HIGH IMPACT – Iveric Bio announced topline data from GATHER2, its second phase 3 study of C5 aptamer, Zimura (Avacincaptad pegol) in geographic atrophy.
Efficacy (anatomical):
- 14.3% reduction in mean rate of GA growth (slope; mm) at month 12 (p=0.0064).
- 17.7% reduction in mean rate of GA growth (slope; mm2) at month 12 (p=0.0039).
- Point analysis results were consistent with slope analysis.
- Improvements were seen early in the study; 6 mos reduction in mean change in GA area of 14.1% (descriptive p-value 0.0293).
- Mean rate of growth showed reduction for all analyzed subgroups based on baseline lesion size, baseline visual acuity, baseline auto-fluorescence pattern, age and gender.
- Regional post-hoc analysis at 12 mos showed
- 25.5% reduction in mean rate of GA growth (slope; mm) (descriptive p-value =0.0037).
- 32.0% reduction in mean rate of GA growth (slope; mm2) (descriptive p-value =0.0033).
- patients in US (42.7% of enrolled patients) had mean baseline lesion size 13% smaller than outside the US, which may have led to the differences.
Efficacy (functional):
- Favorable trend observed for mean change in BCVA mirroring GATHER1 study.
- No favorable trends observed for LLVA.
Safety:
- No endophthalmitis, intraocular inflammation events, or ischemic optic neuropathy.
- Most frequent ocular AE was related to injection procedure.
- 6.7% CNV events with Zimura vs 4.1% in sham
- 4.9% eMNV vs 3.2% in sham
- 0.5% neMNV vs 0% in sham
- 1.3% peripapillary CNV vs 0.9% in sham
Upcoming milestones:
- Results will be presented at AAO 2022.
- Iveric plans to file for Zimura in the US by end of 1Q 2023.
- Plans to meet with EMA in 1Q 2023 to discuss path forward.
Q&A from call
- Q: Explain differences between slope analysis and observed analysis? What caused difference between the two? Baseline differences in GATHER1 and GATHER2?
- A: Not that much of a difference between point and slope analysis, because data showed a linear progression. Still studying regional differences, current hypothesis is that lesions in US was smaller, may be a proxy to early stage of disease. Consistent with hypothesis that Zimura is more effective in patients earlier in disease. In GATHER1 75% were in the US, vs 40% in GATHER2, still looking at the data.
- Q: Rate of CNV declined relative to GATHER1, why?
- A: Inhibiting a C5 allows for a favorable safety profile. When physicians chose a drug, the safety becomes important. No endophthalmitis, inflammation and ION, very consistent with GATHER1.
- Q: Comment on market research on how 14% reduction in GA growth would be?
- A: Have 2 trials, only that have both been positive in 2 independent trials in this field. GATHER1 slope was 27% and 14% in GATHER2 with favorable and consistent safety profiles. Only 1 yr. data, confident will be able to show clinical impact in patients over their lifetime. Will do additional analysis to see if treatment can be personalized based on baseline characteristics.
- Q: Color on trends in BCVA?
- A: BCVA is not necessarily a good proxy for this disease. Saw a trend in improvement in GATHER1 and GATHER2. BCVA improvements usually lag behind, happy to see the trend. Will be reporting all functional outcomes at a future meeting.
- Q: all eMNV receive VEGF? Any patients outside these numbers receive anti-VEGF?
- A: All patients with CNV received anti-VEGF. Provided Eylea or Lucentis but required patient to be treated on label. None other received anti-VEGF.
- Q: What’s left to file NDA with FDA? Comment on potential ex-US application?
- A: All pieces in place to populate NDA including CMC. Plan is to be expeditious. Extremely pleased with safety results. Plan is to meet with EMA in 1Q 2023 to discuss path forward.
- Q: Any imbalances between Zimura and sham arm in GATHER2? How can BCVA trend differentiate from competitors? Have you looked at other functional endpoints? Anything else from LL BCVA we can expect?
- A: Baseline characteristics are well balanced (in 8K). Secondary endpoint will be presented at future medical meeting.
- Q: Any other differences between US and ex-US beyond baseline lesion size? Between the ex-US regions were there any differences?
- A: Very early stages of analysis, has only done US vs ex-US – lesion size is the only difference we see. Believes will find differences between ex-US regions too, hypothesis is that it depends on stage of disease when patients are recruited.
- Q: What is the reason behind seeing trend in BCVA but not LL BCVA? EM vs EOM label? When will we get update on 2yr outcome?
- A: Gain in BCVA will lag behind change in GA lesion. Seeing a modest trend at 12mos. Still have to investigate why there is no difference in LL BCVA. Premature to have label discussion. Results for EOM will be second part of the study, will have more information at that point.
- Q: Confirm anti-VEGF decision was made by central reader? Regional differences in CNV?
- A: PI was required to treat VEGF once CNV was reported. Very confident CNV numbers are comprehensive, confirmed by Duke reading center. Don’t have additional analysis on regional differences in CNV yet.
- Q: Comments on 6 mos data? Differences in first and second 6 mos?
- A: Too early to tell, will be looking at data.
- Q: How representative is US population representative of GA population? What additional data do we expect to see at AAO?
- A: Difficult to answer, hypothesis only that treating early might be better, but need to generate more data. Once approved will educate physicians to treat as early as possible. Not disclosed what will be presented at AAO, slated for 2 talks.
inThought Analysis
In Iveric Bio’s first pivotal trial, GATHER1, which was initially designed as a phase 2/3 study, Zimura 2mg achieved 27.7% reduction of mean rate of GA growth (slope; mm). Reduction in mean GA growth rate in GATHER2, although statistically significant, was less impressive than GATHER1. In contrast, 12 pegcetacoplan (targets C3) was only successful in achieving primary endpoint in one of its two pivotal trials; in the DERBY and OAKS studies showed 12% (p=0.0528) and 22% (p=0.0003) reduction in rate of GA growth versus sham respectively in the every month arm.
While numerically efficacy with Zimura might appear better than pegcetacoplan, there are a few differences in study design that preclude comparisons. First, the Zimura trials specifically recruited patients with extra-foveal lesions, a population which is thought to be more fast-progressing, with a more active complement pathway involvement and therefore potentially more amenable to complement inhibiting treatments. Pegcetacoplan trials on the other hand, recruited patients with both foveal and extra-foveal lesions. When only extra-foveal lesions were assessed in a pre-specified analysis of the combined DERBY and OAKS data, reductions in GA growth rates were 26% (p<0.0001). Second, the design of the GATHER1 study had several limitations which brings into question the validity of the data including treatment of sham data and accounting for missing data in the trial.
Long-term follow-up will determine whether the difference between treatment and sham arms continue to grow, similar to what has been observed with pegcetacoplan. While some experts note that any statistically significant difference is meaningful, others deem >20% reduction as clinically meaningful.
Zimura, interestingly, showed trends in BCVA improvement in both GATHER1 and GATHER2, as early as 12 mos, while pegcetacoplan 24-mos data failed to show a separation in BCVA between treatment and sham arms. However, it might not be appropriate to speculate too much on these signals, given that BCVA is not considered an appropriate functional outcome to study in GA.
On the safety front, Zimura presents a cleaner profile than pegcetacoplan as expected from its mechanism of action with no cases of intraocular inflammation and endophthalmitis; Zimura targets the more terminal part of the complement pathway leaving much of the C3-mediated mechanisms intact leading less changes of infection. The incidences of ischemic optic neuropathy were of particular concern with pegcetacoplan, an AE that was not observed with Zimura.
If the FDA considers GATHER1 as one of the two pivotal trials, Zimura is on track to be the second treatment approved in the US for geographic atrophy, after pegcetacoplan, expecting approval by November 2022. Given that pegcetacoplan will likely be in the market for >1 yr. when Zimura is approved, the former is likely to enjoy significant first-mover advantage. Secondly, pegcetacoplan’s every-other-month dosing also offers an attractive value proposition. The second part of the GATHER2 study will also evaluate every-other-month dosing but no data from this regimen is expected to be part of the initial NDA.
Source: Iveric Bio Press Release
