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Renewed Momentum in Ocular Gene and Cell Therapy, Broadening Application to Chronic Diseases

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Renewed Momentum in Ocular Gene and Cell Therapy, Broadening Application to Chronic Diseases FEATURE Renewed momentum in ocular gene and cell therapy, broadening application to chronic diseases BY ROD MCNEIL Gene and cell therapies offer the prospect of ground-breaking new avenues for the treatment of diseases, reflected in a renewed explosion of interest and investment in retinal gene therapy. Rod McNeil reports recent clinical trial readouts across a diverse range of investigational ocular gene and cell therapy candidates. ene therapy is literally giving transfer clinical trials to date involving (VA) at 24 months in patients treated with sight to children who would subretinal and intravitreal delivery. The timrepigene emparvovec compared with otherwise not see,” said Dr majority of these studies use an adeno- untreated patients in the natural history GJean Bennett, delivering the associated virus (AAV) vector. study. At two years over 90% of patients “ treated with timrepigene emparvovec Charles L Schepens MD Lecture jointly with Prof Albert Maguire at the American Gene therapy for choroideremia maintained VA. In a subset of treated Academy of Ophthalmology 2019 Retina Investigational gene therapy timrepigene patients with moderate to severe VA loss, Subspecialty Day. Dr Bennett has developed emparvovec (BIIB111/AAV2-REP1, Biogen) 21% experienced a VA improvement of at gene transfer approaches to test treatment is an AAV2 vector administered by least 15 letters from baseline compared with strategies for retinal degenerative and subretinal injection being evaluated as a 1.0% of untreated patients. ocular neovascular diseases and her work treatment for choroideremia (CHM). Biogen led to the first approved gene therapy announced November 2019 completion GenSight Biologics targets novel product targeting a retinal disease of patient enrolment in the global phase gene therapies for LHON and worldwide.” 3 STAR clinical trial of 170 adult males retinitis pigmentosa patients Gene therapy has definitely arrived. There with CHM evaluating treatment with a GenSight Biologics’ lead gene therapy are currently at least five different retinal single subretinal injection of timrepigene candidate is a recombinant adeno- gene therapy phase 3 trials active and many emparvovec. Data from the proof-of- associated viral vector serotype 2 containing more planned, with more than 30 clinical concept phase 1/2 studies demonstrate the wild-type NADH Dehydrogenase 4 sites with ~1167 patients enrolled in gene a slower rate of decline in visual acuity (ND4) gene (rAAV2/2-ND4, GS010) being investigated for the treatment Leber Figure",'! 1: Gene therapy to%!"$ produce working mRNA, with MTS*&$! ! Hereditary Optic Neuropathy (LHON). technology "!! !%! to shuttle mRNA directly! to affected!( mitochondria. GS010 targets LHON via a mitochondrial targeting sequence (MTS) proprietary technology platform, which, when associated with the gene of interest, allows the platform to specifically address defects inside the mitochondria using an AAV "! vector (Figure 1). Based on results from two pivotal phase 3 clinical trials, GenSight expects to submit an application for marketing approval in Europe in the third quarter of 2020. ! " # $ Results at 96 weeks (n-39) from the RESCUE phase 3 clinical trial in 39 subjects %%#$& 0%*! 0%*! *+%(0%*! (%'% # % % # # % % #!# %$ with LHON due to the ND4 mutation with (0%*!% # %#$#% !% % ! *$ $ %#$ %$% &&$ %%% % # +(#% an onset of vision loss up to six months % #$&#+ ! % prior to study treatment showed a durable (#!# %$*%$$ "! &#$ bilateral improvement in VA of 25.0 ETDRS letters equivalent versus nadir (i.e. worst best corrected visual acuity (BCVA) after *MTS3 :% = mitochondrial #%#%$"& targeting sequence baseline, up to the week of interest) in &#,% $- Source: GenSight Biiologics. GS010-treated eyes. Sixty-three percent Eye News | FEBRUARY/MARCH 2020 | VOL 26 NO 5 | www.eyenews.uk.com "-' ,)-!!* "! ' " !#!! ! %!! $!( #$! $$19/92(#% #& 8 %$%#% $ ))1/$!1$# +FEATURE 7& 7&,',/1+ *-!(/$# "-' ,)-!!* "! ' " !#!! ! "2(16 %!!Figure 2: Sepofarsen $! phase( 1/2 trial top-line results: sustained improvement in BCVA of subjects achieved a ‘clinically relevant for#$! at $$19/92( least one year#% in patients #&with LCA. 8 %$%#% $ recovery’ (CRR) from nadir in at least one All responses (7/7) were maintained for a minimum of six months after a maintenance dose. eye at week 96, while in the REVERSE03- # phase ))1/$!1$# + 7& 7&,',/1+ /2/1'00/2/)'00< 3 clinical trial in LHON subjects,& the rate of 14357'27 /,,+5+2)+ *-!(/$# 3- # CRR from nadir was 78%, significantly/2 better "2(16 outcomes than the natural history (~28%) in 03- # '6+0/2+ any prior studies [1]. Clinically significant and /2/1'00/2/)'00< & 14357'27 /,,+5+2)+ sustained bilateral visual improvement with 3- # /2 ,531( unilateral GS010 gene therapy was observed, '6+0/2+ with a non-clinical study demonstrating.'2-+ presence of GS010 DNA in the untreated ,531( *-/,3$# .'2-+ contralateral eye. "2(16 *-/,3$# Optogenetics is a neuromodulation "2(16 technique that uses light to control cells that have been genetically modified to express LCA, Leber’s congenital amaurosis. %5+'7+%5+'7+*+<+*+<+3275'0'7+5'% 3275'0'7+5'0+<+ % 0+<+ light-sensitive ion channels. GenSight’s + #.$Source: ProQR %&# Therapeutics. $$- + #.$ %&# $$- &#, # #!&%$- ".' ,)-!!*%!!! $! GS030-DP is an optogenetic &#, # gene#!&%$- therapy Figure 3: Sepofarsen phase 1/2 trial top-line efficacy data in patients with LCA. !% ( & ( '% targeting retinal ganglion cells, encoding Target registration dose level: 160µg/80µg (n=6) an optimised form of channelrhodopsin, ChrimsonR, ChR-tdT, which is administered /,2-*$!+ /$!1$# $6$ ,+1/!)!1$/!)$6$ via a modified AAV2 vector (AAV2.7m8). & 3- # " 96 ('6+0/2+ "!$96 ('6+0/2+ A medical device GS030-MD (stimulating goggles) processes special ‘event’ images of $%#+*3- " 96 ('6+0/2+ "!$96 ('6+0/2+ the visual world, modulating a light source $%08+ 3- projected onto the retina in real time. " 96 ('6+0/2+ "!$96 ('6+0/2+ An ongoing multicentre phase 1/2 study 3(/0/7<0+9+06 (PIONEER) will evaluate the safety and " 96 ('6+0/2+ " 96 ('6+0/2+ tolerability of escalating intravitreal doses Significance assessed by mixed effects repeated measures model of GS030-DP and repeated light stimulation $/-2/,/)'2)+'66+66+*(<1/;+* +,,+)765+4+'7+* 1+'685+6 13*+0 LCA, + #.$ Leber’s %&# congenital $$- amaurosis. in subjects with end-stage non-syndromic Source: &#, # ProQR #!&%$- Therapeutics. retinitis pigmentosa [2]. GenSight believes Sepofarsen for Leber address the underlying cause of Leber’s this technology offers the possibility of congenital amaurosis congenital amaurosis 10 (LCA10) due to the application to other retinal diseases where p.Cys998X mutation in the CEP290 gene. Intravitreal sepofarsen (QR-110, ProQR photoreceptors have degenerated, and may Top-line results from a phase 1/2 dose be transferable to the dry form of age- Therapeutics) is an investigational range finding trial of sepofarsen in patients related macular degeneration (AMD). RNA-based oligonucleotide designed to with LCA10 due to the p.Cys998X mutation Table 1: Clinical trials of gene therapy for LCA-RPE65. NCT Sponsor Sites Phase N target N recruited NCT00643747 UCL Moorfields Eye Hospital 1/2 12 12 AAV2 NCT00516477 Spark Therapeutics The Children’s Hospital of Philadelphia (CHOP) 1 12 12 AAV2 NCT00481546 CHOP CHOP, Univ Florida 1 15 15 AAV2 NCT01208389 Spark Therapeutics CHOP 1 12 12 AAV2 NCT00999609 Spark Therapeutics CHOP/Univ Iowa 3 30 31 AAV2 NCT02781480 MeiraGTx Moorfields Eye Hospital/Kellog Eye Center 1/2 15 15 AAV2/5- OPTIRPE65 NCT00821340 Hadassah Med Hadassah Med 1 10 3 AAV2 NCT00749957 Applied Genetic Casey Eye Institute/Univ Massachusetts 1/2 12 12 AAV2 Technologies NCT01496040 Univ Nantes Nantes University Hospital 1/2 9 9 AAV2/4 Eye News | FEBRUARY/MARCH 2020 | VOL 26 NO 5 | www.eyenews.uk.com FEATURE "/' ,)- * 10( Figure 4: Phase 1/2 trial of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ource: MeiraGTx. &#, #)- in the CEP290 gene show that the target AAV2/5-OPTIRPE65 gene Data suggest treatment with AAV2/5- registration dose (80µg with a 160µg loading therapy for RPE65-associated OPTIRPE65 improves functional vision, dose) was associated with a clinically retinal dystrophy retinal function and central vision. meaningful and statistically significant RPE65-deficiency causes impaired rod Through 24 weeks, statistically significant improvement in vision and had a favourable photoreceptor function from birth and improvement in vision-guided mobility benefit / risk profile (Figures 2 and 3). slowly progressive retinal degeneration, was observed in all treated subjects (study Further, a six-month dosing frequency was with outer retinal degeneration by the eye vs. fellow eye) [4]. Over the six-month associated with durable improvements third decade (Table 1). AAV2/5-OPTIRPE65 period, retinal sensitivity in treated eyes (MeiraGTx) consists of an AAV vector in vision, and the response observed at 12 improved
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