Research ArticleMACULAR DEGENERATION

Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration

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Science Translational Medicine  21 Jun 2017:
Vol. 9, Issue 395, eaaf1443
DOI: 10.1126/scitranslmed.aaf1443
  • Fig. 1. MAHALO clinical trial flowchart.

    This was a phase 2, multicenter, randomized, controlled study that investigated the safety, tolerability, pharmacokinetics, and evidence of activity of lampalizumab in patients with geographic atrophy secondary to AMD. One hundred twenty-nine eligible patients were randomized 1:2:1:2 to sham monthly, 10-mg lampalizumab monthly, sham every other month, or 10-mg lampalizumab every other month. *One hundred twenty-three patients met the prespecified modified intention-to-treat (mITT) criteria for primary efficacy analysis. This population included all randomized patients who had one or more treatment injections and one or more post-baseline geographic atrophy measurements. Sham arms were pooled for analyses.

  • Fig. 2. Changes in geographic atrophy area and best-corrected visual acuity after lampalizumab treatment.

    Shown are mean changes from baseline to month 18 in geographic atrophy area by fundus autofluorescence (A) and in best-corrected visual acuity (B) based on the mITT population. (A) The lampalizumab monthly arm showed a 20% reduction in mean change in geographic atrophy area progression relative to the pooled sham group at month 18; this result met the prespecified significance level (P < 0.2) for the study. (B) The best-corrected visual acuity results showed no safety concerns with lampalizumab treatment relative to the sham control. Adjusted mean in (A) and (B) is the least-squares mean from the stratified analysis of variance (ANOVA) model adjusted for baseline geographic atrophy and baseline best-corrected visual acuity, respectively, using last observation carried forward (LOCF) data. Vertical bars are ±1 SE of the least-squares mean.

  • Fig. 3. Differential geographic atrophy area progression by fundus autofluorescence in the CFI+ (risk-allele carriers) versus CFI− (risk-negative) sham treatment subgroups.

    In sham-treated CFI risk-allele carriers, a numerical increase of 49% in geographic atrophy area progression at month 18 was observed as compared with the sham-treated CFI risk-negative subgroup. The least-squares mean was estimated from a linear mixed-effect model that included baseline geographic atrophy area as a continuous variable, time point as a categorical variable, treatment, time-by-treatment interaction, and baseline geographic atrophy category (≥10 mm2 versus <10 mm2). Vertical bars are 95% CIs of the least-squares mean. In parentheses, n corresponds to the number of patients at the 6-, 12-, and 18-month time points, respectively.

  • Fig. 4. Geographic atrophy progression in CFI risk-allele carriers and risk-negative subpopulations after monthly lampalizumab treatment.

    Shown is geographic atrophy progression by fundus autofluorescence in the CFI+ (risk-allele carriers) and CFI− (risk-negative) subgroups (rs17440077) with monthly lampalizumab treatment versus sham treatment. (A) In the CFI+ subpopulation, there was a 44% reduction in geographic atrophy area progression with monthly lampalizumab treatment versus sham control at month 18. (B) Representative fundus autofluorescence images at baseline and month 18 for the CFI+ subpopulation. Relative geographic atrophy area progression is shown for the sham and lampalizumab monthly treated groups. (C) In the CFI− subpopulation, there was no apparent benefit with monthly lampalizumab treatment versus sham control at month 18. The least-squares mean was estimated from a linear mixed-effect model that included baseline geographic atrophy area as a continuous variable, time point as a categorical variable, treatment, time-by-treatment interaction, and baseline geographic atrophy category (≥10 mm2 versus <10 mm2). Vertical bars are 95% CIs of the least-squares mean. In parentheses, n corresponds to the number of patients at the 6-, 12-, and 18-month time points, respectively.

  • Fig. 5. Geographic atrophy progression in CFI risk-allele carriers and risk-negative subpopulations after lampalizumab treatment.

    Geographic atrophy area by fundus autofluorescence in the CFI+ risk-allele carriers (A) and CFI− risk-negative (B) subpopulations (rs17440077) after monthly and every other month lampalizumab treatment versus sham treatment. (A) In the CFI+ subpopulation, there was an 18% reduction in geographic atrophy area progression with lampalizumab treatment every other month versus sham control at month 18; moreover, there was a potential dose response between the monthly and every other month lampalizumab treatment subpopulations. (B) Consistent with the CFI− monthly lampalizumab subgroup, there was no apparent treatment benefit with every other month lampalizumab treatment versus sham control at month 18. The least-squares mean was estimated from a linear mixed-effect model that included baseline geographic atrophy area as a continuous variable, time point as a categorical variable, treatment, time-by-treatment interaction, and baseline geographic atrophy category (≥10 mm2 versus <10 mm2). Vertical bars are 95% CIs of the least-squares mean. In parentheses, n corresponds to the number of patients at the 6-, 12-, and 18-month time points, respectively.

  • Fig. 6. CFI mRNA expression in normal liver tissue differs by rs17440077 genotype.

    Expression of CFI mRNA in tissue from TCGA database (22) was analyzed and found to differ according to the rs17440077 genotype. The highest expression of CFI mRNA was in the liver, the site of CFI synthesis.

  • Table 1. Baseline characteristics of individual cohorts and all mITT patients.

    EOM, every other month; BCVA, best-corrected visual acuity; DA, disc area (1 DA = 2.54 mm2); GA, geographic atrophy.

    Sham pooled
    (n = 40)
    Lampalizumab monthly
    (n = 42)
    Lampalizumab EOM
    (n = 41)
    All mITT patients
    (n = 123)
    Patient demographics
      Age (years), mean (SD)78.5 (7.3)80.4 (7.2)77.2 (7.3)78.7 (7.3)
      Sex (female), n (%)24 (60.0)28 (66.7)18 (43.9)70 (56.9)
      Race (white), n (%)40 (100.0)40 (95.2)41 (100.0)121 (98.4)
    Study eye characteristics
      BCVA letters, mean (SD)45.9 (13.4)47.6 (12.8)49.5 (11.0)47.7 (12.4)
      Snellen equivalent (median)20/12520/10020/10020/100
      Total area of GA, DA (SD)3.48 (1.65)3.37 (1.52)3.37 (1.93)3.41 (1.69)
      Total area of GA, mm2 (SD)8.85 (4.18)8.56 (3.86)8.56 (4.90)8.65 (4.30)
  • Table 2. Adverse events in the MAHALO phase 2 clinical trial.

    All data are n (%). AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities.

    Overall profile
    Adverse eventSham pooled
    (n = 42)
    Lampalizumab monthly
    (n = 43)
    Lampalizumab EOM
    (n = 44)
    Patients with at least one event, n (%)
      Ocular SAEs in the study eye1 (2.4)03 (6.8)
      Ocular SAEs in the fellow eye1 (2.4)02 (4.5)
      Systemic (nonocular) SAEs15 (35.7)11 (25.6)10 (22.7)
      Ocular AE in the study eye suspected to be caused by study drug04 (9.3)3 (6.8)
      Nonocular AE suspected to be caused by study drug01 (2.3)1 (2.3)
    Ocular adverse events in the study eye (occurring in ≥3 patients in any group; all treated patients)
    MedDRA-preferred termSham pooled
    (n = 42)
    Lampalizumab monthly
    (n = 43)
    Lampalizumab EOM
    (n = 44)
    Any ocular AEs in the study eye, n (%)24 (57.1)36 (83.7)30 (68.2)
    Ocular AEs in the study eye occurring in ≥3 patients in any group, n (%)
      AMD02 (4.7)3 (6.8)
      Blepharitis2 (4.8)1 (2.3)6 (13.6)
      Cataract3 (7.1)2 (4.7)3 (6.8)
      Conjunctival hemorrhage9 (21.4)21 (48.8)15 (34.1)
      Conjunctival edema01 (2.3)3 (6.8)
      Dry eye02 (4.7)3 (6.8)
      Eye irritation1 (2.4)4 (9.3)4 (9.1)
      Eye pain4 (9.5)10 (23.3)6 (13.6)
      Eye pruritus3 (7.1)1 (2.3)3 (6.8)
      Foreign body sensation in eyes1 (2.4)4 (9.3)2 (4.5)
      Intraocular pressure increased06 (14.0)7 (15.9)
      Lacrimation increased1 (2.4)3 (7.0)4 (9.1)
      Ocular hyperemia2 (4.8)3 (7.0)5 (11.4)
      Punctate keratitis1 (2.4)4 (9.3)2 (4.5)
      Retinal hemorrhage3 (7.1)1 (2.3)3 (6.8)
      Vision blurred1 (2.4)2 (4.7)3 (6.8)
      Vitreous detachment3 (7.1)2 (4.7)4 (9.1)
      Vitreous floaters1 (2.4)3 (7.0)2 (4.5)

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/9/395/eaaf1443/DC1

    Fig. S1. Kaplan-Meier plot of time to study discontinuation by treatment group.

    Fig. S2. Geographic atrophy progression with monthly and every other month lampalizumab treatment.

    Fig. S3. Average CFI serum concentrations by rs17440077 genotype.

    Fig. S4. Average CFI serum concentrations by rs4698775 genotype.

    Table S1. Mean change in geographic atrophy area from baseline to month 18 by fundus autofluorescence and color fundus photography based on the mITT population (LOCF method).

    Table S2. Least-squares mean change in best-corrected visual acuity from baseline based on the mITT population using LOCF data.

    Table S3. SNP genotype counts and allele frequencies for patients assayed in the MAHALO study.

    Table S4. Least-squares mean change in geographic atrophy area from baseline to month 18 by risk-allele status.

    Table S5. Least-squares mean change in geographic atrophy area (mm2) by fundus autofluorescence from baseline by CFI status (rs17440077) based on the mITT population (observed data).

    Table S6. Geographic atrophy progression by fundus autofluorescence in CFI+ subgroups (rs17440077) with monthly and every other month lampalizumab treatment versus sham control and baseline best-corrected visual acuity of 20/50 to 20/100 (Snellen equivalent).

    Table S7. Least-squares mean change in geographic atrophy area (mm2) from baseline to month 18 by gender: CFI risk-allele carriers in mITT patients.

    Table S8. Least-squares mean change in geographic atrophy area (mm2) by fundus autofluorescence from baseline by CFI status (rs4698775) based on the mITT population (observed data).

    Table S9. Ocular adverse events in the fellow eye during the 18-month treatment period occurring among ≥3 patients in any treatment group (safety-evaluable patients).

    Table S10. Systemic (nonocular) adverse events during the 18-month treatment period occurring among ≥3 patients in any treatment group (safety-evaluable patients).

    Table S11. Adverse events suspected to be caused by study drug during the 18-month treatment period (safety-evaluable patients).

    Table S12. Serum and aqueous exposures in lampalizumab-treated patients.

    Table S13. Summary of estimated accumulation ratios in lampalizumab-treated patients.

    Table S14. CFI SNPs and relationships.

    Table S15. Predicted mean change in geographic atrophy area from baseline: mITT patients.

    Table S16. Predicted mean change in geographic atrophy area from baseline by CFI status: mITT patients.

    Table S17. Least-squares mean change in geographic atrophy area from baseline to month 18 (study eye): mITT patients.

    Source data

  • Supplementary Material for:

    Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration

    Brian L. Yaspan, David F. Williams, Frank G. Holz, Carl D. Regillo, Zhengrong Li, Amy Dressen, Menno van Lookeren Campagne, Kha N. Le, Robert R. Graham, Tatiana Beres, Tushar R. Bhangale, Lee A. Honigberg, Ashley Smith, Erin C. Henry, Carole Ho, Erich C. Strauss;* for the MAHALO Study Investigators

    *Corresponding author. Email: strauss.erich{at}gene.com

    Published 21 June 2017, Sci. Transl. Med. 9, eaaf1443 (2017)
    DOI: 10.1126/scitranslmed.aaf1443

    This PDF file includes:

    • Fig. S1. Kaplan-Meier plot of time to study discontinuation by treatment group.
    • Fig. S2. Geographic atrophy progression with monthly and every other month lampalizumab treatment.
    • Fig. S3. Average CFI serum concentrations by rs17440077 genotype.
    • Fig. S4. Average CFI serum concentrations by rs4698775 genotype.
    • Table S1. Mean change in geographic atrophy area from baseline to month 18 by fundus autofluorescence and color fundus photography based on the mITT
      population (LOCF method).
    • Table S2. Least-squares mean change in best-corrected visual acuity from baseline based on the mITT population using LOCF data.
    • Table S3. SNP genotype counts and allele frequencies for patients assayed in the MAHALO study.
    • Table S4. Least-squares mean change in geographic atrophy area from baseline to month 18 by risk-allele status.
    • Table S5. Least-squares mean change in geographic atrophy area (mm2) by fundus autofluorescence from baseline by CFI status (rs17440077) based on the
      mITT population (observed data).
    • Table S6. Geographic atrophy progression by fundus autofluorescence in CFI+ subgroups (rs17440077) with monthly and every other month lampalizumab treatment versus sham control and baseline best-corrected visual acuity of 20/50 to 20/100 (Snellen equivalent).
    • Table S7. Least-squares mean change in geographic atrophy area (mm2) from baseline to month 18 by gender: CFI risk-allele carriers in mITT patients.
    • Table S8. Least-squares mean change in geographic atrophy area (mm2) by fundus autofluorescence from baseline by CFI status (rs4698775) based on the mITT population (observed data).
    • Table S9. Ocular adverse events in the fellow eye during the 18-month treatment period occurring among ≥3 patients in any treatment group (safety-valuable patients).
    • Table S10. Systemic (nonocular) adverse events during the 18-month treatment period occurring among ≥3 patients in any treatment group (safety-evaluable patients).
    • Table S11. Adverse events suspected to be caused by study drug during the 18-month treatment period (safety-evaluable patients).
    • Table S12. Serum and aqueous exposures in lampalizumab-treated patients.
    • Table S13. Summary of estimated accumulation ratios in lampalizumab-treated patients.
    • Table S14. CFI SNPs and relationships.
    • Table S15. Predicted mean change in geographic atrophy area from baseline: mITT patients.
    • Table S16. Predicted mean change in geographic atrophy area from baseline by CFI status: mITT patients.
    • Table S17. Least-squares mean change in geographic atrophy area from baseline to month 18 (study eye): mITT patients.

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    Other Supplementary Material for this manuscript includes the following:

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