SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event
(Exact name of registrant as specified in its charter)
(State or other jurisdiction
|(Address of principal executive offices)||(Zip Code)|
(Registrant’s telephone number,
including area code): (
(Former name or former address, if changed since last report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
|Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)|
|Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)|
|Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))|
|Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))|
Securities registered pursuant to Section 12(b) of the Act:
|Title of each class||Trading Symbol(s)||Name of each exchange on which registered|
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ¨
Cautionary Statement Regarding Forward-Looking Statements
This Current Report on Form 8-K 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 similar expressions. Forward-looking statements are based on management's current plans, estimates, assumptions and projections, and speak only as of the date they are made. We undertake no obligation to update any forward-looking statement in light of new information or future events, except as otherwise required by law. Forward-looking statements involve inherent risks and uncertainties, most of which are difficult to predict and are generally beyond our control. Actual results or outcomes may differ materially from those implied by the forward-looking statements as a result of the impact of a number of factors, including: the Company’s ability to execute and effect its restructuring program; the development of the Company’s read-through technology; the approval of the Company’s patent applications; the Company’s ability to successfully defend its intellectual property or obtain necessary licenses at a cost acceptable to the Company, if at all; the successful implementation of the Company’s research and development programs and collaborations; the Company’s ability to obtain applicable regulatory approvals for its current and future product candidates; the acceptance by the market of the Company’s products should they receive regulatory approval; the timing and success of the Company’s preliminary studies, preclinical research, clinical trials, and related regulatory filings; the ability of the Company to consummate additional financings as needed; the impact of global health concerns, such as the COVID-19 global pandemic, on our ability to continue our clinical and preclinical programs and otherwise operate our business effectively; the successful integration of acquired companies, such as Zikani Therapeutics; as well as those discussed in more detail in our Annual Report on Form 10-K and our other reports filed with the Securities and Exchange Commission.
|Item 7.01.||Regulation FD Disclosure.|
We are furnishing this Current Report on Form 8-K in connection with the disclosure of information from a PowerPoint presentation for use, in whole or in part, at meetings with investors, analysts and other persons. This information may be amended, modified or updated at any time and from time to time through another Current Report on Form 8-K, a later Company filing, or other means, as management of the Company determines.
We do not have, and expressly disclaim, any obligation to release publicly any updates or any changes in our expectations or any change in events, conditions, or circumstances on which any forward-looking statement contained in the presentation is based.
The presentation included with this Current Report on Form 8-K is available on our website located at www.eloxxpharma.com, although we reserve the right to discontinue that availability at any time.
The information presented in Item 7.01 of this Current Report on Form 8-K and Exhibit 99.1 shall not be deemed to be “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, unless the Company specifically states that the information is to be considered “filed” under the Exchange Act or specifically incorporates it by reference into a filing under the Securities Act of 1933, as amended, or the Exchange Act. By filing this Current Report on Form 8-K and furnishing the information contained herein, the Company makes no admission as to the materiality of any information in this report that is required to be disclosed solely by reason of Regulation FD.
|Item 9.01.||Financial Statements and Exhibits.|
|99.1||Presentation Slide Deck April 2021.|
Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|ELOXX PHARMACEUTICALS, INC.|
|Date: April 20, 2021||By:|
|Name:||Neil S. Belloff|
Chief Operating Officer, General Counsel
and Corporate Secretary
RARE Thinking for RARE Solutions Creating a World Leader in Ribosome Targeted Genetic Therapies April 2021
/ 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 similar expressions . Forward - looking statements are based on management's current plans, estimates, assumptions and projections, and speak only as of the date they are made . We undertake no obligation to update any forward - looking statement in light of new information or future events, except as otherwise required by law . Forward - looking statements involve inherent risks and uncertainties, most of which are difficult to predict and are generally beyond our control . Actual results or outcomes may differ materially from those implied by the forward - looking statements as a result of the impact of a number of factors, including : the development of the Company’s readthrough technology ; the approval of the Company’s patent applications ; the Company’s ability to successfully defend its intellectual property or obtain necessary licenses at a cost acceptable to the Company, if at all ; the successful implementation of the Company’s research and development programs and collaborations ; the Company’s ability to obtain applicable regulatory approvals for its current and future product candidates ; the acceptance by the market of the Company’s products should they receive regulatory approval ; the timing and success of the Company’s preliminary studies, preclinical research, clinical trials, and related regulatory filings ; the ability of the Company to consummate additional financings as needed ; the impact of global health concerns, such as the COVID - 19 global pandemic, on our ability to continue our clinical and preclinical programs and otherwise operate our business effectively ; including successfully integrating the combined companies ; as well as those discussed in more detail in our Annual Report on Form 10 - K and our other reports filed with the Securities and Exchange Commission .
/ 3 * RDEB and JEB : Recessive Dystrophic and Junctional Epidermolysis Bullosa; APC : Adenomatous Polyposis Coli Eloxx + Zikani: Positioned to be the world leader in ribosome RNA - targeted genetic therapies Strengthened leadership Complementary platforms targeting the human ribosome Rare disease and oncology pipeline Compelling assets in CF • President and CEO: Sumit Aggarwal • Head of R&D: Dr. Vijay Modur • Eukaryotic Ribosome Selective Glycosides (ERSGs): Safer Aminoglycosides designed with human ribosome selectivity • TURBO - ZM : Proprietary synthetic chemistry platform to design novel macrolide - based oral Ribosome Modulating Agents (RMAs) • ELX - 02: in Phase 2 development for Cystic Fibrosis (CF) – ELX - 02 data readout in 2H 2021 • Preclinical CF program from Zikani pipeline • Expect to file IND for RDEB* and JEB* program in 2022 • Advance programs in inherited and advanced colon cancer targeted at restoring APC* tumor suppressor protein
/ 4 Meet the new Eloxx Leadership Team Sumit Aggarwal President and CEO • 20+ years investing and transforming healthcare companies • Raised >$150M • Biotech Investor Vijay Modur Head of Research & Development • 20+ years in translation and drug development • Led Venglustat rare disease program at Sanofi Neil Belloff COO and General Counsel • 30+ years business and legal experience • GC and executive leadership roles Daniel Geffken Interim Chief Financial Officer • 30+ years building companies • Closed $2B in equity and debt financings for public and private companies
/ 5 Transaction overview • Eloxx issued ~ 7.6 million shares • Zikani stockholders have pro forma ownership ~ 16% of Eloxx • Silvia Noiman, Ph.D., and Martijn Kleijwegt stepped down from Eloxx Board • Alan Walts, Ph.D., and Raj Parekh, Ph.D., current Zikani directors, appointed to fill vacancies and serve out remaining terms Board changes Consideration
/ 6 Strong advisors and collaborators supporting programs Prof. Eitan Kerem Cystic Fibrosis Former Head of Pediatrics Hadassah Hospital Former SAB member Vertex Keith Flaherty Oncology, Chairman SAB Loxo Oncology co - founder Pedro Huertas Clinical Translation ex - CMO Eloxx, Shire Dr. David Sidransky Oncology Advaxis, Champions Oncology Dr. Andrew South Epidermolysis Bullosa David Bedwell Readthrough, Rare diseases Key advisors Rina Arbesfeld KOL FAP/APC Mei Chen KOL DEB Key collaborators
/ 7 RMA: Ribosome Modulating Agent; ERSG: Eukaryotic Ribosome Selective Glycoside Complementary human ribosome targeting technologies that address defects in protein translation Ribosome = “protein factory”: Correcting mRNA and ribosomal mutations Ribosome large subunit Ribosome small subunit mRNA Amino acid
/ 8 RMA: Ribosome Modulating Agent; ERSG: Eukaryotic Ribosome Selective Glycoside Complementary human ribosome targeting technologies that address defects in protein translation Ribosome = “protein factory”: Correcting mRNA and ribosomal mutations Truncated peptide chain = Loss of Function Premature stop codon Nonsense Mutations
/ 9 RMA: Ribosome Modulating Agent; ERSG: Eukaryotic Ribosome Selective Glycoside Complementary human ribosome targeting technologies that address defects in protein translation Ribosome = “protein factory”: Correcting mRNA and ribosomal mutations Ribosomal mutations Dysregulated Onco - and Mitoribosomes
/ 10 RMA: Ribosome Modulating Agent; ERSG: Eukaryotic Ribosome Selective Glycoside Complementary human ribosome targeting technologies that address defects in protein translation Ribosome = “protein factory”: Correcting mRNA and ribosomal mutations Ribosome large subunit Ribosome small subunit ERSG Restore full length proteins and inhibit protein translation mRNA RMA Amino acid
/ 11 Clinically relevant readthrough reported in over 36 different rare diseases Diseases Evidence Readthrough Agent(s) Tested Macrolides Aminoglycosides Familial Adenomatous Polyposis (FAP) Clinical 1 Ery, Tyl Gen Cystic Fibrosis Class 1 Clinical 2 Tyl Gen, G418 Duchenne Muscular Dystrophy Clinical 3 Gen Dystrophic Epidermolysis Bullosa (RDEB) Clinical 4 Gen, G418 Lysosomal Storage Disorders, e.g., MPSI (Hurler), cystinosis ex vivo 5 Gen, G418 Rett Syndrome ex vivo 5 Ery Gen Spinal Muscular Atrophy (SMA) ex vivo 5 Azm, Ery Gen Ataxia - Telangiectasia (ATM) ex vivo 5 Ery Gen Usher syndrome/ retinitis pigmentosa (RP) in vivo Preclinical 6 Gen, G418 1 Kariv, R. Ann. Oncol. 2018, 29, suppl3; 2 Sermet - Gaudelus, I. BMC Med. 2007, 5, 5; 3 Malik, V. Ther. Adv. Neurol. Disord. 2010, 3, 379; 4 Woodley, D. J Clin Invest. 2017;127(8):3028, 5 Caspi, M., J Mol Med (Berl). 2016 Apr;94(4):469 - 82; 6 Goldmann, T, Hum Gene Ther. 2011 May;22(5):537 - 47. Strong evidence of readthrough activity with macrolides and aminoglycosides Macrolides: Erythromycin (Ery); Tylosin (Tyl); Azithromycin (Azm) Aminoglycosides: Gentamicin (Gen); Geneticin (G418)
/ 12 Large and broad applications for human ribosome targeted genetic therapies Readthrough = “Functional Gene Therapy” RMA ERSG Protein Translation Inhibition RMA Stop codon readthrough in rare diseases and cancer • 10 – 12% of patients across >1800 rare diseases • 6 – 10% of cancer patients have nonsense mutations in tumor suppressor genes • 20 – 30% of neoantigens in cancer patients have nonsense mutations Onco - and mitoribosomal cancers: • Myc amplified lymphomas – (e.g., MALT, Burkitt, DLBCL) • Hereditary Ribosomopathies • HPV associated cancers (Head & Neck, Cervical) • Triple Negative Breast, KRAS mutated Pancreatic Cancer, etc.
/ 13 *Class 1 CF: Cystic fibrosis patients with class1 mutations; ADPKD: Autosomal dominant polycystic kidney disease; FAP: Familial adenomatous polyposis; CRC: Colorectal cancer Deep pipeline of synergistic potential first - in - class therapies Target Indication Discovery Early research Lead optimization IND enabling Phase 1 – first in human Phase 2 Nonsense readthrough: rare disease CFTR Class 1 CF Collagen VII A1/LAMB3 RDEB/JEB CFTR Class 1 CF PKD1, PKD2 and Oca2 ADPKD/inherited retinal diseases Nonsense readthrough: oncology APC FAP and CRC Undisclosed Pan cancer/ IO combination Protein translation inhibition Onco - ribosome & mito - ribosome mutations Undisclosed RMA RMA ZKN013/ZKN074 ERSG RMA ZKN013/ZKN034 ELX - 02
/ 14 ELX - 02 (Clinical) and ERSG Preclinical programs
/ 15 Data adapted from: Kandasamy. Increased Selectivity toward Cytoplasmic versus Mitochondrial Ribosome Confers Improved Efficie ncy of Synthetic Aminoglycosides in Fixing Damaged Genes: A Strategy for Treatment of Genetic Diseases Caused by Nonsense Mutations. J. Med. Chem . (2012) ERSGs like ELX - 02 designed to expand human ribosome selectivity and therapeutic index over aminoglycosides ELX - 02 and other ERSGs 0.0001 0.001 0.01 0.1 1 10 0.1 1 10 100 1000 10000 Selectivity over prokaryotic ribosome S e l e c t i v i t y o v e r m i t o c h o n d r i a l r i b o s o m e ( f o l d ) Eukaryotic ribosome selectivity comparison Gentamicin G418 (fold) Eukaryotic ribosome selectivity comparison
/ 16 Class 1 CF opportunity and clinical rationale 1 Allelic frequency based on CFTR2 database (July 2020); CF population data based on 2019 Patient Registry Report. 2 Sermet - Gaudelus, I. BMC Med . 2007, 5, 5; Clinical validation for gentamicin supports ELX - 02 use in treating Class 1 Cystic Fibrosis nonsense mutation patients No currently approved drugs to treat CFTR nonsense mutations Nonsense allele frequency of global CF patient population N=12% of all CF patients 1 23% 3% 7% 13% 17% 37% 73 remaining nonsense alleles E60X R1162X R553X W1282X G542X Class 1 CF Gentamicin treatment 9 patients (10 mg/kg iv, qd for 15 days) 2 Change in sweat chloride (mM/L) 109 85 Placebo Gentamicin - 22%
/ 17 Swelling response in G542X CF patient organoids 1 Ussing chamber results heterozygous G542X/Fdel508 HBE cells 1 Ordinary one - way ANOVA with Tukey’s multiple comparison testing was used; **** p<0.0001 versus vehicle control, ## p<0.01 versus next lower concentration, #### p<0.0001 versus next lower concentration. Data represent >40 biological replicates per group from 2 or 4 independent patient organoids, respectively. High ELX - 02 efficacy in organoid swelling and Ussing chamber experiments *p<0.05, **p<0.01 HBE cells were incubated for 2 days with ELX - 02 0 25 50 75 100125 0 2 4 6 8 10 ELX-02 (mg/ml) l s c ( m A / c m 2 ) * ** -1000 0 1000 2000 3000 4000 5000 S w e i l l i n g A U C Organoid Swelling **** **** ## **** **** #### 0 80 160 (mM) ELX02 0 80 160 G542X/ 2nd nonsense G542X/ Class II
/ 18 Swelling response in Class 1 and Class 2 CF patient organoids when treated with ELX - 02 vs. Symdeko ClinicalTrials.gov Identifier: US Trial NCT04135495, EU/IL Trial NCT04126473 * From baseline to Day 7 of treatment periods 1 - 3, and Days 7 and 14 of treatment period 4 ** Lancet Respir Med. 2014 Jul;2(7):527 - 38., N Engl J Med . 2010 Nov 18; 363(21): 1991 – 2003. Swelling response in Class 1 CF organoids with ELX - 02 compares favorably with Symdeko in Class 2 organoids Organoid swelling (0.8 μ M forskolin) G542X; G542X G542X; Class 2 G542X; F508del G542X; F508del F508del; F508del 0 2000 4000 6000 8000 10000 A U C C u m u l a t i v e S w e l l i n g ( t = 1 2 0 m i n ) Organoid Swelling 0.8 mM forskolin ELX-02 tezacaftor/ ivacaftor
/ 19 Swelling response in CF patient organoids ELX - 02 efficacy seen across CFTR nonsense mutations W1282X response example R553X response example R1162X response example
/ 20 Ussing Chamber experiment: Treatment of Het G542X HBE cells ELX - 02 shows synergy with Kalydeco (VX770 - a potentiator) 0 5 10 15 20 (mg/mL) l s c ( m A / c m 2 ) ELX-02 ELX-02 & VX-770 (10µM) 0 25 50 75 100125250 **** ** *** * G542X/F508del
/ 21 Phase I trial records: NCT03776539, NCT03309605, NCT03292302, Phase II trial record: NCT04069260 ELX - 02 well tolerated in Phase 1 and 2 clinical studies • Single and Multiple ascending doses studied from 0.3 to 7.5 mg/kg. Generally well tolerated • No dose limiting toxicities, SAEs or off target effects – No nephrotoxicity or vestibular toxicity • Most common AE was mild injection site reaction • 5 transient and reversible cases of high frequency audiometry shift • Highly reproducible PK over the dose range studied • Generally well tolerated: No treatment - related serious adverse events, nephrotoxicity, or ototoxicity • Mild injection site reactions reported • No meaningful changes in eGFR or serum creatinine – Consistent with preservation of kidney function • Pharmacokinetics consistent with previous studies in healthy volunteers • Safety Review Committee approval to enroll patients ages 12 years and older >100 subjects exposed to ELX - 02 to date with NO treatment - related serious adverse events or off target effects reported Data presented at scientific meetings in 2019 and published in peer reviewed journals in 2021 PHASE 1: Healthy volunteers and subjects with various severities of renal dysfunction PHASE 2: Nephropathic cystinosis with homozygous CTNS W138X who previously received kidney transplant
/ 22 ClinicalTrials.gov Identifier: US Trial NCT04135495, EU/IL Trial NCT04126473 * From baseline to Day 7 of treatment periods 1 - 3, and Days 7 and 14 of treatment period 4 ELX - 02 Phase 2 cystic fibrosis trial designed to evaluate safety and short term sweat chloride reduction Up to 3 mg/kg SC QD for 14 days Dose 4 (individualized) ELX - 02 Phase 2 program principally designed for safety and dose finding in CF patients, with sweat chloride as PD biomarker Population • Up to 24 CF patients with a G542X mutation on one or both alleles Primary outcome measures • Safety, tolerability, and pharmacokinetics Secondary outcome measures • Change from baseline in sweat chloride concentration* • Change from baseline in percent predicted forced expiratory volume (ppFEV1)* Locations • Europe, Israel & USA, opening additional sites in Canada and Australia DESIGN: Intra - patient dose escalation through 4 increasing doses of ELX - 02 1.5 mg/kg SC QD for 7 days Dose 3 0.75 mg/kg SC QD for 7 days Dose 2 0.3 mg/kg SC QD for 7 days Dose 1
/ 23 Larger and longer ORKAMBI Ph3 trial showed +2.6% FEV 1 change leading to its approval FEV 1 improvement is not significant for any dose group in small short trial -18 -16 -14 -12 -10 -8 -6 -4 -2 0 Day 7 Day 14 Day 21 Mean change (mmol/L Placebo Lumacaftor 200 mg once per day + ivacaftor 150 mg every 12 h (N=20) Lumacaftor 200 mg once per day + ivacaftor 250 mg every 12 h (N=18) * W/DRL = Withdrawal period Lancet Respir Med . 2014 Jul;2(7):527 - 38. doi: 10.1016/S2213 - 2600(14)70132 - 8 ORKAMBI confirmed sweat chloride reduction, but no FEV 1 change in similar small P2 safety trial Orkambi Ph 2 (Cohort 1) trial – Changes in sweat chloride MONOTHERAPY COMBINATION W/DRL* Sweat chloride change at day 21 is decreased ( – 10·9 mmol/L) for high dose group FEV 1 – Ph2 P2 trials for Kalydeco and Orkambi found changes in sweat chloride to be less variable in small studies than FEV 1 /ppFEV 1 , which were not significant in many cohorts FEV 1 – Ph3 Treatment in homozygous delta F508 CF patients
/ 24 Expect to complete enrollment in Phase 2 clinical trials by midyear and report data in 2H 2021 ELX - 02: Potential for transformative efficacy in Class 1 CF patients Demonstrated efficacy in clinically relevant pre - clinical models • Swelling response in Class 1 CF patient organoids • Induces CFTR activity of up to 30% of normal; confirmed in Ussing Chamber • Active across broad range of mutations Safety demonstrated in clinical studies • Generally well - tolerated for chronic dosing, with no serious adverse events in over 100 subjects exposed to ELX - 02 to date • Consistent pharmacokinetics across both single and multiple - dose accumulations Phase 2 CF trials designed for rapid clinical signal • Study designed to confirm safety and biological activity via changes in sweat chloride • Funding provided by Cystic Fibrosis Foundation (CFF), sanctioned by CFF - TDN & ECFS - CTN (high priority ranking)
/ 25 Readthrough shown in preclinical models with other ERSG’s in rare kidney and ocular diseases -4.5 -4.0 -3.5 -3.0 -2.5 -2.0 0 5 10 15 20 25 PKD1 Dual luciferase % Read-through, ELX-10 Log [ELX-10] (M) % r e a d - t h r o u g h Q4042X R4228X R2430X PKD1 • Mutations in PKD1 or PKD2 lead to cyst growth • Affects 6 – 10% of patients on dialysis and renal transplant in the US • Usher syndrome and Retinitis Pigmentosa are most common diseases • Approx. 2000 patients in the US Single dose study in SJL/J mouse with R262X mutation in OCA2 gene 1 Inherited Retinal Diseases (IRDs) Polycystic Kidney Disease (ADPKD) Readthrough in nonsense mutations in PKD1 gene with ELX - 10 in dual luciferase assay
/ 27 TURBO - ZM : Applying macrolide SAR to RMA design TURBO - ZM ( TU ning the R i BO some with Z ikani M olecules) platform fully unlocks the potential of macrolides Optimize for: • Readthrough • Protein translation inhibition Interact with the peptide sequence Modulate: • PK • Safety: cardiac, liver • Oral bioavailability RMA core required for ribosomal binding A B C D F E X O TURBO - ZM E ssential for ribosomal binding Modulate cytoplasm and mitochondrial ribosome binding activity
/ 28 Nascent peptide exit tunnel in E. coli vs. human ribosomes 1 1 Nucleic Acids Res . 2019;47(8):4198 - 4210 Strong rationale for macrolides to bind to the human ribosome Macrolide binding site in prokaryotic (bacterial) ribosome 75% of binding site conserved in the human (eukaryotic) ribosome 1 First constriction site Second constriction site E. coli H. Sapiens
/ 29 Zikani RMA Library (2000+) Growing library of RMAs with drug - like properties
/ 30 Readthrough Emax of selected RMA hits relative luciferase units compared to DMSO in W134X Nanoluc reporter assay RMAs show superior readthrough to alternatives 3,005 5,613 1,791 18,188 7,420 14,811 10,157 8,597 24,330 12,614 ZKN - 3 ZKN - 1 ZKN - 5 ZKN - 2 ZKN - 4 ZKN - 6 +710% +333% ZKN - 7 G418 (100µM) Active control 1 Active control 2
/ 31 RMA Preclinical programs: RDEB/JEB, CF and FAP
/ 32 RDEB and JEB : Recessive Dystrophic and Junctional Epidermolysis Bullosa 1 Woodley, DT. J Clin Investig 2017, 127, 3028 - 3038; 2 Hammersen, Johanna et al. Dermatology May 2019 RDEB/JEB: Clinically validated path for RMAs in rare skin disease targeting patients with nonsense mutations • Mutations in COL7A1 gene (Collagen) and LAMB3 (Laminin) • Most RDEB patient develop skin cancer by age 35 • Average mortality of JEB patients is 18 months Gentamicin treatment of RDEB patients (0.1% gentamicin ointment tid for 2 weeks; n=5) 1 Wound closure at 3 months, % Total blistering events at 3 months 13 4 Placebo Gentamicin - 69% 47 78 Gentamicin Placebo +66% RDEB RDEB and JEB ~4,000 patients, $1.5B TAM
/ 33 COL7 with 48 hr. exposure in RDEB patient derived primary fibroblasts* * Fibroblasts isolated from patients two and five in gentamicin clinical trial. J Clin Invest 2017, 127, 3028 - 3038 ** 48 hours treatment with media and compounds replaced and refreshed at 24 hours. Study repeated twice with equivalent results . RDEB: RMAs restore functional collagen protein in primary patient cells comparable to high dose gentamicin Data generated in collaboration with academic partner • Assay with proven translation to clinic • 30 to 60 - day Col7 protein half - life • RMAs compounds exceed clinical efficacy threshold of 10% Gentamicin 845uM Full length protein in Hom R578X COL7A Fibroblasts** Full length protein in R613X/R1683X COL7A Fibroblasts**
/ 34 Summary of Class 1 CF data * Forskolin 10 µM/1µM VX - 770 - both chambers ** VX 809 and RMA data averaged from 2 separate Ussing chamber results Class 1 CF: RMA lead showed highest ever readthrough preclinical Ussing chamber assay Data generated at Chantest VX - 809 (3uM) DMSO RMA (15 uM) RMA (30 uM) G418 (100 uM) G418 (50 uM) Isc chloride transport (µA/cm 2 ) Het G542X Human Broncho Epithelial (HBE) cells Ussing Chamber steady state modulator response measurement** Never seen before impressive single agent activity from non aminoglycoside class – need to advance this program – CF Foundation Encouraged to apply for “Path to Cures” Submitted $2.5M grant to CF Foundation to support through development candidate +47%
/ 35 1 Kariv, R. Int J Cancer . 2019 doi: 10.1002/ijc.32557 APC readthrough: Supported by positive prior clinical success of Erythromycin in FAP Erythromycin treatment (250 mg/day po for 4 months) Change in polyp burden at 12 months 1 45.7 34.9 - 42.2 - 55.1 Change in polyp number Change in polyp cumulative size - 1 yr to baseline 8 months post treatment • Mutations in the Adenomatous Polyposis Coli (APC) gene (tumor suppressor gene) • FAP patients develop CRC by age 40 • 80% of CRC patients have an APC mutation Clinical trial success in FAP with Erythromycin APC mutant Familial Adenomatous Polyposis (FAP) and CRC 8,000 – 12,500 FAP patients in the US/EU; 210,000 CRC patients WW
/ 36 Efficacy of ZN013 in colorectal cancer patient derived tumor grafts ex - vivo Clear path treating FAP supported by efficacy in APC mutant cancer patient tumor grafts • Ex - vivo sensitivity assessment in tumor grafts • Potent tumor growth inhibition – GI50<15uM • Cancer xenograft studies planned in 2021 ZNK013 CTG - 0382 (R1450X/fsX912X) CTG - 1170 (Q1429X)
/ 37 Positioned to be the world leader in ribosome targeted genetic therapies Proprietary ribosome targeted small molecule platforms targeting rare diseases and oncology Deep pipeline led by clinical stage program to treat class 1 nonsense mutations in Cystic Fibrosis Expect to file first IND for first - in - class oral RDEB/JEB program expected in 2022; expect to file 1 IND per year after 2022 Right leadership, team, and advisors