanomicellar formulation of cyclosporine 0.09%
• In this 12 week, multicenter, randomized, double-masked, vehicle controlled Phase 3 confirmatory study, 744 dry eye patients were treated either with OTX-101 or its vehicle. • Met primary endpoint of Schrimer’s Score (p<0.0001)
• The demonstration of efficacy at 12 weeks is earlier than other drugs approved for dry eye in the same class.
NovaTears / EvoTears
• Innovative mode of action due to the patented EyeSol®-Technology – Made in Germany
• Forms a protective layer over the tear film
• Long-lasting effect for greater patient satisfaction – clinically proven¹
• Extremely well tolerated as free from preservatives, phosphates and emulsifiers
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Neuropathic Dry Eye Pain
• Role of cannabis
• EyeSol, Novaliq – a novel semi-fluorinated alkane drug delivery technology • Low surface tension
• No water
• Metabolically inert
• Refractive index similar to H20
Steven, P. Realm of dry eye therapy expanding. Ophthalmology Times. November 15, 2017
What About Glaucoma???
Nordstrom, Friedman, et al. Ophthalmology 2005
How Adherent are Glaucoma Patients with QD Medication?
Glaucoma Considerations
• When COMPLIANCE with drops is low
• When MEDICAL THERAPY FAILS
• When the PROGRESSION continues to WORSEN
• Treatment options • More medications
• Laser therapy
• Surgical intervention
Ocular Science Glaucoma Drops
$25.00/ 1 month
supply $30.00/ 1 month
Supply
$35.00/ 1 month
supply
• 180 day shelf life
• 0.02% BAK preservative
• Ships directly to patient
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Glaucoma Drops On the Horizon New Drug Company Type
57 Centers for Medicare and Medicaid Services. 2002 – 2007. Medicare Standard Analytical File. Baltimore, MD. 2007 .
Significant Treatment Opportunity
One in five Cataracts Eyes on OHT
Medication
Pathway for Trabecular Bypass Devices
• Shunting the canal • Express MiniShunt (Alcon)
• Stenting the canal • iStent (Glaukos Corp)
• Reduce aqueous production • Endocyclophotocoagulation
• Dilating the canal • Visco 360 / Ab-Interno
Canaloplasty (ABIC)
• Divert aqueous into the suprachoroidal space • Cypass Microshunt (Alcon)
• Divert aqueous into the subconjunctival space • Xen Gen Stent (Allergan)
MIGS ADVANTAGES
Safer
Faster recovery Gentler
Combined with cataract sx
Less glaucoma meds Reduction of IOP
Less OR time
Avoids serious complications
Spares the conjunctiva
Decreased IOP fluctuations
No Bleb
Good for contact lens wearers
Fewer follow-up appointments
Are Patients Interested in MIGS?
• 28pts
• 79% did not mind instilling drops
• 64% did not mind wearing glasses
• 86% were interested in reducing their need for topical medications
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Istent Video Courtesy of Constance Okeke, MD, MSCE
0
20
40
60
80
100
Cataract Surgery iStent
Percent of Patients With IOP ≤21 mm Hg Without Medication Use
iStent + Phaco Ferguson, Berdahl, Schweitzer et. Al
Ferguson TJ, Berdahl JP, Schweitzer JA, Sudhagoni RG. Clinical evaluation of trabecular microbypass stents with phacoemulsification in patients with open-angle glaucoma
and cataract. Clinical Ophthalmology 2016:10 1767-1773
iStent + Phaco Ferguson, Berdahl, Schweitzer et. Al. Retrospective Case Series IOP reduction higher with higher baseline IOP
Ferguson TJ, Berdahl JP, Schweitzer JA, Sudhagoni RG. Clinical evaluation of trabecular microbypass stents with phacoemulsification in patients with open-angle glaucoma
and cataract. Clinical Ophthalmology 2016:10 1767-1773
The XEN® Gel Stent
• A glaucoma implant designed to reduce intraocular pressure in eyes suffering from refractory glaucoma1
• 6-mm length, 45-micron inner diameter—about the length of an eyelash1,2
• Composed of gelatin, cross-linked with glutaraldehyde1
1. XEN® Directions for Use; 2. Vogt et al. In: Blume-Peytavi et al, eds. Hair Growth and Disorders. 2008.
The XEN® Procedure
1. XEN® Directions for Use.
In the clinical investigation, standard ophthalmic surgery techniques,
viscoelastic, and mitomycin C (0.2 mg/mL) were used before injection.1
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Established Effectiveness at 12 Months
1. XEN® Directions for Use.
76.3% (95% CI = 65.8%, 86.8%);
using observed data and failures
for subjects with glaucoma-
related secondary surgical
intervention and multiple
imputations for missing data (N
= 65).1
-6.4 ± 1.1 (95% CI = -8.7, -4.2); using
observed data and worst within-eye
IOP for subjects with glaucoma-
related secondary surgical
intervention and multiple imputations
for missing data (N = 65).1
Cypass Microstent
• Ab-interno insertion into the supraciliary space
• Fenestrated microstent made of biocompatible polyimide material
• Magnetic resonance safe
CyPass® Micro-Stent: Enhanced Aqueous Outflow
The supraciliary space has a negative pressure gradient that drives aqueous outflow and reduction of intraocular pressure1
The uveoscleral pathway bypasses Schlemm’s canal and collector channels, which may be atrophic in glaucoma patients2
The CyPass® Micro-Stent utilizes the same outflow pathway as first line prostaglandin analogues3
1. Saheb H, Ianchulev T, Ahmed I. Optical coherence tomography of the suprachoroid after CyPass Micro-Stent implantation for the treatment of open-angle glaucoma. Br J Ophthalmol. 2012;98:19–23.
2. Fellman. Episcleral venous fluid wave correlates with the type and extent of canal-based surgery. AGS 2014 abstract. 3. Weinreb RN, Toris CB, Gabelt BT, et al. Effects of prostaglandins on the aqueous humor outflow pathways. Surv Ophthalmol. 2002;47(Suppl 1):S53–S64.
Clinical Data ̶̶̶̶̶̶̶̶̶ Delivers superior, long-term IOP-lowering efficacy Two-year COMPASS Trial is the largest MIGS randomized controlled trial
completed to date Landmark FDA study with two-year follow-up on >500 patients with baseline/terminal washout
• 72.5% of eyes
achieved a
≥20%
reduction in
unmedicated
diurnal IOP
at 2 years*
• 61.2% of eyes
maintained an
unmedicated
diurnal IOP
range between
6 and 18 mmHg
at 24 months
(a 41% increase)*
*Prospective, randomized, multicenter clinical trial in patients (n=505) with open-angle glaucoma undergoing cataract surgery randomized to microstent (n=374) or phacoemulsification (n=131).
Primary outcome measure was unmedicated diurnal IOP reduction at 24 months versus cataract surgery alone at baseline. Secondary outcomes measures included mean change in 24 month
DIOP from baseline and 24 month unmedicated mean IOP (between 6 mmHg to 18 mmHg) versus cataract surgery alone. Medication use at 24 months was also analyzed. The primary and
secondary effectiveness analyses were performed using intent to treat (ITT) population.
And There’s More
• Canaloplasty
• Glaukos Istent Supra
• Glaukos Istent Inject
• Allergan Bimatoprost SR
• Ocular Therapeutix SR Travaprost
Solx Gold Shunt
Kahook Dual Blade
Ocular Therapeutix
• Sustained-release travoprost in an intracanalicular depot composed of polyethylene glycol hydrogel and drug-containing microparticles • Drug elutes over 90 day period
• Rapid release kinetics • May differ based on CL material / drug combos
• Rate of drug release is not constant over time
24.Li CC, Chauhan A (2006) Modeling ophthalmic drug delivery by soaked contact lenses. Ind Eng Chem Res 45: 3718-3734.
CL Drug Delivery – What does the future hold? • Molecular imprinting - Creates specific drug recognition sites within the
polymer through the use of molecular templates
• Vitamin E coatings - Form diffusion barriers within the lens, which forces the target drug to take long complex paths to diffuse from the lens
• Nanoparticles - Encapsulated with the target drug can be loaded and released from the CL, and the extended release is controlled by the degradation of the nanoparticles
