Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration: A Nonrandomized Controlled Trial

Tiarnan D. L. Keenan; Clare Bailey; Maria Abraham; Christine Orndahl; Supriya Menezes; Sunil Bellur; Thilaka Arunachalam; Cathy Kangale-Whitney; Sowmya Srinivas; Ayesha Karamat; Muneeswar Nittala; Denise Cunningham; Brett G. Jeffrey; Henry E. Wiley; Alisa T. Thavikulwat; SriniVas Sadda; Catherine A. Cukras; Emily Y. Chew; Wai T. Wong

doi:10.1001/jamaophthalmol.2024.0118

Comment

Csaky 听K锘�, Ferris 听F 听III锘�, Chew 听EY锘�, Nair 听P锘�, Cheetham 听JK锘�, Duncan 听JL锘�. 听Report from the NEI/FDA Endpoints Workshop on age-related macular degeneration and inherited retinal diseases.听锘� 听Invest Ophthalmol Vis Sci. 2017;58(9):3456-3463. doi:

Apellis Pharmaceuticals. FDA approves SYFOVRE (pegcetacoplan injection) as the first and only treatment for geographic atrophy (GA), a leading cause of blindness. Accessed February 28, 2023.

Iveric Bio. Iveric Bio receives US FDA approval for IZERVAY (avacincaptad pegol intravitreal solution), a new treatment for geographic atrophy. Accessed August 11, 2023.

Liao 听DS锘�, Grossi 听FV锘�, El Mehdi 听D锘�, 听et al. 听Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial.听锘� 听翱辫丑迟丑补濒尘辞濒辞驳测. 2020;127(2):186-195. doi:

Jaffe 听GJ锘�, Westby 听K锘�, Csaky 听KG锘�, 听et al. 听C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial.听锘� 听翱辫丑迟丑补濒尘辞濒辞驳测. 2021;128(4):576-586. doi:

Mai 听J锘�, Lachinov 听D锘�, Riedl 听S锘�, 听et al. 听Clinical validation for automated geographic atrophy monitoring on OCT under complement inhibitory treatment.听锘� 听Sci Rep. 2023;13(1):7028. doi:

Pfau 听M锘�, Schmitz-Valckenberg 听S锘�, Ribeiro 听R锘�, 听et al. 听Association of complement C3 inhibitor pegcetacoplan with reduced photoreceptor degeneration beyond areas of geographic atrophy.听锘� 听Sci Rep. 2022;12(1):17870. doi:

Zhang 听Y锘�, Wong 听WT锘�. 听Innate immunity in age-related macular degeneration.听锘� 听Adv Exp Med Biol. 2021;1256:121-141. doi:

Allingham 听MJ锘�, Loksztejn 听A锘�, Cousins 听SW锘�, Mettu 听PS锘�. 听Immunological aspects of age-related macular degeneration.听锘� 听Adv Exp Med Biol. 2021;1256:143-189. doi:

10.

Fleckenstein 听M锘�, Keenan 听TDL锘�, Guymer 听RH锘�, 听et al. 听Age-related macular degeneration.听锘� 听Nat Rev Dis Primers. 2021;7(1):31. doi:

11.

Guillonneau 听X锘�, Eandi 听CM锘�, Paques 听M锘�, Sahel 听JA锘�, Sapieha 听P锘�, Sennlaub 听F锘�. 听On phagocytes and macular degeneration.听锘� 听Prog Retin Eye Res. 2017;61:98-128. doi:

12.

Fletcher 听EL锘�. 听Contribution of microglia and monocytes to the development and progression of age-related macular degeneration.听锘� 听Ophthalmic Physiol Opt. 2020;40(2):128-139. doi:

13.

Levy 听O锘�, Calippe 听B锘�, Lavalette 听S锘�, 听et al. 听Apolipoprotein E promotes subretinal mononuclear phagocyte survival and chronic inflammation in age-related macular degeneration.听锘� 听EMBO Mol Med. 2015;7(2):211-226. doi:

14.

Bharti 听K锘�, den Hollander 听AI锘�, Lakkaraju 听A锘�, 听et al. 听Cell culture models to study retinal pigment epithelium-related pathogenesis in age-related macular degeneration.听锘� 听Exp Eye Res. 2022;222:109170. doi:

15.

Handa 听JT锘�, Bowes Rickman 听C锘�, Dick 听AD锘�, 听et al. 听A systems biology approach towards understanding and treating nonneovascular age-related macular degeneration.听锘� 听Nat Commun. 2019;10(1):3347. doi:

16.

Soundara Pandi 听SP锘�, Ratnayaka 听JA锘�, Lotery 听AJ锘�, Teeling 听JL锘�. 听Progress in developing rodent models of age-related macular degeneration (AMD).听锘� 听Exp Eye Res. 2021;203:108404. doi:

17.

Schnichels 听S锘�, Paquet-Durand 听F锘�, L枚scher 听M锘�, 听et al. 听Retina in a dish: Cell cultures, retinal explants, and animal models for common diseases of the retina.听锘� 听Prog Retin Eye Res. 2021;81:100880. doi:

18.

Yrj盲nheikki 听J锘�, Kein盲nen 听R锘�, Pellikka 听M锘�, H枚kfelt 听T锘�, Koistinaho 听J锘�. 听Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia.听锘� 听Proc Natl Acad Sci U S A. 1998;95(26):15769-15774. doi:

19.

Yrj盲nheikki 听J锘�, Tikka 听T锘�, Kein盲nen 听R锘�, Goldsteins 听G锘�, Chan 听PH锘�, Koistinaho 听J锘�. 听A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window.听锘� 听Proc Natl Acad Sci U S A. 1999;96(23):13496-13500. doi:

20.

Kraus 听RL锘�, Pasieczny 听R锘�, Lariosa-Willingham 听K锘�, Turner 听MS锘�, Jiang 听A锘�, Trauger 听JW锘�. 听Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity.听锘� 听J Neurochem. 2005;94(3):819-827. doi:

21.

Pi 听R锘�, Li 听W锘�, Lee 听NT锘�, 听et al. 听Minocycline prevents glutamate-induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways.听锘� 听J Neurochem. 2004;91(5):1219-1230. doi:

22.

Shimazawa 听M锘�, Yamashima 听T锘�, Agarwal 听N锘�, Hara 听H锘�. 听Neuroprotective effects of minocycline against in vitro and in vivo retinal ganglion cell damage.听锘� 听Brain Res. 2005;1053(1-2):185-194. doi:

23.

Krady 听JK锘�, Basu 听A锘�, Allen 听CM锘�, 听et al. 听Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy.听锘� 听顿颈补产别迟别蝉. 2005;54(5):1559-1565. doi:

24.

Zhao 听L锘�, Ma 听W锘�, Fariss 听RN锘�, Wong 听WT锘�. 听Minocycline attenuates photoreceptor degeneration in a mouse model of subretinal hemorrhage microglial: inhibition as a potential therapeutic strategy.听锘� 听Am J Pathol. 2011;179(3):1265-1277. doi:

25.

Hughes 听EH锘�, Schlichtenbrede 听FC锘�, Murphy 听CC锘�, 听et al. 听Minocycline delays photoreceptor death in the rds mouse through a microglia-independent mechanism.听锘� 听Exp Eye Res. 2004;78(6):1077-1084. doi:

26.

Yang 听LP锘�, Li 听Y锘�, Zhu 听XA锘�, Tso 听MO锘�. 听Minocycline delayed photoreceptor death in rds mice through iNOS-dependent mechanism.听锘� 听Mol Vis. 2007;13:1073-1082.

27.

Garrido-Mesa 听N锘�, Zarzuelo 听A锘�, G谩lvez 听J锘�. 听Minocycline: far beyond an antibiotic.听锘� 听Br J Pharmacol. 2013;169(2):337-352. doi:

28.

Liefers 听B锘�, Colijn 听JM锘�, Gonz谩lez-Gonzalo 听C锘�, 听et al. 听A deep-learning model for segmentation of geographic atrophy to study its long-term natural history.听锘� 听翱辫丑迟丑补濒尘辞濒辞驳测. 2020;127(8):1086-1096. doi:

29.

Shen 听L锘�, Liu 听F锘�, Grossetta Nardini 听H锘�, Del Priore 听LV锘�. 听Natural history of geographic atrophy in untreated eyes with nonexudative age-related macular degeneration: a systematic review and meta-analysis.听锘� 听Ophthalmol Retina. 2018;2(9):914-921. doi:

30.

Yehoshua 听Z锘�, Rosenfeld 听PJ锘�, Gregori 听G锘�, 听et al. 听Progression of geographic atrophy in age-related macular degeneration imaged with spectral domain optical coherence tomography.听锘� 听翱辫丑迟丑补濒尘辞濒辞驳测. 2011;118(4):679-686. doi:

31.

Feuer 听WJ锘�, Yehoshua 听Z锘�, Gregori 听G锘�, 听et al. 听Square root transformation of geographic atrophy area measurements to eliminate dependence of growth rates on baseline lesion measurements: a reanalysis of age-related eye disease study report No. 26.听锘� 听JAMA Ophthalmol. 2013;131(1):110-111. doi:

32.

Wagner 听AK锘�, Soumerai 听SB锘�, Zhang 听F锘�, Ross-Degnan 听D锘�. 听Segmented regression analysis of interrupted time series studies in medication use research.听锘� 听J Clin Pharm Ther. 2002;27(4):299-309. doi:

33.

Fitzmaurice 听G锘�, Laird 听N锘�, Ware 听J锘�. 听Applied Longitudinal Analysis. Wiley; 2011. doi:

34.

Hariri 听A锘�, Heussen 听FM锘�, Nittala 听MG锘�, Sadda 听SR锘�. 听Optical coherence tomographic correlates of angiographic subtypes of occult choroidal neovascularization.听锘� 听Invest Ophthalmol Vis Sci. 2013;54(13):8020-8026. doi:

35.

Hu 听Z锘�, Medioni 听GG锘�, Hernandez 听M锘�, Hariri 听A锘�, Wu 听X锘�, Sadda 听SR锘�. 听Segmentation of the geographic atrophy in spectral-domain optical coherence tomography and fundus autofluorescence images.听锘� 听Invest Ophthalmol Vis Sci. 2013;54(13):8375-8383. doi:

36.

Evaluation of Oral Minocycline in the Treatment of Geographic Atrophy Associated With Age-Related Macular Degeneration. ClinicalTrials.gov identifier: NCT02564978. Updated September 23, 2022. Accessed July 7, 2023.

37.

Afrin 听A锘�, Cohen 听PR锘�. 听Doxycycline-associated hyperpigmentation: a case report and literature review.听锘� 听颁耻谤别耻蝉. 2022;14(4):e23754. doi:

38.

Rok 听J锘�, Rzepka 听Z锘�, Kowalska 听J锘�, Banach 听K锘�, Beberok 听A锘�, Wrze艣niok 听D锘�. 听Molecular and biochemical basis of minocycline-induced hyperpigmentation鈥攖he study on normal human melanocytes exposed to UVA and UVB radiation.听锘� 听Int J Mol Sci. 2021;22(7):3755. doi:

39.

Young 听K锘�, Pagan 听AD锘�, Yoon 听J锘�, 听et al. 听Differences in risk of tetracycline-associated hyperpigmentation between racial and ethnic groups in patients with acne vulgaris: a national US retrospective study.听锘� 听J Am Acad Dermatol. 2023;88(4):872-875. doi:

40.

Barrett 听T锘�, de Zwaan 听S锘�. 听Picosecond alexandrite laser is superior to Q-switched Nd:YAG laser in treatment of minocycline-induced hyperpigmentation: a case study and review of the literature.听锘� 听J Cosmet Laser Ther. 2018;20(7-8):387-390. doi:

41.

US Food and Drug Administration. Minocin (minocycline hydrochloride) pellet-filled capsules. Accessed June 12, 2023.

42.

Taylor 听PN锘�, Lansdown 听A锘�, Witczak 听J锘�, 听et al. 听Age-related variation in thyroid function鈥攁 narrative review highlighting important implications for research and clinical practice.听锘� 听Thyroid Res. 2023;16(1):7. doi:

43.

Kim 听MI锘�. Hypothyroidism in older adults. In: Feingold 听KR锘�, Anawalt 听B锘�, Blackman 听MR锘�, 听et al, eds. 听Endotext [Internet]. MDText.com; 2000.

44.

Sunness 听JS锘�, Margalit 听E锘�, Srikumaran 听D锘�, 听et al. 听The long-term natural history of geographic atrophy from age-related macular degeneration: enlargement of atrophy and implications for interventional clinical trials.听锘� 听翱辫丑迟丑补濒尘辞濒辞驳测. 2007;114(2):271-277. doi:

45.

Clinical Study to Evaluate Treatment With ORACEA for Geographic Atrophy (TOGA). ClinicalTrials.gov identifier: NCT01782989. Updated November 4, 2022. Accessed December 12, 2022.

46.

Holz 听FG锘�, Sadda 听SR锘�, Busbee 听B锘�, 听et al; Chroma and Spectri Study Investigators. 听Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri Phase 3 randomized clinical trials.听锘� 听JAMA Ophthalmol. 2018;136(6):666-677. doi:

47.

Keenan 听TD锘�, Agr贸n 听E锘�, Domalpally 听A锘�, 听et al; AREDS2 Research Group. 听Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16.听锘� 听翱辫丑迟丑补濒尘辞濒辞驳测. 2018;125(12):1913-1928. doi:

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Key Points

Question听 What are the safety and possible anatomic efficacy of oral minocycline, a microglial inhibitor, for the treatment of geographic atrophy (GA) in age-related macular degeneration (AMD)?

Findings听 In this phase 2 nonrandomized controlled trial that included 37 participants, the mean square root GA enlargement rate was 0.31 mm per year during the 9-month run-in phase and 0.28 mm per year during the 24-month treatment phase. The difference was not significant.

Meaning听 Results suggest that oral minocycline at this dose likely was not associated with slower rate of enlargement of GA in AMD.

Abstract

Importance听 Existing therapies to slow geographic atrophy (GA) enlargement in age-related macular degeneration (AMD) have relatively modest anatomic efficacy, require intravitreal administration, and increase the risk of neovascular AMD. Additional therapeutic approaches are desirable.

Objective听 To evaluate the safety and possible anatomic efficacy of oral minocycline, a microglial inhibitor, for the treatment of GA in AMD.

Design, Setting, and Participants听 This was a phase 2, prospective, single-arm, 45-month, nonrandomized controlled trial conducted from December 2016 to April 2023. Patients with GA from AMD in 1 or both eyes were recruited from the National Institutes of Health (Bethesda, Maryland) and Bristol Eye Hospital (Bristol, UK). Study data were analyzed from September 2022 to May 2023.

Intervention听 After a 9-month run-in phase, participants began oral minocycline, 100 mg, twice daily for 3 years.

Main Outcomes and Measures听 The primary outcome measure was the difference in rate of change of square root GA area on fundus autofluorescence between the 24-month treatment phase and 9-month run-in phase.

Results听 Of the 37 participants enrolled (mean [SD] age, 74.3 [7.6] years; 21 female [57%]), 36 initiated the treatment phase. Of these participants, 21 (58%) completed at least 33 months, whereas 15 discontinued treatment (8 by request, 6 for adverse events/illness, and 1 death). Mean (SE) square root GA enlargement rate in study eyes was 0.31 (0.03) mm per year during the run-in phase and 0.28 (0.02) mm per year during the treatment phase. The primary outcome measure of mean (SE) difference in enlargement rates between the 2 phases was 鈭�0.03 (0.03) mm per year (P鈥�=鈥�.39). Similarly, secondary outcome measures of GA enlargement rate showed no differences between the 2 phases. The secondary outcome measures of mean difference in rate of change between 2 phases were 0.2 letter score per month (95% CI, 鈭�0.4 to 0.9; P鈥�=鈥�.44) for visual acuity and 0.7 渭m per month (鈭�0.4 to 1.8; P鈥�=鈥�.20) for subfoveal retinal thickness. Of the 129 treatment-emergent adverse events among 32 participants, 49 (38%) were related to minocycline (with no severe or ocular events), including elevated thyrotropin level (15 participants) and skin hyperpigmentation/discoloration (8 participants).

Conclusions and Relevance听 In this phase 2 nonrandomized controlled trial, oral minocycline was not associated with a decrease in GA enlargement over 24 months, compared with the run-in phase. This observation was consistent across primary and secondary outcome measures. Oral minocycline at this dose is likely not associated with slower rate of enlargement of GA in AMD.

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