Eloxx Pharmaceuticals, Inc. · NASDAQ:ELOX
Eloxx Pharmaceuticals — Investor Presentation (August 2023)
54 slides from Eloxx Pharmaceuticals's investor presentation, Aug 21, 2023
Slide 1: RARE Thinking for RARE Solutions: Small Molecule Gene Therapy
RARE Thinking for RARE Solutions Small Molecule Gene Therapy August 2023
Slide 2: Forward-looking statements
/ 2 Forward-looking statements This presentation contains forward-looking statements, which are generally statements that are not historical facts. Forward-looking statements can be identified by the words "expects," "anticipates," "believes," "intends," "estimates," "plans," "will," "outlook" and s
Slide 3: Clinical stage small molecule gene therapy biopharma poised for value creation
/ 3 Clinical stage small molecule gene therapy biopharma poised for value creation Small molecule genetic therapies for nonsense mutations proven to restore full-length proteins ELX-02: Ready for Alport Syndrome pivotal study with biopsy confirmed disease regression. Preclinical POC in ADPKD* ZKN-01
Slide 4: Nonsense mutation overview and MOA of Eloxx therapies
/ 4 Nonsense mutation overview and MOA of Eloxx therapies Two clinical stage drugs designed to treat inherited diseases with nonsense mutations Truncated peptide chain = Loss of Function Premature stop codon (PTC) Nonsense Mutations Ribosome – Small sub-unit Clinical leads ELX-02 and ZKN-013 have de
Slide 5: Lead drugs designed for superior efficacy than proven readthrough antibiotics
/ 5 1Data adapted from: J Med Chem. 2012 Dec 13;55(23):10630-43.1; Lead drugs designed for superior efficacy than proven readthrough antibiotics Designer aminoglycosides: Eukaryotic ribosome selective glycosides (ERSGs) Designer macrolides: Ribosome modulating agents (RMAs) ERSGs designed for nonsen
Slide 6: Pipeline of potential first-in-class therapies for rare kidney and orphan diseases
/ 6 Indication Protein restored Discovery Lead optimization IND-enabling Phase 1 – first-in-human Phase 2 Class 1 CF: Cystic fibrosis patients with class1 mutations; RDEB/JEB: Recessive Dystrophic/Junctional Epidermolysis Bullosa; FAP: Familial adenomatous polyposis; PoC: Proof of concept; SC: Subcu
Slide 7: ELX-02: Alport Syndrome and ADPKD with Nonsense Mutations
/ 7 ELX -02: Alport Syndrome and ADPKD with Nonsense Mutations
Slide 8: Summary of ELX-02 nonsense mutation readthrough activity
/ 8 Summary of ELX-02 nonsense mutation readthrough activity Disease In vitro In vivo Organoids or Primary patient cells Patients Cystic fibrosis ✓ ✓ ✓ ✓ Cystinosis ✓ ✓ ✓ ✓ Alport syndrome ✓ ✓ ADPKD ✓ ✓ RDEB ✓ ✓ JEB ✓ ✓ DMD ✓ ✓ MPS ✓ ✓ Rett syndrome ✓ ✓ Inherited retinal disorders ✓ ✓ ADPKD: Autosom
Slide 9: Estimated human exposure in Plasma, Lung and Kidney
/ 9 Estimated human exposure in Plasma, Lung and Kidney at 1 mg/kg Estimation based on allometric scaling of mouse, rat and dog plasma and kidney data PLUS plasma PK from SAD and MAD studies Source: d1pbpk\pbpk\cognigen\2018-01-30-pbpk-elx02-refined-simulation\listing-ratio-auc168ss-human-bytissue.r
Slide 10: Alport syndrome nonsense mutation disease overview
/ 10 • Inherited glomerular kidney disease caused by defect in Col4 gene – X-linked in 85% - Col4A5 gene – Recessive in ~15% - Col4A3/4 genes • Nonsense mutations result in truncated proteins resulting in worse outcomes – Over 70 nonsense mutations in Alport described • No approved therapies – Limit
Slide 11: Alport syndrome disease progression and clinical manifestation
/ 11 Alport syndrome disease progression and clinical manifestation Glomerular and podocyte injury leads to proteinuria and hematuria resulting in loss of kidney function Progressive podocyte damage/loss of basement membrane from COL4A3, A4 or A5 mutations Podocyte foot process effacement (loss) lea
Slide 12: Preclinical studies in Cystinosis and Alport
/ 12 Preclinical studies in Cystinosis (ELX-02) and Alport (COL4A3 replacement) Kidney cystine levels in CTNSY226X/Y226X mice after 3-week ELX-02 treatment1 COL IV A3 bone marrow treatment of C57BL/6 Alport mice over 3 weeks2 1PLoS One 2019 Dec 4;14(12); Bi-weekly treatment with ELX-02 of Cystinosis
Slide 13: Alport Phase 2 POC trial design
/ 13 Study Start (2H 2022) Alport Phase 2 POC trial designed to show evidence for proteinuria reduction and disease regression Inclusion Parameters Criteria Genotype Any patient with nonsense mutations in the Col4 gene except UAA Age All patients >6 years eGFR >60ml/min/1.73m2 BSA Proteinuria >500mg
Slide 14: Proteinuria remission rate likely approvable endpoint
/ 14 1AJKD Vol75 Issue1 4-5 January 2020 Proteinuria remission rate likely approvable endpoint reflecting glomerular repair in Alport Definition of remission and rationale “FDA has already accepted [for a number of primary glomerular diseases] complete remission” or near-“normalization” of proteinur
Slide 15: Baseline characteristics of patients in Phase 2
/ 15 Baseline characteristics of patients in Phase 2 Patient Age Sex COl4 Gene Affected Nonsense Mutation RAAS Block dose Cr (mg/dL) Proteinuria (mg/g) 4401-01 13 Male COL4A4 c.2906C>G*; p.Ser969X Enalapril 2.5 mg QD 0.7 1299 4401-02 13 Male COL4A4 c.2906C>G*; p.Ser969X Enalapril 32.5 mg QD 0.5 1646
Slide 16: Alport patient ages in trial consistent with RaDaR registry
/ 16 Alport patient ages in trial consistent with data from RaDaR registry for those with truncated COL IV A4 proteins
Slide 17: High proteinuria at baseline consistent with RaDaR data
/ 17 High proteinuria at baseline also consistent with RaDaR data suggesting worst renal outcomes
Slide 18: Phase 2 Alport patient results
/ 18 Phase 2 Alport patient results 539 678 1,299 1,646 1,659 1,799 850 2,209 2328 1169 1236 0 500 1000 1500 2000 2500 3000 3500 4401-01 4401-02 4402-01 Urine Protein/Urine Creatinine (mg/g) -1 year Baseline Average of treatment period* Average 3 months post end of treatment * UPCR averaged over 6 v
Slide 19: TEM assessment of podocyte foot process effacement in kidney biopsies
/ 19 Transmission electron microscopy (TEM) assessment of podocyte foot process effacement in kidney biopsies of all patients in Phase 2 trial Patient Pre-treatment podocyte foot process effacement Post-treatment podocyte foot process effacement 4401-01 Widespread foot process effacement present Seg
Slide 20: TEM sample images from kidney biopsies of patient 4401-02
/ 20 TEM sample images from kidney biopsies of patient 4401-02 Pre-treatment: Widespread podocyte foot process effacement Post-treatment (Day 60): Segmental podocyte foot process effacement TEM images and analysis done at Mayo Clinic by kidney pathologist on a blinded basis Responder biopsies shows
Slide 21: TEM sample images from kidney biopsies from patient 1-01
/ 21 TEM sample images from kidney biopsies from patient 4401-01 Pre-treatment: Widespread podocyte foot process effacement Post-treatment (Day 60): Segmental podocyte foot process effacement TEM images and analysis done at Mayo Clinic by kidney pathologist on a blinded basis Improvement in podocyte
Slide 22: TEM sample images from kidney biopsies from patient 2-01
/ 22 TEM sample images from kidney biopsies from patient 4402-01 Pre-treatment: Widespread podocyte foot process effacement Post-treatment (Day 60): Segmental podocyte foot process effacement TEM images and analysis done at Mayo Clinic by kidney pathologist on a blinded basis Improvement in podocyte
Slide 23: Proteinuria (UPCR) change in patient 4401-02
/ 23 Proteinuria (UPCR) change in patient 4401-02 1,646 845 707 2,938 1,028 1,816 1,554 1,169 0 500 1000 1500 2000 2500 3000 3500 4000 Baseline Week 2 Week 4 Week 6 Week 8 week 12 (f/u) week 16 (f/u) Week 20 (f/u) Urine protein/Cr (mg/G) * UPCR averaged over 6 values collected in 8 weeks. UPCR value
Slide 24: Cumulative ELX-02 safety experience across all clinical studies
/ 24 Cumulative ELX-02 safety experience across all clinical studies *Patient had an undisclosed history of tinnitus SAE: Serious adverse events Robust safety experience for advancing to longer treatment duration in pivotal study No ELX-02 related SAEs in Phase 1 and 2 studies at doses up to 7.5 mg/
Slide 25: ELX-02 has potential as first gene therapy for Alport patients with nonsense mutations
/ 25 ELX-02 has potential as first gene therapy for Alport patients with nonsense mutations ELX-02 development in Alport and supported by robust preclinical data / 24 Alport patients with truncated proteins have poor renal outcomes and those with 2xCol4A3/4 having worst outcomes High unmet need in A
Slide 26: Alport success opens potential for expansion into other renal diseases
/ 26 Source: Torra et al, UGA hopping: a sport for nephrologists too? Nephrol Dial Transplant (2010) 25: 2391–2395 Alport success opens potential for expansion into other renal diseases Substantial unmet need remains in multiple renal diseases with high rates of nonsense mutations
Slide 27: Rationale for nonsense readthrough therapy in ADPKD
/ 27 Rationale for nonsense readthrough therapy in ADPKD Relative survival of nonsense vs other PKD1 mutant patients • Autosomal Dominant Polycystic Kidney Disease (ADPKD): – Most common genetic kidney disease with >100k patients in US – Progressive cystic growth and transformation of kidneys and ot
Slide 28: Renal plasticity revealed through reversal of polycystic kidney disease in mice
/ 28 Ke Dong, , et. A, l Nature Genetic 53, 1649-1663, 2021 Expression of PKD2 reverses cyst formation: Kidney weight, cystic index and BUN Normal Untreated 13 weeks Untreated 16 weeks After 1 week treatment After 3 week treatment Renal plasticity revealed through reversal of polycystic kidney disea
Slide 29: ELX-02 mediated read-through in nonsense mutant PKD1 and PKD2 organoids
/ 29 ELX-02 mediated read-through in nonsense mutant PKD1 and PKD2 organoids* *Data generated in collaboration with Freedman lab at University of Washington. Single organoids transferred to suspension culture 96-well plates. Treatment is initiated and cyst formation monitored over 14 days. Compellin
Slide 30: ZKN-013: RDEB and FAP
/ 30 ZKN-013: RDEB and FAP
Slide 31: Preclinical activity of ZKN-013
/ 31 Preclinical activity of ZKN-013 Disease Gene Mutations evaluated Model Results Cystic Fibrosis (CF) CFTR G542X ex vivo ZKN-013 = ELX-02 Recessive Dystrophic Epidermolysis bullosa (RDEB) COL7A1 Q251X, R578X, R613X, R1683X, R2610X ex vivo ZKN-013 > Gentamicin Junctional Epidermolysis Bullosa (JEB
Slide 32: RDEB and JEB disease overview
/ 32 RDEB and JEB: recessive dystrophic and junctional epidermolysis bullosa Disease overview 1 International database of DEB patients with COL7A1 mutations: https://deb-central.org/ 2 Varik.et.al. 2006. J. Med. Genet 43: 641 RDEB/JEB are rare skin diseases frequently caused by nonsense mutations in
Slide 33: COL VII protein restoration with gentamicin
/ 33 COL VII protein restoration with gentamicin 1 Cogan et al., Molecular Therapy (2014) 2 Woodley, DT. J Clin Investig 2017, 127, 3028-3038 RDEB: Recessive Dystrophic Epidermolysis Bullosa Gentamicin restored COL VII in RDEB patient cells and showed clinical benefit Total blistering events at 3 mo
Slide 34: ZKN-013 treatment of primary patient fibroblasts
/ 34 ZKN-013 treatment of primary patient fibroblasts1 COL VII protein expression in R578X/R578X RDEB fibroblasts with ZKN-0132 R578X/R578X patient fibroblast motility after ZKN-013 treatment3 1Fibroblasts derived from patients in Woodley et al. J Clin Invest. 2017. 248 hours treatment with media an
Slide 35: FAP nonsense mutation market opportunity
/ 35 FAP patients in the US and Europe by mutation type1,2 FAP nonsense mutation market opportunity 1 Orphanet Journal of Rare Diseases 2009, 4:22 doi:10.1186/1750-1172-4-22 2 https://doi.org/10.1016/j.critrevonc.2006.07.004 FAP: Familial adenomatous polyposis; APC: Adenomatous polyposis coli FAP is
Slide 36: Results of treatment of APCmin mice (FAP model) with ZKN-013
/ 36 Results for 8 weeks of treatment of APCmin mice (FAP model) with ZKN0131 1Study conducted at CRO FAP: Familial adenomatous polyposis; APC: Adenomatous polyposis coli Change in survival post treatment (n=10)1 Intestinal polyp number and polyp burden post treatment (n=10)1 0.00 0.25 0.50 0.75 1.0
Slide 37: Exposure at NOAEL of ZKN-013 in rat
/ 37 Exposure at no adverse effect level (NOAEL) of ZKN-013 in rat Skin exposure at NOAEL in 14-day non-GLP rat oral DRF study Summary of preclinical safety findings • Rats and dogs chosen as tox species based on comparable protein binding, in vitro metabolism and drug stability in hepatocytes • NOA
Slide 38: Value creation potential
/ 38 Value creation potential
Slide 39: Estimated peak sales potential of current rare disease clinical programs
/ 39 Estimated peak sales potential of current rare disease clinical programs, $M 1Recent orphan US drug pricing range from $300K to $570K for orphan drugs and >$800K for gene therapy drugs Substantial potential of three clinical stage programs leading with Alport syndrome 2,600 10,950 2,700 650 700
Slide 40: Examples of US rare disease drug pricing
/ 40 Examples of US rare disease drug pricing Strong rare disease drug pricing supports estimated sales potential 300 621 370 485 535 Trikafta (Cystic Fibrosis) Vyjuvek (Dystrophic Epidermolysis Bullosa) Skyclaris (Fredrich’s Ataxia) Naglazyme (MPS Type VI)* Soliris (PNH, others)* Estimated US prici
Slide 41: Multiple upcoming milestones in remainder of 2023
/ 41 •IND Submission •End of Phase 2 FDA meeting • Full results from Phase 2 •Initiate pivotal trial RDEB/JEB: Recessive Dystrophic/Junctional Epidermolysis Bullosa; FAP: Familial adenomatous polyposis Multiple upcoming milestones in remainder of 2023 1H 2023 2H 2023 Alport Syndrome (SC ELX-02) ✓Enr
Slide 42: Clinical stage small molecule gene therapy biopharma poised for value creation
/ 42 Clinical stage small molecule gene therapy biopharma poised for value creation Small molecule genetic therapies for nonsense mutations proven to restore full-length proteins ELX-02: Ready for Alport Syndrome pivotal study with biopsy confirmed disease regression. Preclinical POC in ADPKD* ZKN-0
Slide 43: Eloxx Pharmaceuticals
a Eloxx PHARMACEUTICALS Eloxx
Slide 44: Appendix
/ 44 Appendix
Slide 45: Results from Phase 2 trial in CF patients with ELX-02 and Ivacaftor
/ 45 Results from Phase 2 trial in CF patients with ELX-02 1.5mg/kg daily and Ivacaftor Biological activity: Change in sweat chloride vs. baseline sweat chloride Clinical efficacy: Change in ppFEV1 (%) at end of treatment and safety follow up ELX-02 efficacy and biologically activity in CF patients
Slide 46: ELX-02 readthrough COL4A5 nonsense mutation in HEK293 cells
/ 46 ELX-02 readthrough COL4A5 nonsense mutation in HEK293 cells at 24 hours1 1 doi: https://doi.org/10.1101/2021.06.11.448099: Experiment conducted at Washington University by Dr. Jeff Miner 2 additional mutations tested in same system and lab at Washington university High levels COL IV protein res
Slide 47: Treatment effect of COL IV protein restoration in Alport mouse studies
/ 47 Treatment effect of COL IV protein restoration in Alport mouse studies COL IV A3 bone marrow treatment of C57BL/6 Alport mice over 3 weeks1 Single dose exon skipping therapy in nonsense mutation Alport mouse2 1 ..JASN November 2009, 20 (11) 2359-2370. Wild type (WT) Bi-weekly COL4A3 +/- bone ma
Slide 48: Proteinuria change in patient 4401-01 and 4402-01
/ 48 Proteinuria change in patient 4401-01 and 4402-01 Patient 4401-01 UPCR change over treatment Patient 4402-01 UPCR change over treatment 1,659 1,403 3,522 1,828 2,635 1,280 1,194 0 500 1000 1500 2000 2500 3000 3500 4000 Baseline Week 2 Week 4 Week 6 Week 8 Week 12 f/u week 16 f/u Urine protein/C
Slide 49: TEM sample images from kidney biopsies of patient 4401-02
/ 49 TEM sample images from kidney biopsies of patient 4401-02 Pre-treatment: Widespread podocyte foot process effacement Post-treatment (Day 60): Segmental podocyte foot process effacement TEM images and analysis done at Mayo Clinic by kidney pathologist on a blinded basis Responder biopsies shows
Slide 50: Disease regression in all patients and 33% proteinuria remission rate in Phase 2
/ 50 Disease regression in all patients and 33% proteinuria remission rate in Phase 2 supports advancing to pivotal study Inclusion Parameters Criteria Genotype Any patient with nonsense mutations in the COL4 gene Age All patients >6 years eGFR >45ml/min/1.73m2 BSA Proteinuria >300mg/g N = 16 ELX-02
Slide 51: Treatment effect on iPSC model harboring PKD2 nonsense mutation R186X
/ 51 Treatment effect on iPSC model harboring PKD2 nonsense mutation R186X* iPSC cells treated with ELX-02** Cyst burden reduction when treated with ELX-02** *Presented at ASN Kidney Week 2021. ABSTRACT: TH-OR39 November 04, 2021 | Location: Simulive, Virtual Only Abstract Time: 04:30 PM - 06:00 PM
Slide 52: PKD1 mutant organoids treated with ELX-02
/ 52 PKD1 mutant organoids treated with ELX-02 for 14 days* *Data generated in collaboration with Freedman lab at University of Washington. ELX-02 treatment of ADPKD kidney organoids results in increase PKD1 protein levels
Slide 53: ELX-02 reduced cyst formation and growth in ADPKD organoid models
/ 53 ELX-02 mediated read-through in nonsense mutant PKD1 and PKD2 organoids* *Data generated in collaboration with Freedman lab at University of Washington. Single organoids transferred to suspension culture 96-well plates. Treatment is initiated and cyst formation monitored over 14 days. ELX-02 re
Slide 54: ELX-02 inhibits growth of pre-existing cysts in ADPKD organoids
/ 54 ELX-02 mediated read-through in nonsense mutant PKD1 and PKD2 organoids* *Data generated in collaboration with Freedman lab at University of Washington. Single organoids transferred to suspension culture 96-well plates. Treatment is initiated and cyst formation monitored over 14 days. ELX-02 tr
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