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Will an Effective Drug Ever Reach the Market for Geographic Atrophy?

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Roche/Genentech’s lampalizumab fails Phase III development for geographic atrophy

Genentech reported on November 9, 2017 that lampalizumab failed to meet the primary end point for reducing mean change in geographic atrophy (GA) lesion area compared with sham treatment at one year in CHROMA, its second Phase III trial in GA.1 Although these results are not unexpected given the announcement in September 2017 that lampalizumab did not show a significant effect on the primary end point in its first Phase III trial in GA (SPECTRI),2 they deal a blow to the AMD market, as the complement factor D inhibitor was the most advanced drug in active development for GA and was forecast to reach blockbuster sales in the G7 within a few years of its launch.3 Indeed, given the absence of any available treatments for GA, the most advanced type of dry AMD in which bilateral disease and visual impairment are common, interviewed retinal specialists and surveyed physicians had been hopeful that lampalizumab would provide the first therapeutic option for this underserved patient population.3,4 Results from the Phase II MAHALO study had previously demonstrated that monthly lampalizumab treatment significantly reduced mean change in lesion area relative to sham at 18 months, an effect that was enhanced in patients positive for a complement factor I (CFI) biomarker.5 However, as discussed at the American Academy of Ophthalmology 2017 Annual Meeting on November 10, 2017, no treatment effect was observed even in CFI biomarker positive patients in the SPECTRI trial.6 Although the full trial results have not yet been released from the CHROMA trial, Genentech has announced that based on the negative results from SPECTRI and CHROMA, they will not pursue regulatory approval of lampalizumab for GA,1 again delaying the launch of a treatment that could potentially slow vision loss for this patient population.

What do these results mean for other complement system inhibitors in development for GA?

Targeting complement pathways to treat GA is a logical therapeutic approach given that complement system dysregulation appears to be involved in the development of GA.7,8 However, lampalizumab’s Phase III failure now calls into question whether this target is likely to be effective for GA. However, other agents in development for GA target different factors in the complement pathways. For example, while complement factor D, as inhibited by lampalizumab, is a rate-limiting enzyme in the activation of the alternative complement pathway, Apellis Pharmaceuticals’ APL-2 inhibits complement component C3, a key regulator of the three complement pathways (classical, alternative, lectin), and Ophthotech’s Zimura inhibits complement component 5, a downstream factor in the complement cascade. Of note, positive efficacy results have been reported from APL-2’s Phase II trial in GA (FILLY); the agent demonstrated a significant reduction in GA area growth relative to sham at 12 months.9 These results will need to be confirmed in larger Phase III trials, which the company suggested could begin in 2018,10 but targeting a broader factor in the complement cascade may prove to be effective in GA (assuming that APL-2 also has an acceptable safety profile). Preliminary efficacy of Zimura in GA has been suggested from results of Phase I/IIa trial and the agent is currently being studied in a Phase IIb trial.11 Results from this trial are expected in the second half of 2019. Other agents in development for GA that target the complement system include Novartis’s CLG-561, an inhibitor of the positive regulatory factor properdin, which is being studied as a monotherapy and as a combination therapy with the complement factor D inhibitor LFG-316 (Novartis).

What other approaches are being evaluated for the treatment of GA?

Lampalizumab joins several other agents that have failed to show efficacy in GA, including the visual cycle modulator emixustat (Acucela),12 the amyloid beta inhibitor GSK933776 (GlaxoSmithKline),13 and the 5-HT1a receptor agonist AL-8309B (tandospirone; Novartis).14 However, therapeutic options other than complement system inhibitors are being investigated for GA, such as Allergan’s brimonidine tartrate intravitreal implant, an alpha-2 adrenergic receptor agonist, which has shown positive efficacy results in a Phase II trial in GA.14 Cell-based approaches are also an active area of development in GA. The continued interest in developing therapies for GA, despite recent developmental failures, provides hope that GA patients may eventually have options to slow disease progression and prevent vision loss.

References:

  1. Genentech, statement, November 9, 2017.
  2. Roche, press release, September 8, 2017.
  3. DRG’s Dry and Wet Age-Related Macular Degeneration | Disease Landscape & Forecast, 2017
  4. DRG’s Geographic Atrophy | Unmet Need (US/EU), 2017
  5. Williams DF, et al. Lampalizumab (anti-factor D) in Geographic Atrophy: the MAHALO Phase II Results. American Society of Retina Specialists 31st Annual Meeting; August 27, 2013; Toronto, Canada.
  6. Heier JS. Lampalizumab Phase III Trial for Geographic Atrophy Secondary to AMD, the Spectri Topline Results. AAO 2017. November 10, 2017; New Orleans, Louisiana.
  7. Boyer DS, et al. The Pathophysiology Geographic Atrophy Secondary to Age-Related Macular Degeneration and the Complement Pathway as a Therapeutic Target. Retina. 2017;37(5):819-835.
  8. Ambati J, et al. Immunology of Age-Related Macular Degeneration. Nat Rev Immunol. 2013;13(6):438–451.
  9. Apellis Pharmaceuticals, press release, August 24, 2017.
  10. Apellis Pharmaceuticals, company website, accessed November 15, 2017.
  11. Ophthotech, corporate overview, November 2017.
  12. Acucela, press release, May 25, 2016.
  13. Rosenfeld PJ. Results of a Phase 2 Study using an Anti-Amyloid Beta Monoclonal Antibody for the Treatment of Geographic Atrophy Secondary to Age-Related Macular Degeneration. AAO 2016. October 15, 2016; Chicago, Illinois.
  14. Jaffe GJ, et al. Randomized trial to evaluate tandospirone in geographic atrophy secondary to age-related macular degeneration: the GATE Study. Am J Ophthalmol. 2015;160:1226‒1234
  15. Freeman WR. Intravitreal Brimonidine Drug Delivery System (Brimonidine DDS) in Patients with Geographic Atrophy: A Phase 2 Study. AAO 2016. October 14, 2016; Chicago, Illinois.