Emerging treatments for Leber Hereditary Optic Neuropathy and Retinitis Pigmentosa

Abstract

Leber Hereditary Optic Neuropathy (LHON) and Retinitis Pigmentosa (RP) are rare inherited diseases which can lead to blindness, with limited treatment available. The aim of this study was to understand emerging patterns in clinical development programs (CDPs) being pursued by pharmaceutical companies when developing safe and effective innovative medicines to treat LHON and RP. Medicinal products (MPs) authorised within the EU to treat LHON and RP were retrieved from the European Medicines Agency (EMA) website. Investigational medicinal products (IMPs) to treat LHON and RP were retrieved from the EU Clinical Trials (EudraCT) Register and from the United States national library of medicines (USNML) database of clinical trials (CTs). CTs included in the study were those which were (i) carried out between 2006 and 2018, (ii) interventional and (iii) performed on MPs. Prospective treatment protocols were proposed for LHON and RP based on emerging MPs. Emerging patterns in primary endpoints of CTs were identified and compared. Regulatory pathways available within the EU to support the development and authorisation of orphan MPs were reviewed. Idebenone (Raxone) is the only small molecule MP authorised in the EU to treat LHON. Voretigene neparvovec-rzyl (Luxturna) is the only gene therapy MP authorised in the EU to treat RP caused by mutation RPE65. Twenty-three CTs for 9 IMPs for LHON were included. Out of 9 IMPs, 6 were small molecules and 3 were advanced therapy medicinal products (ATMPs) (2 gene therapy and 1 somatic therapy). Forty-nine CTs for 24 IMPs for RP were included. Out of 24 IMPs, 14 were ATMPs (8 gene therapy and 6 somatic therapy), 8 were small molecules and 2 were growth factors. IMPs in phase II and phase III stage of development were included in the treatment protocols. Five MPs (3 small molecules and 2 ATMPs) were included in the proposed treatment protocol for LHON. The included MPs for LHON were idebenone (Raxone), cysteamine bitartrate, EPI-743, autologous bone marrow stem cells and GS010. Twelve MPs (5 small molecules, 6 ATMPs and 1 growth factors) were included in the proposed treatment protocol for RP. The included MPs for RP were QLT091001, valproic acid, brimonidine tartrate, levodopa-carbidopa, fluocinolone acetonide, voretigene neparvovec-rzyl (Luxturna), CPK850, AAV-RPGR, jCell, bone marrow-derived mesenchymal stem cells, autologous bone marrow-derived mononuclear stem cells and NT-501. The most common endpoints studied in CTs were change in visual acuity (N=6) for LHON and change in visual field (N=8) for RP. Raxone was authorised under exceptional circumstances for LHON in 2015 and protocol assistance was requested during its development. Luxturna was granted a full marketing authorisation for RP in 2018 after protocol assistance was requested two times during its development. Three main patterns have been observed (i) the number of CTs carried out to evaluate ATMPs is increasing from 2009, when the first CT was carried out to evaluate ATMPs for both LHON and RP (ii) specific mutations are being addressed through the development of gene therapy MPs (e.g. rAAV2-ND4 for LHON and voretigene neparvovec-rzyl for RP) and small molecules (e.g. QLT091001 for RP) (iii) the number of regulatory pathways to support companies developing orphan MPs is increasing to help speed the authorisation of drugs for unmet medical needs. Advances in research of MPs to treat LHON and RP are being made, but an unmet medical need is still present.