UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of The Securities Exchange Act of 1934
Date of Report (Date of Earliest Event Reported): February 5, 2020
Zafgen, Inc.
(Exact name of registrant as specified in its charter)
| DELAWARE | 001-36510 | 20-3857670 | ||
| (State or other jurisdiction of incorporation) |
(Commission File Number) |
(I.R.S. Employer Identification No.) | ||
| 3 Center Plaza, Suite 610 Boston, Massachusetts |
02108 | |||
| (Address of principal executive offices) | (Zip Code) | |||
Registrant’s telephone number, including area code (617) 622-4003
Not Applicable
(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 | ||
| Common Stock | ZFGN | NASDAQ Global Market |
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).
Emerging growth company ☐
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. ☐
| Item 7.01 | Regulation FD Disclosure. |
Members of Zafgen, Inc. management will be participating in upcoming meetings with investors. A copy of the presentation used in connection with the meetings with investors is filed as Exhibit 99.1 and incorporated herein by reference.
The information disclosed under this Item 7.01, including Exhibit 99.1 attached hereto is intended to be furnished and shall not be deemed “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, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits
| Exhibit No. |
Description | |
| 99.1 | Zafgen, Inc. presentation for investor meetings | |
SIGNATURE
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.
| ZAFGEN, INC. | ||||||
| Date: February 5, 2020 | By: | /s/ Jeffrey S. Hatfield | ||||
| Jeffrey S. Hatfield, Chief Executive Officer | ||||||
Exhibit 99.1 Zafgen and Chondrial Therapeutics Planned Definitive Merger February 2020Exhibit 99.1 Zafgen and Chondrial Therapeutics Planned Definitive Merger February 2020
Forward Looking Statements Additional Information about the Proposed Merger and Where to Find It This communication relates to the proposed merger transaction involving Zafgen, Inc. (“Zafgen”) and Chondrial Therapeutics, Inc. (“Chondrial”) and may be deemed to be solicitation material in respect of the proposed merger involving Zafgen and Chondrial. In connection with the proposed merger, Zafgen intends to file relevant materials with the Securities and Exchange Commission (the “SEC”), including a proxy statement relating to the approval of the merger agreement. Investors and security holders of Zafgen are urged to read these materials when they become available because they will contain important information about Zafgen, Chondrial and the proposed merger. The proxy statement and other relevant materials (when they become available), and any other documents filed by Zafgen with the SEC, may be obtained free of charge at the SEC web site at www.sec.gov. In addition, investors and security holders may obtain free copies of the documents filed with the SEC by Zafgen by directing a written request to: Zafgen, Inc., 3 Center Plaza, Suite 610, Boston, Massachusetts 02108, Attention: Secretary. Investors and security holders are urged to read the proxy statement and other relevant materials when they become available before making any voting or investment decision with respect to the proposed merger. This communication shall not constitute an offer to sell or the solicitation of an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. Participants in the Solicitation Zafgen and its directors and executive officers and Chondrial and its directors and executive officers may be deemed to be participants in the solicitation of proxies from the stockholders of Zafgen in connection with the proposed merger. Information regarding the special interests of these directors and executive officers in the proposed merger will be included in the proxy statement referred to above. Additional information regarding the directors and executive officers of Zafgen is also included in Zafgen’s definitive proxy statement in connection with its 2019 Annual Meeting of Stockholders filed with the SEC on April 26, 2019. These documents are available free of charge at the SEC web site (www.sec.gov) and from the Secretary of Zafgen at the address above. 2Forward Looking Statements Additional Information about the Proposed Merger and Where to Find It This communication relates to the proposed merger transaction involving Zafgen, Inc. (“Zafgen”) and Chondrial Therapeutics, Inc. (“Chondrial”) and may be deemed to be solicitation material in respect of the proposed merger involving Zafgen and Chondrial. In connection with the proposed merger, Zafgen intends to file relevant materials with the Securities and Exchange Commission (the “SEC”), including a proxy statement relating to the approval of the merger agreement. Investors and security holders of Zafgen are urged to read these materials when they become available because they will contain important information about Zafgen, Chondrial and the proposed merger. The proxy statement and other relevant materials (when they become available), and any other documents filed by Zafgen with the SEC, may be obtained free of charge at the SEC web site at www.sec.gov. In addition, investors and security holders may obtain free copies of the documents filed with the SEC by Zafgen by directing a written request to: Zafgen, Inc., 3 Center Plaza, Suite 610, Boston, Massachusetts 02108, Attention: Secretary. Investors and security holders are urged to read the proxy statement and other relevant materials when they become available before making any voting or investment decision with respect to the proposed merger. This communication shall not constitute an offer to sell or the solicitation of an offer to sell or the solicitation of an offer to buy any securities, nor shall there be any sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. Participants in the Solicitation Zafgen and its directors and executive officers and Chondrial and its directors and executive officers may be deemed to be participants in the solicitation of proxies from the stockholders of Zafgen in connection with the proposed merger. Information regarding the special interests of these directors and executive officers in the proposed merger will be included in the proxy statement referred to above. Additional information regarding the directors and executive officers of Zafgen is also included in Zafgen’s definitive proxy statement in connection with its 2019 Annual Meeting of Stockholders filed with the SEC on April 26, 2019. These documents are available free of charge at the SEC web site (www.sec.gov) and from the Secretary of Zafgen at the address above. 2
Forward Looking Statements Zafgen Forward-Looking Information is Subject to Risks and Uncertainty This communication contains forward-looking statements based upon Zafgen’s and Chondrial’s current expectations. Forward-looking statements involve risks and uncertainties, and include, but are not limited to, statements about the structure, timing and completion of the proposed merger; the combined company’s listing on Nasdaq after the closing of the proposed merger; expectations regarding the ownership structure of the combined company; the combined company’s expected cash position at the closing of the proposed merger; the future operations of the combined company; the nature, strategy and focus of the combined company; the development and commercial potential and potential benefits of any product candidates of the combined company; the executive and board structure of the combined company; the location of the combined company’s corporate headquarters; and other statements that are not historical fact. Actual results and the timing of events may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation: (i) the risk that the conditions to the closing of the proposed merger are not satisfied, including the failure to timely obtain stockholder approval for the proposed merger, if at all; (ii) uncertainties as to the timing of the consummation of the proposed merger and the ability of each of Zafgen and Chondrial to consummate the proposed merger; (iii) risks related to Zafgen’s ability to manage its operating expenses and its expenses associated with the proposed merger pending closing; (iv) risks related to the failure or delay in obtaining required approvals from any governmental or quasi-governmental entity necessary to consummate the proposed merger; (v) the risk that as a result of adjustments to the exchange ratio, Zafgen stockholders and Chondrial stockholders could own more or less of the combined company than is currently anticipated; (vi) risks related to the market price of Zafgen’s common stock relative to the exchange ratio; (vii) unexpected costs, charges, expenditures or expenses resulting from the proposed merger; (viii) potential adverse reactions or changes to business relationships resulting from the announcement or completion of the proposed merger; (ix) Zafgen’s ability to retain personnel as a result of the announcement or completion of the proposed merger; and (x) risks associated with the possible failure to realize certain anticipated benefits of the proposed merger, including with respect to future financial and operating results. Actual results and the timing of events may differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. These and other risks and uncertainties are more fully described in periodic filings with the SEC, including the factors described in the section entitled “Risk Factors” in Zafgen’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 filed with the SEC, and in other filings that Zafgen makes and will make with the SEC in connection with the proposed merger, including the proxy statement described above under “Additional Information about the Proposed Merger and Where to Find It.” You should not place undue reliance on these forward-looking statements, which apply only as of the date of this communication. Zafgen expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based. 3Forward Looking Statements Zafgen Forward-Looking Information is Subject to Risks and Uncertainty This communication contains forward-looking statements based upon Zafgen’s and Chondrial’s current expectations. Forward-looking statements involve risks and uncertainties, and include, but are not limited to, statements about the structure, timing and completion of the proposed merger; the combined company’s listing on Nasdaq after the closing of the proposed merger; expectations regarding the ownership structure of the combined company; the combined company’s expected cash position at the closing of the proposed merger; the future operations of the combined company; the nature, strategy and focus of the combined company; the development and commercial potential and potential benefits of any product candidates of the combined company; the executive and board structure of the combined company; the location of the combined company’s corporate headquarters; and other statements that are not historical fact. Actual results and the timing of events may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation: (i) the risk that the conditions to the closing of the proposed merger are not satisfied, including the failure to timely obtain stockholder approval for the proposed merger, if at all; (ii) uncertainties as to the timing of the consummation of the proposed merger and the ability of each of Zafgen and Chondrial to consummate the proposed merger; (iii) risks related to Zafgen’s ability to manage its operating expenses and its expenses associated with the proposed merger pending closing; (iv) risks related to the failure or delay in obtaining required approvals from any governmental or quasi-governmental entity necessary to consummate the proposed merger; (v) the risk that as a result of adjustments to the exchange ratio, Zafgen stockholders and Chondrial stockholders could own more or less of the combined company than is currently anticipated; (vi) risks related to the market price of Zafgen’s common stock relative to the exchange ratio; (vii) unexpected costs, charges, expenditures or expenses resulting from the proposed merger; (viii) potential adverse reactions or changes to business relationships resulting from the announcement or completion of the proposed merger; (ix) Zafgen’s ability to retain personnel as a result of the announcement or completion of the proposed merger; and (x) risks associated with the possible failure to realize certain anticipated benefits of the proposed merger, including with respect to future financial and operating results. Actual results and the timing of events may differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. These and other risks and uncertainties are more fully described in periodic filings with the SEC, including the factors described in the section entitled “Risk Factors” in Zafgen’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 filed with the SEC, and in other filings that Zafgen makes and will make with the SEC in connection with the proposed merger, including the proxy statement described above under “Additional Information about the Proposed Merger and Where to Find It.” You should not place undue reliance on these forward-looking statements, which apply only as of the date of this communication. Zafgen expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in its expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based. 3
Definitive merger agreement announced December 2019 Criteria included: üNear-term milestones within 6 – 9 months post-transaction üWell funded beyond value inflection milestone üEither early stage (IND or Phase 1) or late (pivotal trial) üInnovative scientific approach in an attractive field – both market opportunity and patient need – especially if focus is on rare disease üPlatform opportunity for multiple assets or multiple value streams Thorough evaluation of strategic alternatives Unanimous decision by Zafgen Board of Directors and leadership team 4Definitive merger agreement announced December 2019 Criteria included: üNear-term milestones within 6 – 9 months post-transaction üWell funded beyond value inflection milestone üEither early stage (IND or Phase 1) or late (pivotal trial) üInnovative scientific approach in an attractive field – both market opportunity and patient need – especially if focus is on rare disease üPlatform opportunity for multiple assets or multiple value streams Thorough evaluation of strategic alternatives Unanimous decision by Zafgen Board of Directors and leadership team 4
About the proposed merger • Post-transaction ownership ~60% Chondrial / ~40% Zafgen stockholders • Anticipated 1H 2020 closing • New company will operate under new name, Larimar Therapeutics • Blended Board of Directors (four from Chondrial / three from Zafgen) • President and Chief Executive Officer will be Dr. Carole Ben-Maimon 5About the proposed merger • Post-transaction ownership ~60% Chondrial / ~40% Zafgen stockholders • Anticipated 1H 2020 closing • New company will operate under new name, Larimar Therapeutics • Blended Board of Directors (four from Chondrial / three from Zafgen) • President and Chief Executive Officer will be Dr. Carole Ben-Maimon 5
Compelling value-creation opportunity • Publicly traded, clinical-stage biopharmaceutical company focused on rare disease • Strong scientific approach and platform opportunity • Targeting significant market opportunities • Upcoming near-term value creating events expected • Experienced leadership team • Potential to have impact on significant and devastating diseases 6Compelling value-creation opportunity • Publicly traded, clinical-stage biopharmaceutical company focused on rare disease • Strong scientific approach and platform opportunity • Targeting significant market opportunities • Upcoming near-term value creating events expected • Experienced leadership team • Potential to have impact on significant and devastating diseases 6
Chondrial Therapeutics Overview 7Chondrial Therapeutics Overview 7
Introduction to Chondrial Therapeutics • Clinical-stage biotech with a novel protein replacement therapy platform to address untreated, serious and complex rare diseases • Lead candidate, CTI-1601, in Phase 1 clinical development for potential treatment of Friedreich’s ataxia (FA) • Only frataxin (FXN) protein replacement therapy in clinical development to our knowledge • Nonclinical studies have shown promising results in several models of FA, including heart, brain and muscle function, and overall survival • Topline Phase 1 data expected end of 2020 • Experienced leadership team • Strong IP with 12 years market exclusivity expected if approved and patents pending around efficacy biomarkers 8Introduction to Chondrial Therapeutics • Clinical-stage biotech with a novel protein replacement therapy platform to address untreated, serious and complex rare diseases • Lead candidate, CTI-1601, in Phase 1 clinical development for potential treatment of Friedreich’s ataxia (FA) • Only frataxin (FXN) protein replacement therapy in clinical development to our knowledge • Nonclinical studies have shown promising results in several models of FA, including heart, brain and muscle function, and overall survival • Topline Phase 1 data expected end of 2020 • Experienced leadership team • Strong IP with 12 years market exclusivity expected if approved and patents pending around efficacy biomarkers 8
Proprietary protein replacement platform • Peptide technology with proven ability to design molecules using cell-penetrating peptides (CPPs) that enable intracellular delivery of bioactive cargos • Highly relevant and applicable to a range of cargos and rare disease indications 9Proprietary protein replacement platform • Peptide technology with proven ability to design molecules using cell-penetrating peptides (CPPs) that enable intracellular delivery of bioactive cargos • Highly relevant and applicable to a range of cargos and rare disease indications 9
Friedreich’s ataxia (FA): significant medical need • Rare disease caused by a genetic defect resulting in abnormally low levels of frataxin (FXN), affects ~5,000 patients in U.S. and ~10,000 patients in EU-5 • Progressive, irreversible, systemic disease that affects multiple body systems, particularly the brain and heart • Onset: Age of onset correlated with severity and speed of progression (earlier onset correlated with more drastic progression) • Significant asymptomatic period; >70% of patients present before age 14 • Initial symptoms (age 10 – 15) may include unsteady posture, frequent falling and progressive difficulty in walking due to impaired ability to coordinate voluntary movements (ataxia) • By the time symptoms occur, heart damage has already occurred • Progression of disease: Symptoms worsen and may include development of advanced limb ataxia often requiring patient confinement to wheelchair, hypertrophic cardiomyopathy, scoliosis, fatigue, diabetes and hearing loss • Life expectancy: 30 – 50 years, early death usually caused by heart disease due to advanced cardiomyopathy • Treatment limited to symptom management; no approved therapies 10Friedreich’s ataxia (FA): significant medical need • Rare disease caused by a genetic defect resulting in abnormally low levels of frataxin (FXN), affects ~5,000 patients in U.S. and ~10,000 patients in EU-5 • Progressive, irreversible, systemic disease that affects multiple body systems, particularly the brain and heart • Onset: Age of onset correlated with severity and speed of progression (earlier onset correlated with more drastic progression) • Significant asymptomatic period; >70% of patients present before age 14 • Initial symptoms (age 10 – 15) may include unsteady posture, frequent falling and progressive difficulty in walking due to impaired ability to coordinate voluntary movements (ataxia) • By the time symptoms occur, heart damage has already occurred • Progression of disease: Symptoms worsen and may include development of advanced limb ataxia often requiring patient confinement to wheelchair, hypertrophic cardiomyopathy, scoliosis, fatigue, diabetes and hearing loss • Life expectancy: 30 – 50 years, early death usually caused by heart disease due to advanced cardiomyopathy • Treatment limited to symptom management; no approved therapies 10
CTI-1601 – Delivering frataxin to the mitochondria CTI-1601: recombinant fusion protein intended to deliver human frataxin, the protein deficient in FA NH3 CPP MTS Human FXN Mature Human FXN COOH Site of MPP cleavage STEP 1: CTI-1601 crosses cell membrane into cytoplasm and then crosses mitochondrial membrane STEP 2: Mitochondrial Processing Peptidase (MPP) cleaves CTI-1601 STEP 3: Mitochondrial Targeting Sequence (MTS) and CPP complex leave and cell mitochondria STEP 4: Mature human frataxin remains trapped within the mitochondria to function 11CTI-1601 – Delivering frataxin to the mitochondria CTI-1601: recombinant fusion protein intended to deliver human frataxin, the protein deficient in FA NH3 CPP MTS Human FXN Mature Human FXN COOH Site of MPP cleavage STEP 1: CTI-1601 crosses cell membrane into cytoplasm and then crosses mitochondrial membrane STEP 2: Mitochondrial Processing Peptidase (MPP) cleaves CTI-1601 STEP 3: Mitochondrial Targeting Sequence (MTS) and CPP complex leave and cell mitochondria STEP 4: Mature human frataxin remains trapped within the mitochondria to function 11
CTI-1601: Proof of concept achieved through multiple nonclinical studies • Nonclinical efficacy and PD data provides proof of concept in support of continued development to potentially replace FXN in patients with FA • Extended survival in a well-characterized nonclinical model of FA • Prevents ataxic gait in another nonclinical model of FA • Demonstrated capability of delivering sufficient amounts of FXN to mitochondria • Safe and well tolerated in multiple species 12CTI-1601: Proof of concept achieved through multiple nonclinical studies • Nonclinical efficacy and PD data provides proof of concept in support of continued development to potentially replace FXN in patients with FA • Extended survival in a well-characterized nonclinical model of FA • Prevents ataxic gait in another nonclinical model of FA • Demonstrated capability of delivering sufficient amounts of FXN to mitochondria • Safe and well tolerated in multiple species 12
CTI-1601 extends survival in FXN-deficient KO Mice Initial Proof of Concept for FXN Replacement Therapy in FA Dramatic Survival in Cardiac üCTI-1601 extended survival in a well characterized KO Mouse Model cardiac mouse model of FRDA üConfirms that CTI-1601 is capable of delivering sufficient amounts of FXN to mitochondria, rescuing a severe disease phenotype P=0.0001 TAT-FXN was administered 10 mg/kg SC every other day Median Survival of MCK-Cre FXN-KO Mice • 166 days (CTI-1601) vs 98.0 days (Vehicle) Days Survival beyond Vehicle mean (107.5 days) • 87.5% (CTI-1601) vs. 33% (Vehicle) 13 MCK = Muscle creatine kinase Percent SurvivalCTI-1601 extends survival in FXN-deficient KO Mice Initial Proof of Concept for FXN Replacement Therapy in FA Dramatic Survival in Cardiac üCTI-1601 extended survival in a well characterized KO Mouse Model cardiac mouse model of FRDA üConfirms that CTI-1601 is capable of delivering sufficient amounts of FXN to mitochondria, rescuing a severe disease phenotype P=0.0001 TAT-FXN was administered 10 mg/kg SC every other day Median Survival of MCK-Cre FXN-KO Mice • 166 days (CTI-1601) vs 98.0 days (Vehicle) Days Survival beyond Vehicle mean (107.5 days) • 87.5% (CTI-1601) vs. 33% (Vehicle) 13 MCK = Muscle creatine kinase Percent Survival
CTI-1601 prevents neurological phenotype in neuro KO mouse model and ataxic gait in FXN-KO mice (brain and DRG KO) In- Vivo Efficacy Data in Neurologic KO Mouse Model Pvalb-Cre FXN-KO mouse • CTI-1601 given intraperitoneally (IP) three times per week • Single dose level: 10 mg/kg CTI-1601 or Vehicle • Dosing Groups: Wild Type, Pvalb-CRE (Vehicle), Pvalb-Cre (CTI-1601) Outcome Measures • Prevents behavioral phenotype in mice that lack • Gait parameters remain similar to endogenous FXN in the brain/DRG wild type in CTI-1601-treated mice • Gait analysis over time in adult mice • hFXN replacement via IP treatment with CTI-1601 prevents • Computerized assessment (DigiGait) development of ataxic gait • Stance width phenotype • Stance phase (swing) • Treated mice survive longer than • Stance length variability untreated mice • Survival analysis 14CTI-1601 prevents neurological phenotype in neuro KO mouse model and ataxic gait in FXN-KO mice (brain and DRG KO) In- Vivo Efficacy Data in Neurologic KO Mouse Model Pvalb-Cre FXN-KO mouse • CTI-1601 given intraperitoneally (IP) three times per week • Single dose level: 10 mg/kg CTI-1601 or Vehicle • Dosing Groups: Wild Type, Pvalb-CRE (Vehicle), Pvalb-Cre (CTI-1601) Outcome Measures • Prevents behavioral phenotype in mice that lack • Gait parameters remain similar to endogenous FXN in the brain/DRG wild type in CTI-1601-treated mice • Gait analysis over time in adult mice • hFXN replacement via IP treatment with CTI-1601 prevents • Computerized assessment (DigiGait) development of ataxic gait • Stance width phenotype • Stance phase (swing) • Treated mice survive longer than • Stance length variability untreated mice • Survival analysis 14
CTI-1601 effectively traffics to mitochondria; delivers hFXN ü hFXN concentration within mitochondria increases in a dose-dependent manner ü Given subcutaneously CTI-1601 functionally replaces hFXN in mitochondria of KO mice ü SDH* activity increases in a dose-dependent manner after administration of CTI-1601; activity plateaus at 30 mg/kg and is equivalent to activity in wildtype animals ü Demonstrated normalization of gene expression in cardiac tissue Normalized SDH activity N o r m a l i z e d M i t o c h o n d r i a l h F X N (Muscle) ( H e a r t ) 80 *** *** 2 0 0 *** K O V e h i c l e *** 60 K O 2 M P K ** 1 5 0 K O 1 0 M P K 40 K O 3 0 M P K 1 0 0 K O 6 0 M P K Wildtype K O 1 0 0 M P K activity 20 5 0 W i l d T y p e V e h i c l e 0 0 15 *Succinate dehydrogenase KO Vehicle KO 2MPK KO 10MPK KO 30MPK KO 60MPK KO 100MPK Wild Type Vehicle F e m a l e s M a l e s N o r m a l i z e d h F X N ( p g / m g p r o t e i n ) SDH Activity mU/mg proteinCTI-1601 effectively traffics to mitochondria; delivers hFXN ü hFXN concentration within mitochondria increases in a dose-dependent manner ü Given subcutaneously CTI-1601 functionally replaces hFXN in mitochondria of KO mice ü SDH* activity increases in a dose-dependent manner after administration of CTI-1601; activity plateaus at 30 mg/kg and is equivalent to activity in wildtype animals ü Demonstrated normalization of gene expression in cardiac tissue Normalized SDH activity N o r m a l i z e d M i t o c h o n d r i a l h F X N (Muscle) ( H e a r t ) 80 *** *** 2 0 0 *** K O V e h i c l e *** 60 K O 2 M P K ** 1 5 0 K O 1 0 M P K 40 K O 3 0 M P K 1 0 0 K O 6 0 M P K Wildtype K O 1 0 0 M P K activity 20 5 0 W i l d T y p e V e h i c l e 0 0 15 *Succinate dehydrogenase KO Vehicle KO 2MPK KO 10MPK KO 30MPK KO 60MPK KO 100MPK Wild Type Vehicle F e m a l e s M a l e s N o r m a l i z e d h F X N ( p g / m g p r o t e i n ) SDH Activity mU/mg protein
CTI-1601 prevents left ventricle (LV) dilation ü Left ventricular volume increases in systole in untreated mice by 8 weeks (after 4 weeks of dosing with vehicle), but remains similar to wildtype when treated with CTI-1601 ü CTI-1601-treated mice similar to controls; echocardiogram shows significant differences between KO: Vehicle and KO: CTI-1601 treated mice LV Internal Diameter, Systole LV Volume, Systole KO: CTI-1601 KO: Vehicle Wildtype: Vehicle 16CTI-1601 prevents left ventricle (LV) dilation ü Left ventricular volume increases in systole in untreated mice by 8 weeks (after 4 weeks of dosing with vehicle), but remains similar to wildtype when treated with CTI-1601 ü CTI-1601-treated mice similar to controls; echocardiogram shows significant differences between KO: Vehicle and KO: CTI-1601 treated mice LV Internal Diameter, Systole LV Volume, Systole KO: CTI-1601 KO: Vehicle Wildtype: Vehicle 16
CTI-1601 preserves left ventricle (LV) function ü Left Ventricular function drops significantly in untreated mice by week 8 ü CTI-1601-treated mice are similar to controls; echocardiogram again shows significant differences between KO: Vehicle and KO: CTI-1601 treated mice LV Ejection Fraction LV Fractional Shortening KO: CTI-1601 KO: Vehicle Wildtype: Vehicle 17CTI-1601 preserves left ventricle (LV) function ü Left Ventricular function drops significantly in untreated mice by week 8 ü CTI-1601-treated mice are similar to controls; echocardiogram again shows significant differences between KO: Vehicle and KO: CTI-1601 treated mice LV Ejection Fraction LV Fractional Shortening KO: CTI-1601 KO: Vehicle Wildtype: Vehicle 17
PK/PD study in healthy cynomolgus monkey (study PK-1601-08) CTI-1601 Human Human/Monkey ü Treatment of monkeys with CTI-1601 results in sustained levels of hFXN in peripheral tissues that are accessible in the clinic ü FXN levels increase 4x or more following CTI-1601 administration • For comparison, FRDA patients have 10-20% of levels of “healthies” • Parents who are heterozygous carriers and show no phenotype have ~50% of “healthies” levels (2-3x higher than FRDA patients • CSF was collected pre- and post-dose; measured levels of processed hFXN in the CSF that was not present before dosing was initiated 18PK/PD study in healthy cynomolgus monkey (study PK-1601-08) CTI-1601 Human Human/Monkey ü Treatment of monkeys with CTI-1601 results in sustained levels of hFXN in peripheral tissues that are accessible in the clinic ü FXN levels increase 4x or more following CTI-1601 administration • For comparison, FRDA patients have 10-20% of levels of “healthies” • Parents who are heterozygous carriers and show no phenotype have ~50% of “healthies” levels (2-3x higher than FRDA patients • CSF was collected pre- and post-dose; measured levels of processed hFXN in the CSF that was not present before dosing was initiated 18
Human frataxin found to be distributed into all tissues tested following CTI-1601 dosing Observed hFXN across all tissue and cell types tested: ü Brain ü Spinal Cord ü Skin ü Heart ü Cardiac Mitochondria ü Buccal Cells ü Liver ü CSF (Cerebrospinal Fluid) ü Platelets ü Dorsal Root Ganglia ü Skeletal Muscle Tissues Examined, By Study Study Study Vehicle Human Frataxin Distribution TOX-1601-01 Rats Brain, Heart, Liver PHARM-1601-02 Neuro KO Mice Brain, Dorsal Root Ganglia, Spinal Cord PHARM-1601-03 Cardiac KO Mice Mitochondria of Skeletal Muscle and Cardiomyocytes PK-1601-08 Cynomolgus Monkey CSF, Skin, Buccal Cells, Platelets 19Human frataxin found to be distributed into all tissues tested following CTI-1601 dosing Observed hFXN across all tissue and cell types tested: ü Brain ü Spinal Cord ü Skin ü Heart ü Cardiac Mitochondria ü Buccal Cells ü Liver ü CSF (Cerebrospinal Fluid) ü Platelets ü Dorsal Root Ganglia ü Skeletal Muscle Tissues Examined, By Study Study Study Vehicle Human Frataxin Distribution TOX-1601-01 Rats Brain, Heart, Liver PHARM-1601-02 Neuro KO Mice Brain, Dorsal Root Ganglia, Spinal Cord PHARM-1601-03 Cardiac KO Mice Mitochondria of Skeletal Muscle and Cardiomyocytes PK-1601-08 Cynomolgus Monkey CSF, Skin, Buccal Cells, Platelets 19
CTI-1601: Safe and well tolerated in multiple animal models No systemic clinical or pathological observations related to CTI-1601 in GLP studies Cynomolgus Monkey Sprague Dawley Rat Injection Site Observations Injection Site Observations • Some injection sites raised and firm; • Some injection sites showed irritation, increased injection site pathology at higher firmness, inflammation at higher doses most likely due to local irritation doses Systemic Toxicity Analysis Systemic Toxicity Analysis • No other clinical observations or treatment- • No significant clinical observations or related changes in food consumption, body clinical pathology results weight or organ weight • No systemic histopathological findings • No systemic histopathological findings 20CTI-1601: Safe and well tolerated in multiple animal models No systemic clinical or pathological observations related to CTI-1601 in GLP studies Cynomolgus Monkey Sprague Dawley Rat Injection Site Observations Injection Site Observations • Some injection sites raised and firm; • Some injection sites showed irritation, increased injection site pathology at higher firmness, inflammation at higher doses most likely due to local irritation doses Systemic Toxicity Analysis Systemic Toxicity Analysis • No other clinical observations or treatment- • No significant clinical observations or related changes in food consumption, body clinical pathology results weight or organ weight • No systemic histopathological findings • No systemic histopathological findings 20
CTI-1601: Initiated Phase 1 clinical program evaluating safety and efficacy in FA patients • Double, placebo-controlled SAD/MAD clinical trials • Assessing safety, tolerability, PK/PD of subcutaneous CTI-1601 vs. placebo in adult patients with Friedreich's ataxia • Changes from baseline in frataxin levels and gene expression will also be evaluated • Patient dosing began December 2019 • Sufficient drug supply for clinical program (5 GMP batches) • Topline results from this Phase 1 clinical program expected by the end of 2020 Rare Pediatric Disease (RPD) Orphan Drug Fast Track Designation Designation Designation (Voucher) 21CTI-1601: Initiated Phase 1 clinical program evaluating safety and efficacy in FA patients • Double, placebo-controlled SAD/MAD clinical trials • Assessing safety, tolerability, PK/PD of subcutaneous CTI-1601 vs. placebo in adult patients with Friedreich's ataxia • Changes from baseline in frataxin levels and gene expression will also be evaluated • Patient dosing began December 2019 • Sufficient drug supply for clinical program (5 GMP batches) • Topline results from this Phase 1 clinical program expected by the end of 2020 Rare Pediatric Disease (RPD) Orphan Drug Fast Track Designation Designation Designation (Voucher) 21
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