APL-2, a complement C3 inhibitor, slows the growth of geographic atrophy

secondary to AMD: 18-month results of a phase 2 trial (FILLY).Charles C. Wykoff1,2, MD, PhD; Federico V Grossi3, MD, PhD.

1.Retina Consultant of Houston, Houston, TX; 2.Blanton Eye Institute, Houston Methodist Hospital & Weill Cornell Medical College, Houston, TX; 3. Apellis Pharmaceuticals, Crestwood, KY.

STUDY DESIGN

CONCLUSIONS

§ The Filly Phase 2 trial met its primary endpoint. APL-2 demonstrated pronounced and statistically significant reductions in GA growth over 18 months as compared to sham groups despite no treatments for 6 months.

§ No differences in visual acuity were observed between the groups.§ Incidence of exudative AMD, reported by the Investigators, seems to be more

frequent in the APL-2 treated subjects.§ The risk/benefit profile at 18 months supports the decision to move to Phase 3

trial.

The Filly phase 2 trial was designed to evaluate thesafety and efficacy of APL-2 (pegcetacoplan, 15mg)administered intravitreally for 12 months, followed byan additional 6 months without treatment, in subjectswith GA secondary to AMD.

PURPOSE

§ Geographic Atrophy (GA) is an advanced stage of age-related macular degeneration (AMD) and a major cause of legal blindness. Vision loss associated with GA significantly affects quality of life.1

§ GA is characterized by a loss of RPE, photoreceptors, and atrophy of the choriocapillaris.2

§ GA affects almost 1 million people in the United States alone. Additionally, about 50% of patients develop bilateral GA within 7 years of diagnosis of GA in the first eye. GA also frequently develops within 5 years of starting treatment with VEGF inhibitors in patients with neovascular AMD.3

§ To date there is no treatment available to prevent GA or slow GA progression.

§ Dysregulation of the complement system is a major contributor to the pathogenesis of AMD. Complement genetic variants and oxidative stress may activate the three complement activation pathways.4

§ Due to the key position of C3 in the complement cascade, APL-2, a PEGylated cyclic peptide inhibitor of C3, may block all complement activation pathways and effectors of the complement cascade and is being investigated as a therapeutic to slow GA progression.

BACKGROUND

MAJOR ENTRY CRITERIA

§ At least 50 years old

§ With reference to study eye: o Best-corrected visual acuity (BCVA) of 24 letters or

better (20/320 Snellen equivalent).o GA secondary to AMD, with a GA area size of ≥2.5

and ≤17.5 mm2, and at least one focal lesion ≥1.25 mm2 if GA was multifocal.

o Major exclusion criteria: GA due to causes other than AMD, history or current evidence of exudative AMD, retinal disease other than AMD.

§ GA or exudative AMD was permitted in the fellow eye.

RESULTS: PRIMARY EFFICACY ENDPOINTS – GA LESION GROWTH

BASELINE CHARACTERISTICS

Figure 1: Clinical trial flowchart. Eligible subjects were randomized to receive intravitrealinjection of sham or APL-2 monthly, or every other month (EOM), for 12 months. Patientsreturn at months 15 and 18 for safety and efficacy follow-up. *modified intent-to-treat(mITT) population was used for the analysis and is defined as all patients who received atleast one injection and had at least one visit at month 2 or later at which primary efficacydata was collected.

RESULTS: SAFETY DATA

RESULTS: VISUAL ACUITY

Figure 2: Change from baseline in GA area. Panel A. Least-squares (LS) means and their standard errors (SE) were estimated from a mixed effectmodel that included treatment and visit as factors, and baseline GA lesion as a covariate, as well as the interaction term of treatment × visit and visit ×baseline. The p-values versus Sham-Pooled for APL-2 Monthly and Every-Other-Month (EOM), respectively, were 0.010 and 0.061 at Month 12, and0.044 and 0.097 at Month 18. Panel B. LS means and SEs were estimated from a mixed effect model that included treatment and visit[eye] as factors,and baseline GA lesion as a covariate, as well as the interaction term of treatment × visit[eye] and visit[eye] × baseline, where visit[eye] was a compositefactor incorporating both visit and eye (Study/Fellow) factors. Panel C. Means and SEs of subjects who had values at both visits in each summary periodare shown. Pairwise comparisons for either APL-2 arm vs. Sham-Pooled based a one-way ANOVA using the least significant difference (LSD) method formultiplicity showed no significant difference for Month 0 to 6 and Month 12 to 18, and had a p-value of <0.001 for APL-2 Monthly and 0.009 for APL-2EOM for the lesion growth from Month 6 to 12.

Figure 3: Change from baseline in visual acuity.BCVA = best corrected visual acuity assessed with theETDRS chart, LL = low luminance, LL-VA deficit =low-luminance visual acuity deficit which is derived bysubtracting LL-BCVA from BCVA. Least-squares (LS)means and standard errors (SE) were estimated froma mixed effect model that included treatment and visitas factors, and baseline value of the endpoint as acovariate, as well as the interaction term of treatment× visit and baseline × visit.

A- BCVA

B- LL-BCVA

C- LL-VA deficitA- GA lesion growth in the study eye B- GA lesion growth study eye vs fellow eye

Table 1: Baseline characteristics in ITT population.

-3.3

-7.7 -5.8 -8.8

-4.4 -6.4

-10

-5

0

5

10

0 2 4 6 8 10 12 14 16 18

LSM

ean(±SE)C

hangefrom

Baselinein

BCVA

(letters)

Month

-2.7

-4.4 -3.2 -3.7

-0.6

-2.1

-10

-5

0

5

10

0 2 4 6 8 10 12 14 16 18

LSM

ean(±SE)C

hangefrom

Baselinein

LL-BCVA(letters)

Month

-0.8

-2.7 -2.4

-4.6 -3.6 -4.2

-10

-5

0

5

10

0 2 4 6 8 10 12 14 16 18

LSM

ean(±SE)C

hangefrom

Baselinein

LL-VADeficit(letters)

MonthOff Treatment

Off Treatment

Off Treatment

0.26

0.39

0.28

0.410.35

0.49

0

0.1

0.2

0.3

0.4

0.5

0.6

0 6 12 18

LSM

ean(±SE)C

hangefrom

Baseline

inSquareRo

otGALesion(m

m)

MonthOff Treatment

Sham pooled (n=80)

Off Treatment

Table 2: Major safety data in ITT population. *Two cultures positive for coagulase-negativeStaphylococcus. One culture negative in the monthly group. ** Coded as visual impairment in theMonth-12 analysis.

We thank all Investigators who participated in the FILLY study and their institutions. This study was sponsored by Apellis Pharmaceuticals.

1- Bourne, R.R., et al. Causes of vision loss worldwide, 1990-2010: a systematic analysis. Lancet Glob Health, 2013. 1(6): p. e339-49; 2- Holz, F.G., et al. Geographic atrophy: clinical features and potential therapeuticapproaches. Ophthalmology, 2014. 121(5): p. 1079-91; 3- Lindblad, A.S., et al. Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26. Arch Ophthalmol, 2009. 127(9):p.1168-74; 4- Whitmore, S.S., et al. Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy. Prog Retin Eye Res, 2015. 45: p. 1-2.

REFERENCES

Parameters Sham pooled (n=81)

APL-2 monthly (n=86)

APL-2 EOM (n=79)

Patient demographics

Age (Years), mean (SD) 78.4 (7.43) 79.6 (7.51) 81.0 (7.55)

Sex (Female), n (%) 49 (60.5) 55 (64.0) 50 (63.3)

Race (White), n (%)* 81 (100) 84 (97.7) 76 (96.2)

Study Characteristics

Total area of GA, mm2 (SD) 8.2 (4.05) 8.0 (3.85) 8.9 (4.47)

Bilateral GA, n (%) 72 (90.0) 71 (85.5) 64 (82.1)

CNV in the fellow eye, n (%) 29 (35.8) 36 (41.9) 28 (35.4)

BCVA Letter Score, mean (SD) 59.8 (17.2) 59.8 (15.7) 58.4 (16.0)

20/200 or worse 12 (14.8) 9 (10.5) 10 (12.7)

20/160 to 20/50 33 (40.7) 50 (58.1) 44 (55.7)

20/40 or better 36 (44.4) 27 (31.4) 25 (31.6)

Snellen Equivalent (median) 20/50 20/63 20/63

LL-BCVA Letter Score, mean (SD) 33.6 (17.8) 36.3 (16.8) 31.4 (17.1)

Snellen Equivalent (median) 20/200 20/200 20/250

LL-VA deficit Letter Score, mean (SD) 26.2 (17.1) 23.5 (14.5) 27.1 (15.7)

ParametersSham Pooled

(n=81)APL-2 Monthly

(n=86)APL-2 EOM

(n=79)Adverse events, number of subjects (%) SAEs in the study eye 1 (1.2) 4 (4.7) 2 (2.5) SAEs in the fellow eye 1 (1.2) 0 0 Systemic (non-ocular) SAEs 23 (28.4) 19 (22.1) 24 (30.4) Treatment-related AEs in the study eyes 0 22 (25.6) 11 (13.9) Systemic (non-ocular) treatment-related AEs 0 0 0Ocular SAEs in the study eye, number of subjects (%), number of events Endophthalmitis* 0 2(2.3), 2 1 (1.3), 1 Intraocular pressure increased 0 1 (1.2), 2 1 (1.3), 1 Retinal detachment 0 1 (1.2), 1 0 Dry AMD** 1 (1.2), 1 0 0Incidence of investigator-determined exudative AMD in the study eye during trial

Subjects with wAMD in Study eye (%) 1 (1.2) 18 (20.9) 7 (8.9)95% Exact CI for incidence (0.0%, 6.7%) (12.9%, 31.0%) (3.6%, 17.4%)

With History of CNV in Fellow Eye n = 29 n = 36 n =28Subjects with wAMD in Study eye (%) 0 12 (33.3) 5 (17.9)

95% Exact CI for incidence (0.0%, 11.9%) (18.6%, 51.0%) (6.1%, 36.9%)No CNV History in Fellow Eye n = 52 n = 50 n =51

Subjects with wAMD in Study eye (%) 1 (1.9) 6 (12.0) 2 (3.9)95% Exact CI for incidence (0.0%, 10.3%) (4.5%, 24.3%) (0.5%, 13.5%)

C- Post hoc exploratory analysis: Growth in GA lesion size (mm) per 6-month period

0.170 0.159 0.1560.175

0.1170.096

0.1480.134 0.130

0.00

0.05

0.10

0.15

0.20

ShamPooled(n=72)

APL-2EOM

(n=68) APL-2Monthly

(n=68)

ShamPooled(n=62)

APL-2EOM

(n=54) APL-2Monthly

(n=60)

ShamPooled(n=62)

APL-2EOM

(n=51) APL-2Monthly

(n=58)

Mean(±SE)Growthin

SquareRootGALesion(mm)

Month0to6 Month6to12 Month12to18(OffTreatment)

p>0.5vssham

p>0.5vssham

p=0.009vssham

p<0.001vssham

p=>0.5vssham

p=0.47vssham