Pipeline: Potential new therapy coming for macular disease

October 9, 2020

Faricimab shows promise in treating diabetic macular edema and age-related macular degeneration

A new option may soon be on the horizon to treat macuar disease, specifically neovascular age-related macular degeneration and diabetic macular edema. Faricimab (Genentech), the first bispecific antibody designed for intraocular use, showed clinically meaningful vision and anatomic improvements comparable to anti-VEGF monotherapy in Phase 2 trials. Phase 3 trials are ongoing.

Diabetic macular edema (DME), a complication of underlying diabetic retinopathy (DR), and neovascular age-related macular degeneration (nAMD) are serious ophthalmologic conditions that impact patients globally.1,2 The introduction of intravitreal anti–vascular endothelial growth factor (anti-VEGF) treatment has provided many patients with DR, DME, and nAMD with improved vision and quality of life.3

However, DR, DME, and nAMD continue to be major causes of vision loss despite the use of anti-VEGF therapy worldwide.4 Patients and caregivers, as well as healthcare professionals, are affected by the high treatment burden of frequent injections, office visits, and patient monitoring.5,6 Real-world research shows that patients receive fewer intravitreal injections than the number required to maintain the vision and anatomic benefits seen in clinical trials, and thus, these individuals experience poorer outcomes.7

Related: Brain stimulation can reduce the effects of macular degeneration

Combined, these factors present an unmet need for novel treatments beyond anti-VEGF monotherapy that will provide patients with increased efficacy and durability in treating DR, DME and nAMD.3 New therapeutic targets or longer-acting formulations may be the key to helping patients keep their disease under control.

Related: Patient education vs patient relations?

Vascular instability

DR, DME, and nAMD involve complex pathogenic processes in the retina and choroid that result in inflammation, leakage, and increased neovascularization, all of which lead to vision impairment.8-10

Together, angiopoietin-2 (Ang-2) and VEGF-A work synergistically to drive vascular instability in these retinal diseases.11,12

Ang-2 is a growth factor that promotes vascular destabilization and inflammation and enhances retinal sensitivity to VEGF and other pro-inflammatory factors; VEGF-A promotes vascular leakage and angiogenesis.3,10-12 Dual inhibition of Ang-2 and VEGF-A has been shown to promote vascular stability by reducing inflammation, leakage, and neovascularization more effectively than inhibiting either target alone.11,13

Faricimab (Genentech) is the first bispecific antibody designed for intraocular use. It binds and neutralizes both Ang-2 and VEGF-A with high potency and specificity.11,12

Related: The evolving standard of care in AMD

Faricimab Phase 2 study data

Phase 2, multicenter, randomized, active comparator–controlled clinical trials have been completed for DME and nAMD. For both conditions, faricimab demonstrated clinically meaningful vision and anatomic improvements comparable or superior to anti-VEGF monotherapy, as summarized below, with a potential for sustained efficacy.

BOULEVARD

In the Phase 2 DME trial BOULEVARD, anti-VEGF treatment-naïve patients with center-involving DME were randomized to intravitreal faricimab 6.0 mg, faricimab 1.5 mg, or ranibizumab 0.3 mg every 4 weeks.14 The trial also enrolled some patients who had been previously treated with anti-VEGF.

The trial included a treatment period of 20 weeks, followed by an observation off-treatment period to Week 36. The off-treatment period allowed the durability of faricimab to be assessed. Patients were assessed every 4 weeks during the off-treatment period for time to disease reactivation and need for re-treatment, as assessed by functional (loss of 5 or more Early Treatment Diabetic Retinopathy Study [ETDRS] best-corrected visual acuity letters) and anatomic measurements (increase in central subfield thickness [CST] of ≥50 μm).

The following study outcomes are for the anti- VEGF treatment-naïve patients. At Month 6, the patients in the faricimab 6.0 mg arm had a mean improvement in visual acuity of +13.9 ETDRS letters compared with +10.3 letters for the ranibizumab arm (P=0.03; Figure 1A).14

Faricimab-treated patients also showed anatomic improvements at Month 6 compared with ranibizumab- treated patients, namely a reduction in CST and improvements in DR severity.14 Faricimab demonstrated a potential for extended durability compared with ranibizumab monotherapy.

In the off-treatment observation period, the median time to disease reactivation in the faricimab 6.0 mg and ranibizumab treatment groups was 15.1 and 8.6 weeks, respectively.14

Related: Macular degeneration A to Z

AVENUE, STAIRWAY

AVENUE15 and STAIRWAY16 were 2 Phase 2 clinical trials of faricimab in nAMD.

In AVENUE, patients with nAMD and subfoveal choroidal neovascularization (CNV) were randomized to one of five treatment groups:

4-weekly intravitreal injections of ranibizumab 0.5 mg

4-weekly intravitreal injections of faricimab 1.5 mg

4-weekly intravitreal injections of faricimab 6.0 mg

3 4-weekly doses of faricimab 6.0 mg followed by faricimab 6.0 mg every 8 weeks

3 4-weekly doses of ranibizumab 0.5 mg followed by faricimab 6.0 mg every 8 weeks

The faricimab 1.5 mg or 6.0 mg dosing schedules were each shown to achieve and maintain meaningful vision gains and anatomic improvements, with CST reductions, comparable to outcomes achieved with ranibizumab 0.5 mg every 3 weeks over 36 weeks (Figure 1B).17

Related: Macular diseases: Emerging best practices for diagnosis, management and follow-up protocols

In STAIRWAY, patients were randomized to receive

Intravitreal ranibizumab 0.5 mg every 4 weeks

Intravitreal faricimab 6.0 mg every 12 weeks

Intravitreal faricimab 6.0 mg every 16 weeks “flex” after 4 monthly loading doses

If patients in the every-16-week flex arm exhibited disease activity at Week 24 (12 weeks after the last monthly loading dose), they received every- 12-week dosing thereafter, whereas the remaining patients continued with the every-16-week regimen.18,19 At Week 24, 65 percent (36/55) of faricimab-treated patients had no active disease and were eligible for every-16-week dosing.18,19

Mean vision improvements at 1 year from baseline were +11.4, +10.1, and +9.6 ETDRS letters for patients in the faricimab every-16-week flex, faricimab every-12-week, and ranibizumab every-4- week groups, respectively (Figure 1C).18,19 Faricimab 6.0 mg dosed every 12 or 16 weeks resulted in vision gains and anatomic improvements comparable with ranibizumab 0.5 mg every 4 weeks.18,19

Faricimab was well tolerated in all Phase 2 trials.14,17-19 No new safety signals were identified. There were low rates of ocular adverse events and serious adverse events. Safety profiles of faricimab and anti-VEGF monotherapy were comparable.

Ongoing Phase 3 trials

Phase 3, global, randomized, double-masked, active comparator–controlled studies assessing faricimab for DME and nAMD are underway. These studies will further evaluate the potential for faricimab to provide sustained clinical efficacy through vascular stability delivered by dual anti–VEGF-A/anti– Ang-2 inhibition.

Related: Why AMD supplementation should not be casual

YOSEMITE, RHINE

The Phase 3 DME trials are YOSEMITE20 and RHINE.21 Treatment-naïve or previously anti- VEGF–treated patients with center-involving DME (N=~900 per study) are randomized to:22

Faricimab 6.0 mg every 8 weeks

Faricimab 6.0 mg per personalized treatment interval (PTI)

Aflibercept (Eylea, Regeneron) 2.0 mg every 8 weeks

The PTI arm will evaluate extended dosing intervals with faricimab 6.0 mg to deliver dosing regimens tailored to the needs of individual patients.

The primary outcome measure is mean change in visual acuity from baseline at 1 year, with key secondary objectives including the proportion of patients on a 4-weekly, 8-weekly, 12-weekly, or 16-weekly treatment interval at 1 year and 2 years.

TENAYA, LUCERNE

The Phase 3 nAMD trials are TENAYA23 and LUCERNE.24 Treatment-naïve patients with subfoveal choroidal neovascularization (CNV) secondary to nAMD (N=~640 per study) are randomized to faricimab 6.0 mg or aflibercept 2.0 mg every- 8-week dosing.25 The every-16-week flex regimen allows every-8-week, every-12-week, or every-16- week dosing based on the patient’s individual disease activity at Week 20 or 24.

The primary outcome measure is mean change in visual acuity from baseline at 48 weeks, with key secondary objectives including the proportion of patients on an 8-weekly, 12-weekly, or 16-weekly treatment interval at 1 year and 2 years.

More by Dr. Ferrucci: How to determine treatment for a patient with a Roth spot

Conclusion

Faricimab is the first biospecific antibody designed for intraocular use, independently binding and neutralizing Ang-2 and VEGF-A, which together synergistically promote vascular instability.

Data from the Phase 2 faricimab clinical trial program suggest treatment with faricimab may lead to improved and sustained efficacy beyond what is achieved with anti-VEGF monotherapy in nAMD and DME. The efficacy and safety of faricimab in DME and nAMD is currently being investigated further in the global Phase 3 program.

Acknowledgments: Funding was provided by Genentech, Inc., a member of the Roche Group, for third-party writing assistance, which was provided by Anne Nunn, PhD, CMPP, of Envision Pharma Group.

More from October 2020's issue: Glaucoma & ocular surface preservation: Key factors for ODs to consider

REFERENCES

1. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015 Sep 30;2:17.

2. Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, Wong TY. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014 Feb;2(2):e106-e116.

3. Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016 Jun;15(6):385- 403.

4. Flaxman SR, Bourne RRA, Resnikoff S, Ackland P, Braithwaite T, Cicinelli MV, Das A, Jonas JB, Keeffe J, et al; Vision Loss Expert Group of the Global Burden of Disease Study. Global causes of blindness and distance vision impairment 1990– 2020: a systematic review and meta-analysis. Lancet Glob Health. 2017 Dec;5(12):e1221-e1234.

5. Kiss S, Chandwani HS, Cole AL, Patel VD, Lunacsek OE, Dugel PU. Comorbidity and health care visit burden in working-age commercially insured patients with diabetic macular edema. Clin Ophthalmol. 2016 Dec 7;10:2443-2453.

6. Prenner JL, Halperin LS, Rycroft C, Hogue S, Williams Liu Z, Seibert R. Disease burden in the treatment of age-related macular degeneration: findings from a time-and-motion study. Am J Ophthalmol. 2015 Oct;160(4):725-731.e1.

7. Holz FG, Tadayoni R, Beatty S, Berger A, Cereda MO, Cortez R, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. Br J Ophthalmol. 2015 Feb;99(2):220-226.

8. Miller JW. Age-related macular degeneration revisited— piecing the puzzle: the LXIX Edward Jackson Memorial Lecture. Am J Ophthalmol. 2013 Jan;155(1):1-35.e13.

9. Romero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A, Lopez- Galvez M, Navarro-Gil R, Verges R. Diabetic macular edema pathophysiology: vasogenic versus inflammatory. J Diabetes Res. 2016;2016:2156273.

10. Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov. 2017 Sep;16(9):635-661.

11. Regula JT, Lundh von Leithner P, Foxton R, et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 2016 Nov 2;8(11):1265-1288.

12. Regula JT, Lundh von Leithner P, Foxton R, et al. Erratum: Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 2019;11(5):e10666.

13. Foxton RH, Uhles S, Grüner S, Revelant F, Ullmer C. Efficacy of simultaneous VEGF-A/ANG-2 neutralization in suppressing spontaneous choroidal neovascularization. EMBO Mol Med. 2019 May;11(5):e10204.

14. Sahni J, Patel SS, Dugel PU, Khanani AM, Jhaveri CD, Wykoff CC, et al. Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-A with faricimab in diabetic macular edema: BOULEVARD phase 2 randomized trial. Ophthalmology. 2019 Aug;126(8):1155-1170.

15. ClinicalTrials.gov. A Proof-of-Concept Study of Faricimab (RO6867461) in Participants With Choroidal Neovascularization (CNV) Secondary to Age-Related Macular Degeneration (AMD) (AVENUE). Available at: https://clinicaltrials.gov/ct2/show/ record/NCT02484690. Accessed 9/24/20.

16. ClinicalTrials.gov. Study to Evaluate Faricimab (RO6867461; RG7716) for Extended Durability in the Treatment of Neovascular Age Related Macular Degeneration (nAMD) (STAIRWAY). Available at: https://clinicaltrials.gov/ct2/show/ record/NCT03038880. Accessed 9/24/20.

17. Dugel PU, Sahni J, Osborne A, et al. Anti-VEGF/anti– angiopoietin-2 bispecific antibody faricimab (RG7716) in neovascular AMD. Presented at: Retina Society 51st Annual Meeting; September 12-15, 2018; San Francisco, CA.

18. Danzig C, Quezada C, Basu K, et al. Efficacy and safety of faricimab every 16 or 12 weeks for neovascular age-related macular degeneration: STAIRWAY phase 2 results. Invest Ophthalmol Vis Sci. 2019;60(9):1212.

19. Khanani AM, Osborne A, Basu K, Grzeschik S, Lin H. Simultaneous inhibition of Ang-2 and VEGF with faricimab in neovascular AMD: STAIRWAY phase 2 results. Presented at: American Academy of Ophthalmology - Subspecialty Day; October 26, 2018; Chicago, IL.

20. ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Faricimab (RO6867461) in Participants With Diabetic Macular Edema (YOSEMITE). Available at: https://clinicaltrials.gov/ct2/ show/record/NCT03622580. Accessed 9/24/20.

21. ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Faricimab (RO6867461) in Participants With Diabetic Macular Edema (RHINE). Available at: https://clinicaltrials.gov/ct2/ show/record/NCT03622593. Accessed 9/24/20.

22. Wykoff CC. Combined blockade of angiopoietin-2 and VEGF-A with faricimab in phase 2 DME and neovascular AMD trials: what’s new and what’s to come. Presented at: American Academy of Ophthalmology Retina Subspecialty Day; October 26-27, 2018; Chicago, IL.

23. ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Faricimab in Participants With Neovascular Age-Related Macular Degeneration (TENAYA). https://clinicaltrials.gov/ct2/ show/record/NCT03823287. Accessed November 23, 2019.

24. ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Faricimab in Participants With Neovascular Age-Related Macular Degeneration (LUCERNE). Available at: https:// clinicaltrials.gov/ct2/show/record/NCT03823300. Accessed 9/24/20.

25. Lai TY, Sahni J, Sadikhov S, et al. Anti–vascular endothelial growth factor A/anti–angiopoietin-2 bispecific antibody faricimab in neovascular age-related macular degeneration: results of phase 2 trials. Presented at: Asia-Pacific Academy of Ophthalmology; March 6-9, 2019; Bangkok, Thailand.and Safety of Faricimab in Participants With Neovascular Age-Related Macular Degeneration (LUCERNE). https://clinicaltrials.gov/ ct2/show/record/NCT03823300. Accessed November 23, 2019.

25. Lai TY, Sahni J, Sadikhov S, Szczesny P, Basu K, Osborne A. Anti–vascular endothelial growth factor A /anti–angiopoietin-2 bispecific antibody faricimab in neovascular age-related macular degeneration: results of phase 2 trials. Presented at: Asia- Pacific Academy of Ophthalmology; March 6-9, 2019; Bangkok, Thailand.

download issueDownload Issue : October digital edition 2020