FLUOCINOLONE ACETONIDE: STEROID LONG ACTING

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1 FLUOCINOLONE ACETONIDE: STEROID LONG ACTING Giuseppe Querques, MD PhD Department of Ophthalmology, IRCCS Ospedale San Raffaele, University Vita Salute San Raffaele, Milan, Italy

2 Financial Disclosure ADVISORY BOARD MEMBER: CONSULTANT: Allergan Bayer Novartis KHB Sandoz Zeiss Alimera sciences Allergan Bayer Bausch and Lomb Heidelberg Novartis Zeiss 2

Corticosteroids & DME Corticosteroids can play an important therapeutic role in the treatment of DME Corticosteroids suppress multiple pathways of inflammation Corticosteroids block leukocyte

3 Corticosteroids & DME Corticosteroids can play an important therapeutic role in the treatment of DME Corticosteroids suppress multiple pathways of inflammation Corticosteroids block leukocyte recruitment and activation Corticosteroids reduce capillary permeability by increasing the density and activity of tight junctions Corticosteroids down regulate the production of vascular endothelial growth factor (VEGF)

Long-lasting intravitreal fluocinolone Long-lasting

implant (190 µg fluocinolone acetonide (FAc) with a

diabetic macular edema (DME) It delivers sustained, daily,

2 micrograms) of the corticosteroid fluocinolone acetonide

4 Long-lasting intravitreal fluocinolone Long-lasting intravitreal fluocinolone (ILUVIEN ) is an intravitreal implant (190 µg fluocinolone acetonide (FAc) with a therapeutic effect for up to 36 months in the treatment of diabetic macular edema (DME) It delivers sustained, daily, submicrogram levels (0.2 micrograms) of the corticosteroid fluocinolone acetonide (FAc) The nonbioerodible implant is made of polyimide, the same material used in the haptics of many intraocular lenses (IOLs)

5 FAMOUS N= DME 12 patients 1 impialnt Campochiaro Ophthalmology 2013

6 FAME Study Fluocinolone Acetonide in patients with diabetic Macular Edema

Design of Phase 3 FAME Studies Additional laser therapy allowed after week 6 a Retreatment any time after month 12 (if eligible b ) Study ends Patients with DME and: 1 previous laser tx BCVA 19 and

7 Design of Phase 3 FAME Studies Additional laser therapy allowed after week 6 a Retreatment any time after month 12 (if eligible b ) Study ends Patients with DME and: 1 previous laser tx BCVA 19 and 68 letters TD-OCT center point 250 μm ILUVIEN 0.2 µg/d FAc (n = 376) 0.5 µg/d FAc (n = 395) Control: sham injection N = 956 (n = 185) Randomization Primary readout 2:2:1 Month: BCVA=best corrected visual acuity; DME=diabetic macular edema; TD-OCT,=time domain optical coherence tomography. a At masked investigator s discretion. b If BCVA loss 5 letters or retinal thickening 50 µm from best reading in previous 12 months. Campochiaro P, et al. Ophthalmology. 2011;118:

8 FAME data sustained efficacy Significant vision improvement through 36 months Rapid and sustained anatomic effects observed 74% of patients required only 1 implant

9 Chronic DME Subgroup Outcomes

10 Chronic DME Patients (DME 3 Years) Patients With 15-Letter Improvement in BCVA From Baseline, % P <.001 P =.003 P <.001 P <.001 P < % 28.8% P = % Months

11 Benefit Is Doubled In Chronic DME Full Population Chronic DME Patients 15-Letter Improvement in BCVA From Baseline, % Δ = 9.8% Δ = 20.6% Months Months Rate of cataract extraction: 80% IOP Lowering Medications: 38.4% Rate of incisional procedures to lower IOP: 4.8%

12 FAME: post-hoc analysis Effects on progression/regression of diabetic retinopathy Wykoff Ophthalmology 2017

13 Long-lasting intravitreal fluocinolone Safety

14 Low rate of endophthalmitis Study Eye Country Related to Drug Days After Drug Administration Yes India Yes 13 Yes India Yes 16 No India No Yes US No 193 (post-ivta) 840 (post-vitrectomy) Incidence Total cases in study eye per treated subject: 0.5% (n=4/768) Includes 2 cases not considered related to study drug Total related cases per injection: 0.2% (n=2/1028)

15 Cataract-related events Patients, % (Study Eye) Control (n = 121) 0.2 µg/d FAc (n = 235) Cataract considered an AE a Cataract extraction performed a a Phakic patients only.

Post-cataract surgery visual acuity outcomes BCVA Letter Score Baseline a Control (n = 32) 0.2 µg/d FAc (n = 184) Months Post Cataract Surgery Control (n = 21) 0.

16 Post-cataract surgery visual acuity outcomes BCVA Letter Score Baseline a Control (n = 32) 0.2 µg/d FAc (n = 184) Months Post Cataract Surgery Control (n = 21) 0.2 µg/d FAc (n = 136) BCVA=best-corrected visual acuity; FAc=fluocinolone acetonide. a Baseline represents the last visit prior to cataract surgery. Data on file. Alimera Sciences.

17 Baseline IOP status Control (n = 185) 0.2 µg/d FAc (n = 375) 0.5 µg/d FAc (n = 393) Baseline IOP (mm Hg), mean (SD) 15.0 (3.07) 15.2 (2.94) 15.2 (2.87) Median (mm Hg) IOP-related events over 36 months Control (n = 185) 0.2 µg/d FAc (n = 375) 0.5 µg/d FAc (n = 393) IOP > 30 mm Hg, % Any IOP-lowering medications b, % Trabeculoplasty, % Incisional IOP-lowering surgery, %

18 Summary of safety Long-lasting intravitreal fluocinolone accelerated the development of cataract Cataract surgery did not diminish post-surgery or long-term BCVA gains 4.8% of patients required incisional surgery to address elevated IOP IOP elevation did not diminish visual acuity outcomes Low rate of endophthalmitis

19 FAME study summary Sustained-release, nonbioerodible micro implant delivers consistent, submicrogram dosing of FAc for up to 36 months The greatest benefit was seen in patients who had chronic DME 34% of chronic DME patients treated with ILUVIEN demonstrated a 15-letter improvement in BCVA vs 13.4% control Ocular adverse events were consistent with side effects of corticosteroid therapy

20 Real-life studies

21 Real-life experience Chronic DME unresponsive to other treatments Mainly retrospective studies/case series Long-term efficacy and safety still debated

22 Real-life experience Autore Rivista Follow up (mesi) n. pazienti (occhi) Uso farmaci ipotonizzanti Incremento VA % pazienti Incremento VA >15 lettere % pazienti Incremento VA >10 lettere Riduzione CFT µm Terapie aggiuntive Elaraoud Ophthal Ther (10) n.a +11 n.a n.a -358 n.a. Massin Clin Ophthal 2016 Alfaqawi Eye % +4/+5 n.a. n.a. -252/ % (28) 11% +8 25% 36% % El-Ghrably EJO (57) 32% +5 23% 32% -126 n.a. Figueira Ophth Res (12) 42% 0/+6 n.a. n.a n.a. Meileres Eye (26) 31% +12 n.a. n.a % Bailey Eye (345) 14% % 34% % Totale impianti =513 (444 pazienti) Uso di farmaci ipotonizzanti 76/513= 15% Chirurgia incisionale 1/513= 0.2%

Real-life experience Review of case series from 10 EU centres (n=28 eyes): patients with chronic DME unresponsive to other treatments, injected with190 μg Fluocinolone Acetonide implant Real-world

23 Real-life experience Review of case series from 10 EU centres (n=28 eyes): patients with chronic DME unresponsive to other treatments, injected with190 μg Fluocinolone Acetonide implant Real-world efficacy similar to FAME study More favorable safety profile compared to FAME study (IOP rises in 7% vs 38.4, respectively) Mean follow up of 13 weeks Prior treatment in all eyes: steroids (57.1%), laser (57.1%), anti-vegf (92.9%) Quhill F, European Ophthalmic Review. 2015;9(1):42-6.

24 Real-life experience Retrospective study on 22 psudophakic eyes with unresponsive DME was conducted to evaluate selection criteria and clinical outcomes of FAc implants After 3 months, 18 patients showed reduction in CRT ( ) and 15 improved in VA ( ETDRS letters). 5 eyes with prior vitrectomy had a VA improvement of 7.2 letters (range 0 to 14) Additional value can be gained by switching from anti-vegf to FAc in unresponsive cases No cases of substantial IOP elevation, but short follow up period (3 months) Elaraoud I, BMC Ophthalmology. 2016; 16:3.

25 Real-life experience Retrospective case series (n=15 eyes) of patients with chronic DME unresponsive to other treatments (anti-vegfs and/or corticosteroids) -> injection of 190 μg Fluocinolone Acetonide implant; follow-up ranged from 2 and 37 weeks Primary outcome: Δ of BCVA Secondary outcomes: Δ of CFT and IOP Schmit-Eilenberger V, Clinical Ophthalmology. 2015;9: 1-11.

Real-life experience Retrospective case series (n=15 eyes) of patients with chronic DME unresponsive to other treatments (anti-vegfs and/or corticosteroids) -> injection of 190 μg Fluocinolone

26 Real-life experience Retrospective case series (n=15 eyes) of patients with chronic DME unresponsive to other treatments (anti-vegfs and/or corticosteroids) -> injection of 190 μg Fluocinolone Acetonide implant; follow-up ranged from 2 and 37 weeks Primary outcome: Δ of BCVA BCVA improved in 11 eyes (73.3%), unchanged in 2 (13.3%), decreased in 2 (13.3%) Mean VA gain was (starting from ), independent from the prior treatment Schmit-Eilenberger V, Clinical Ophthalmology. 2015;9: 1-11.

Real-life experience Secondary outcomes: Δ of CFT and IOP CFT declined in all 10 eyes with baseline OCT available, on average by -206 μm (baseline ranged between 291 and 729 μm) Mean IOP change

27 Real-life experience Secondary outcomes: Δ of CFT and IOP CFT declined in all 10 eyes with baseline OCT available, on average by -206 μm (baseline ranged between 291 and 729 μm) Mean IOP change was mmhg (from a mean baseline of ) 3 of 15 showed and increase of IOP >7 mmhg (2 required sectorial cyclocryotherapy) Schmit-Eilenberger V, Clinical Ophthalmology. 2015;9: 1-11.

28 Prior vitrectomy Total= 26 patients Meireles 2017

Take home messages FAc implant is indicated for chronic DME unresponsive to other available therapy Real life data on FAc are few but show favorable results when it is used in

29 Take home messages FAc implant is indicated for chronic DME unresponsive to other available therapy Real life data on FAc are few but show favorable results when it is used in selected patients Vitrectomy does not preclude the use of FAc implant FAc safety profile is still debated and ocular adverse events were consistent with steroid class side-effects

ILUVIEN IN DIABETIC MACULAR ODEMA

1 ILUVIEN IN DIABETIC MACULAR ODEMA Marie Tsaloumas Consultant Ophthalmic Surgeon Queen Elizabeth Hospital, Birmingham bars conference 2104 1 2 Declaration of interest I have sat on Advisory boards for