2024年10月 larimar therapeutics 公司介绍资料 附件 99.2
本演示包含基于Larimar Therapeutics, Inc.（“公司”）的信念和假设，以及目前管理团队可获得的信息。本演示中包含的所有陈述，除历史事实陈述外，均属前瞻性陈述，其中包括但不限于Larimar能够开发和商业化nomlabofusp（CTI-1601）和其他计划中的产品候选药物的能力，Larimar计划的研发工作，包括其nomlabofusp临床试验的时间安排，与FDA STARt试点计划的预期，与FDA的互动，对于加速批准或加速获得准入以及上市时机和整体发展计划以及Larimar业务策略、筹资能力、资金使用、经营结果和财务状况、未来经营计划和目标等方面的事项。在某些情况下，您可以通过“可能”、“将”、“可能”、“将”、“应该”、“期望”、“打算”、“计划”、“预期”、“相信”、“估计”、“预测”、“项目”、“潜在”、“持续”、“正在进行”或这些术语的否定形式或其他可比较的术语来识别前瞻性陈述，尽管并非所有前瞻性陈述均包含这些词。这些陈述涉及风险、不确定性和可能导致实际结果、表现或成果与这些前瞻性陈述表达或暗示的信息有实质不同的因素。这些风险、不确定性和其他因素包括但不限于Larimar产品开发活动、非临床研究和临床试验、包括nomlabofusp临床里程碑和与FDA的持续互动的成功、成本和时间；初步临床试验结果可能与最终临床试验结果不同，早期的非临床和临床数据以及对nomlabofusp的测试可能无法预测后续临床试验和评估的结果或成功；FDA最终可能不同意Larimar的nomlabofusp发展战略；公共卫生危机对Larimar未来的临床试验、制造、监管、非临床研究时间表和运营以及一般经济状况的潜在影响；Larimar及其外包第三方制造商优化和扩展nomlabofusp的制造流程的能力；Larimar获得nomlabofusp和未来产品候选药物的监管批准能力；Larimar开发销售和营销能力，无论是独自还是与潜在的未来合作伙伴，以成功商业化任何获得批准的产品候选药物的能力；Larimar筹集必要资金进行产品开发活动的能力；以及Larimar向证券交易委员会（SEC）提交的备案，包括但不限于Larimar的定期报告，包括年度10-K表格的年度报告，季度10-Q表格的季度报告和提交给或在SEC可获取,www.sec.gov上可获得的8-K表格的当前报告。这些前瞻性陈述基于Larimar当前已知的事实和因素的结合，以及关于未来的预测，对此Larimar无法确定。因此，前瞻性陈述可能无法被证明为准确。本演示中的前瞻性陈述仅代表Larimar管理层截至本文日期的观点。Larimar无义务根据任何原因更新任何前瞻性陈述，除非有法律要求。前瞻性陈述
临床阶段新型蛋白替代治疗平台主候选药nomlabofusp是一种重组融合蛋白，旨在通过将蛋白输送至线粒体，直接解决FA患者中的frataxin缺乏。获得美国和欧盟的孤儿药品、罕见儿童疾病（美国）、快速通道（美国）、PRIME（欧盟）和ILAP（英国-MHRA）指定。被FDA选中参加其开始控件试点计划Nomlabofusp普遍耐受良好，并在完成的为期4周的安慰剂对照2期研究和完成的多剂量递增1期研究中，皮肤和颊细胞中的FXN水平呈剂量依赖性增加。截至2024年9月30日现金和投资约20400万提供预计现金运行到2026年潜在首个增加frataxin水平的疗法一致的1期和2期研究结果计划与FDA追求加速批准于2024年第一季度以25毫克/天给予OLE的第一位成年患者;所有7个OLE站点已激活;继续招募患者进行中OLE研究中的入组患者数据和开发计划更新预计在2024年12月中旬计划在2024年底开始Pk运行期青少年研究计划;在青少年队列的安全性和暴露数据评估后将青少年转入OLE遵循基于25毫克剂量的FXN PD的进一步特征化目前计划剂量递增至50毫克临床计划强大的财务基础FDA承认FXN缺乏似乎对FA的致病机制至关重要，并且仍然存在需要解决根本疾病病理生理的治疗的不足。支持加速批准的讨论正在进行。BLA提交目标为2025年下半年Nomlabofusp（CTI-1601）；FA：弗里德莱希共济失调
2015年2020年2030年2035年2040年2045年2050年2055年2010年2025年Nomlabofusp物质组成和治疗方法美国专利11,459,363（来自印第安纳大学的独家许可）美国继续专利和海外申请将在2020年到期物质组成专利Larimar Technology得到支持，有效期至2040年。Nomlabofusp（CTI-1601）物质组成专利延伸至2040年。Nomlabofusp的其他知识产权保护包括覆盖关键生物标志物、分析工具和其他疾病指示的治疗方法的美国和海外申请。Nomlabofusp在美国获批后应有12年的市场独家经营权（独立于专利），在欧盟获批后应有至少10年的市场独家经营权（独立于专利）。平台应用组合和定量Nomlabofusp平台技术：用于蛋白质传递的分子，美国专利11,891,420美国继续和海外申请。包含Nomlabofusp的药学组合物，美国专利2022-0193190美国和海外申请。定量Nomlabofusp的方法，美国专利2022-0276258美国和海外申请。估计2021年12月到期。估计2020年7月到期。估计2021年8月到期（与PTA一起）。待批和已批准。
弗氏共济失调（FA）：一种罕见且进行性疾病（参见E.C. Deutsch等，分子遗传学与代谢1008年第101页238-245）。大多数FA患者仅根据组织、采样技术和考虑的检测方法产生正常frataxin水平的~20-40％。两个等位基因上的遗传缺陷降低了frataxin水平。渐进性疾病。最初症状包括不稳定的姿势和频繁摔倒，患者最终被困于轮椅。30-50年的预期寿命，通常因心脏疾病而早逝。全球约有20,000名患者，美国约有5,000名患者，大多数其余患者位于欧盟。~70％的患者在14岁之前出现。尚未批准的治疗方案可以增加frataxin水平。唯一获得批准用于FA的治疗方案不解决frataxin缺乏问题。
Strong Relationship with FARA – Joined FARA’s TRACK-FA Neuroimaging Consortium as an Industry Partner National, non-profit organization dedicated to the pursuit of scientific research leading to treatments and a cure for FA FARA provides industry with several key items Assistance with patient recruitment and education Access to Global Patient Registry with demographic and clinical information on more than 1,000 FA patients Sponsored a Patient-Focused Drug Development Meeting in 2017 resulting in a publication titled “The Voice of the Patient” TRACK-FA collects natural history data to establish disease specific neuroimaging biomarkers for potential use in clinical trials. Larimar will have access to all study data for use in regulatory filings, as appropriate
Nomlabofusp is Designed to Deliver Additional Frataxin The presence of the cleavage site allows the CPP and MTS to be removed by mitochondrial processing peptidase to produce mature human FXN in the mitochondria STRUCTURE OF ENDOGENOUS FXN STRUCTURE OF NOMLABOFUSP Cleavage by mitochondrial processing peptidase (MPP) at this site produces mature human FXN in mitochondria Mitochondrial Targeting Sequence (MTS) Mature Human FXN Cleavage by mitochondrial processing peptidase (MPP) at this site produces mature human FXN in mitochondria Mature Human FXN Cell Penetrating Peptide (CPP) Mitochondrial Targeting Sequence (MTS) Nomlabofusp (CTI-1601) maintains the cleavage site between the MTS and mature human frataxin (FXN)
FXN Levels Predict Disease Progression in FA Lower FXN levels are associated with earlier onset of disease, faster rate of disease progression, and shorter time to loss of ambulation Adapted from H.L.Plasterer et al. PLoS ONE 2013 8(5):e63958 Age of Onset (Years) Median Time to Loss of Ambulation (Years) < 15 11.5 15 to 24 18.3 > 24 23.5 Median Age of Onset and Rate of Disease Progression in Relation to FXN Levels *FXN levels measured in peripheral blood mononuclear cells (PBMCs). FXN levels as measured by % of normal demonstrated to be equivalent in PBMCs, buccal cells, and whole blood. **FARS: Friedreich’s ataxia rating score, measures disease progression with a higher score indicating a greater level of disability. FXN Level* (% of Normal Level) Age of Onset (Years) FARS** (Change/Year) 11.2 7 2.9 22.0 11 2.1 31.0 16 2.0 48.7 19 1.6 Adapted from C. Rummey et al. EClinicalMedicine. 2020 18:100213 Median Age of Onset Predicts Time to Loss of Ambulation
Completed Ph 2 Dose Exploration Study (25 & 50 mg Cohorts) Goal: Further characterize PK/PD and assess safety to inform long-term dose and dose regimen 28-day Treatment Period - nomlabofusp (CTI-1601) or placebo 16 17 18 19 15 20 21 22 23 24 25 26 27 28 2 3 4 5 1 6 7 8 9 10 11 12 13 14 = Subcutaneous administration of nomlabofusp (CTI-1601) or placebo = No Administration Study Details Population Ambulatory and non-ambulatory Friedreich’s ataxia patients ≥18 years of age Nomlabofusp (CTI-1601) treatment naïve or participated (if eligible) in a previous Larimar study Dose Cohort 1: 25 mg Cohort 2: 50 mg Key Endpoints Frataxin levels in peripheral tissue, PK, safety and tolerability; other exploratory endpoints include lipids and gene expression levels Number of Patients Cohort 1: Enrolled 13 participants (9 on nomlabofusp; 4 on placebo) Cohort 2: Enrolled 15 participants (10 on nomlabofusp; 5 on placebo) Key Results Generally well tolerated; most common adverse events were mild and moderate injection site reactions Dose dependent increases of frataxin levels in tissues tested (skin and buccal cells) Baseline FXN levels in skin cells in the 50 mg cohort were < 17% of the average of healthy volunteers. After daily dosing for 14 days, FXN levels increased to 33% to 59% of the average of the healthy volunteers
Dose-Dependent Increase in FXN Levels in Skin Cells Skin Cells FXN Levels* Change from Baseline** FXN Levels* in Skin Cells Change from Baseline at Day 14 Participants dosed daily for 14 days, then every other day until day 28 *FXN levels measured via detection of peptide derived from mature FXN; FXN concentrations are normalized to total cellular protein content in each sample. Data represent median and 25th and 75th percentiles. Only participants with quantifiable levels at both baseline and Day 14 are included in the figures. **Median baseline FXN levels in patients were 3.5 pg/µg for the placebo, 3.7 pg/µg for the 25 mg cohort and 2.1 pg/µg for the 50 mg cohort. Placebo 25 mg cohort 50 mg cohort Placebo 25 mg cohort 50 mg cohort Day 14 (QD, 1-14) Day 28 (QOD, 15-28)
Dose-Dependent Increase in FXN Levels in Buccal Cells Buccal Cells FXN Levels* Change from Baseline** FXN Levels* in Buccal Cells Change from Baseline at Day 14 Participants dosed daily for 14 days, then every other day until day 28 *FXN levels measured via detection of peptide derived from mature FXN; FXN concentrations are normalized to total cellular protein content in each sample. Data represent median and 25th and 75th percentiles. Only participants with quantifiable levels at both baseline and Day 14 are included in the figures. **Median baseline FXN level in patients were 2.1 pg/µg for the placebo, 1.8 pg/µg for the 25 mg cohort and 1.6 pg/µg for the 50 mg cohort. Placebo 25 mg cohort 50 mg cohort Placebo 25 mg cohort 50 mg cohort Day 14 (QD, 1-14) Day 28 (QOD, 15-28)
Skin Cell FXN Levels Achieve Higher % of Healthy Volunteers* Following 14 days of Daily Nomlabofusp Only participants with quantifiable levels at baseline and day 14 are included in the figures. *% of healthy volunteer FXN level is calculated by dividing each participant's FXN level by the average FXN level (16.34 pg/µg) from the noninterventional healthy volunteer study (N=60). 25 mg of Nomlabofusp 50 mg of Nomlabofusp Baseline FXN levels as a % of average FXN level in healthy volunteers FXN levels increased from baseline and reached > 50% of average FXN level in healthy volunteers FXN levels increased from baseline and reached 25% to < 50% of average FXN level in healthy volunteers % of healthy volunteer FXN level % of healthy volunteer FXN level
Buccal Cell FXN Levels Achieve Higher % of Healthy Volunteers* Following 14 days of Daily Nomlabofusp Only participants with quantifiable levels at baseline and day 14 are included in the figures. *% of healthy volunteer FXN level is calculated by dividing each participant's FXN level by the average FXN level (8.24 pg/µg) from Larimar’s noninterventional healthy volunteer study (N=60). 50 mg of Nomlabofusp Baseline FXN levels as a % of average FXN level in healthy volunteers FXN levels increased from baseline and reached 25% to < 50% of average FXN level in healthy volunteers 25 mg of Nomlabofusp % of healthy volunteer FXN level % of healthy volunteer FXN level
Nomlabofusp: Predictable Pharmacokinetics Quick absorption after subcutaneous administration 1 2 3 Dose-proportional increases in exposure observed cc Pharmacokinetic profile consistent with Phase 1 studies
Open-label Extension Study: Dosed first patient in Q1 2024 Available data on enrolled patients in ongoing OLE and development program update expected in mid-Dec 2024 Key Eligibility Criteria Previous participation in Phase 1 or Phase 2 trials Key Study Objectives Safety and tolerability Long-term PK Dose escalation to 50 mg currently planned following further characterization of FXN pharmacodynamics at 25 mg dose Tissue FXN concentrations and potential use as surrogate endpoint to support accelerated approval Clinical efficacy measures compared to the matched set of untreated patients from FACOMS* database *FACOMS: Friedreich’s Ataxia Clinical Outcome Measures Study. **Estimated screening period may be extended for those study participants who have not been on a stable regimen of omaveloxolone for at least six months. Screening Period ≤ 42 days** Treatment Period Planned for ≥ 1 year All 7 sites activated First patient dosed in March 2024 Continuing to enroll patients Amending study to include adolescents (12-17 yrs) and children (2-11 yrs) after completion of PK run-in study Potential extensions Daily subcutaneous injection of 25 mg nomlabofusp; self-administered or by a caregiver Plan to increase dose to 50 mg daily
Nomlabofusp Clinical Development Plan Planned global double-blind placebo-controlled confirmatory/registration study targeted to be initiated by mid- 2025* Plans to Initiate PK run-in study in adolescents (12-17 yrs) before year end 2024, followed by children (2-11 yrs) in 1H 2025 Intend to pursue accelerated approval pathway with potential BLA submission targeted for 2H 2025 Selected by FDA to participate in its START pilot program *Company initiated discussions with FDA on the potential use of FXN levels to support accelerated approval. Also, the Company is planning discussions with regulators and investigators outside the U.S. to expand clinical program to international geographies. Ongoing open-label extension study with 25 mg daily dosing for eligible patients who participated in SAD, MAD, and/or four-week dose exploration studies OLE BLA submission targeted for 2H 2025 Participants completing the PK run-in study eligible to transition into OLE after assessment of safety and exposure data in the adolescent cohort Available data on enrolled patients in ongoing OLE expected in mid-December 2024
Nomlabofusp is a Competitively Differentiated Treatment Approach* *Competitive landscape focuses on clinical-stage, industry-sponsored programs from public companies Acquisition supports the robust market potential for FA treatments Nomlabofusp is a potential first-and-only protein replacement therapy designed to address the underlying cause of FA $7.3B Approach Product Company Mechanism of Action Clinical Status Protein replacement Nomlabofusp (CTI-1601) Larimar Recombinant frataxin protein Phase II Mitochondrial Oxidative Stress Modifier Omaveloxolone (SKYCLARYS™) Reata Pharma/Biogen Nrf2 Activator Approved (US and EU) Vatiquinone PTC Therapeutics 15-Lipoxygenase Inhibitor Phase III Gene Expression Regulator DT-216P2 (new formulation) Design Therapeutics GeneTAC Pre-clinical Gene Therapy LX2006 Lexeo Therapeutics Frataxin Gene Replacement Phase I/II
Nov 2024: Three posters on Ph1 and Ph 2 dose exploration data at International Congress for Ataxia Research in London (Nov 12-15, 2024) Mid-Dec 2024: Available data on enrolled patients in ongoing OLE and development program update Q4 2024: Initiate PK run-in study in adolescents (ages 12-17 years old) 1H 2025: Initiate PK run-in study in children (ages 2-11 years old) Mid 2025: Initiate global confirmatory/registration study 2H 2025: BLA submission; intend to pursue accelerated approval 2024/2025 Milestones Consistent Ph 1 and Ph 2 Findings Nomlabofusp is generally well tolerated at doses tested up to 4 weeks Dose-dependent increases in FXN levels from baseline in evaluated tissues (skin and buccal cells) Baseline FXN levels in skin cells in the 50 mg cohort were < 17% of the average of healthy volunteers. After daily dosing for 14 days, FXN levels increased to 33% to 59% Clinical & Regulatory Updates Plans to Initiate PK run-in study in adolescents by end of 2024; transition adolescents into OLE after PK study Pursuing clinical sites in the U.S., Europe, the U.K., Canada. and Australia for planned initiation of registration/confirmatory study targeted for mid- 2025 Selected by FDA to participate in its START pilot program Initiated discussions with FDA regarding use of FXN as a surrogate endpoint to support accelerated approval Positive Ph2 Data, OLE Updates & Initiating in Adolescents
Clinical-Stage Novel Protein Replacement Therapy Platform Lead candidate nomlabofusp is a recombinant fusion protein designed to directly address frataxin deficiency in patients with FA by delivering the protein to mitochondria. Granted Orphan Drug (US & EU), Rare Pediatric Disease (US), Fast Track (US), PRIME (EU) and ILAP (UK-MHRA) designations. Selected by FDA to participate in its START pilot program Nomlabofusp was generally well tolerated and demonstrated dose-dependent increases in frataxin (FXN) levels from baseline in skin and buccal cells in a completed 4-week placebo-controlled Phase 2 study and a completed multiple ascending dose Phase 1 study Approximately $204 million in cash and investments as of 9/30/24 Provides projected cash runway into 2026 Potential first therapy to increase frataxin levels Consistent Phase 1 and Phase 2 findings Plan to pursue accelerated approval with FDA Dosed first adult patient in OLE with 25 mg daily in Q1 2024; All 7 OLE sites activated; continuing to enroll patients Available data on enrolled patients in the ongoing OLE study and development program update expected mid-Dec 2024 Plans to initiate PK run-in study in adolescents by end of 2024; transition adolescents into OLE after assessment of safety and exposure data in the adolescent cohort Dose escalation to 50 mg currently planned following further characterization of FXN PD at 25 mg dose Clinical program Strong financial foundation FDA acknowledgement that FXN deficiency appears to be critical to the pathogenic mechanism of FA, and that there continues to be an unmet need for treatments that address the underlying disease pathophysiology. Discussions to support an accelerated approval are ongoing. BLA submission targeted for 2H 2025 Nomlabofusp (CTI-1601); FA: Friedreich's ataxia
THANK YOU Larimar Therapeutics October 2024 Corporate Deck
Appendix Larimar Therapeutics
Scientific Advisory Board Co-founder of Chondrial Therapeutics, which became Larimar Therapeutics, Inc. Professor of Pediatrics at Indiana University School of Medicine Mark Payne, MD Executive Director of the Mitochondrial Medicine Frontier Program at The Children’s Hospital of Philadelphia (CHOP) Professor in the Division of Human Genetics, Department of Pediatrics at University of Pennsylvania Perelman School of Medicine Marni J. Falk, MD Medical Director and Division Chief of the University of California San Francisco (UCSF) Movement Disorders and Neuromodulation Center. Carlin and Ellen Wiegner Endowed Professor of Neurology Jill Ostrem, MD Giovanni Manfredi, MD, PhD Finbar and Marianne Kenny Professor in Clinical and Research Neurology at Weill Cornell Medicine. Professor of Neuroscience at Weill Cornell Medicine.
Mitochondrial Localization and Preclinical Data
Nomlabofusp Transduction of Cells In Vitro Leads to hFXN Located in Mitochondria FXN DAPI TOMM20 DAPI FXN TOMM20 DAPI FXN co-localizes with TOMM20 FXN staining TOMM20 (mitochondria) staining Rat cardiomyocytes (H9C2) were transduced with nomlabofusp Cells were fixed and analyzed by immunofluorescence microscopy to detect the presence of human frataxin (hFXN) and TOMM20 ( a mitochondrial outer membrane protein) Nuclei were stained with DAPI
Nomlabofusp Extends Survival in FXN-deficient KO Mice Median survival of MCK-Cre FXN-KO mice 166 days (nomlabofusp) vs. 98 days (Vehicle) Nomlabofusp administered 10 mg/kg SC every other day Survival beyond vehicle mean (107.5 days) 87.5% (nomlabofusp) vs. 33% (Vehicle) Demonstrates that nomlabofusp is capable of delivering sufficient amounts of FXN to mitochondria Days Percent Survival Nomlabofusp (CTI-1601) rescues a severe disease phenotype in a well-characterized cardiac mouse model of FA P=0.0001 Initial proof-of-concept for FXN replacement therapy in cardiac mouse model of FA
Nomlabofusp Prevents Development of Ataxic Gait in Neurologic KO Mouse Model hFXN replacement with nomlabofusp prevents development of ataxic gait Nomlabofusp-treated mice survive longer than untreated mice Human frataxin present in brain, dorsal root ganglia and spinal cord demonstrating central nervous system penetration In-Vivo Efficacy Data in Pvalb-Cre FXN-KO Mouse Model Single dose level: 10 mg/kg nomlabofusp or vehicle given intraperitoneally three times per week
Nomlabofusp Delivers hFXN to Mitochondria and Restores SDH Activity in KO Mice Mitochondria hFXN concentration increases dose-dependently Given subcutaneously, nomlabofusp functionally replaces hFXN in mitochondria of KO mice MPK = mg/kg MPK = mg/kg Mitochondrial FXN (Heart) SDH Activity (Muscle) Succinate dehydrogenase (SDH) activity, which is indicative of mitochondrial function, increases in a dose-dependent manner after administration of nomlabofusp; activity plateaus at 30 mg/kg and is equivalent to activity in wild type Study Design – Cardiac and skeletal muscle FXN knockout mice (MCK-CRE) were treated at varying SQ doses of nomlabofusp every other day for two weeks at Jackson Laboratories (Bar Harbor, ME). After dosing, animals were sacrificed, and heart and skeletal muscle were evaluated for hFXN concentration in mitochondrial extracts and SDH activity was assessed.
Nomlabofusp Prevents Left Ventricle Dilation in KO Mice Left ventricular (LV) 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 nomlabofusp (10 mg/kg every other day) Diameter (mm) Age in Weeks Age in Weeks Volume (μL) KO: CTI-1601 Wild-type: Vehicle KO: Vehicle Left Ventricle Internal Diameter (Systole) Left Ventricle Volume (Systole) Study Design – Cardiac and skeletal muscle FXN knockout mice (MCK-CRE) were treated at 10 mg/kg every other day at Jackson Laboratories (Bar Harbor, ME). Echocardiograms were performed pre-dose and post dose. Nomlabofusp-treated mice have similar LV volume as wild type; echocardiogram shows significant differences between vehicle and nomlabofusp treated (10 mg/kg every other day) KO mice
Nomlabofusp Preserves Left Ventricle Function in KO Mice Percent Change Age in Weeks Left Ventricle Ejection Function Left Ventricle Fractional Shortening Percent Change Age in Weeks KO: CTI-1601 Wild-type: Vehicle KO: Vehicle Study Design – Cardiac and skeletal muscle FXN knockout mice (MCK-CRE) were treated at 10 mg/kg every other day at Jackson Laboratories (Bar Harbor, ME). Echocardiograms were performed pre-dose and post dose. Left ventricular (LV) function drops significantly in vehicle treated mice by Week 8 Nomlabofusp-treated (10 mg/kg every other day) mice have similar LV function as wildtype; echocardiogram shows significant differences between vehicle and nomlabofusp treated KO mice
Phase 1 Clinical Data
CTI-1601: Phase 1 Clinical Program in Patients with FA Phase 1 Development Plan Two double-blind, placebo-controlled dosing trials in patients with FA Patient dosing began December 2019 Safety Review Committee assessed all blinded data between each cohort to ensure patient safety Number of subjects: 28 Dose levels: 25 mg, 50 mg, 75 mg and 100 mg (subcutaneous administration) Treatment Duration: 1 day 1º Endpoint: Safety and tolerability 2º Endpoints: PK; PD; FXN levels; multiple exploratory Status: Complete Single Ascending Dose (SAD) Number of Subjects: 27 Dose Range: 25 mg, 50 mg, 100 mg (subcutaneous administration) Treatment Regimen: Multiple increasing doses administered subcutaneously over 13 days 1º Endpoint: Safety and tolerability 2º Endpoints: PK; PD; FXN levels (buccal cells, platelets, optional skin biopsies); multiple exploratory Status: Complete Multiple Ascending Dose (MAD) Eligible patients from SAD trial could enroll in MAD trial Program consisted of double-blind, placebo controlled single- and multiple-ascending dose trials
Completed Phase 1 Multiple Ascending Dose Study Treatment Schedules for Each Cohort- nomlabofusp (CTI-1601) or placebo 13-day Treatment Period Cohort 2 (50 mg; n = 9) 2 3 4 5 1 6 7 8 9 10 11 12 13 14 = Administration of nomlabofusp or placebo = No Administration 13-day Treatment Period Cohort 1 (25 mg; n = 8) 2 3 4 5 1 6 7 8 9 10 11 12 13 14 = Administration of nomlabofusp or placebo = No Administration 13-day Treatment Period Cohort 3 (100 mg n = 10) 2 3 4 5 1 6 7 8 9 10 11 12 13 14 = Administration of nomlabofusp or placebo = No Administration FXN Level Sampling Days Presented for Each Cohort Cohort 1 Sampling Days Buccal Cells Baseline, Day 4, Day 13 Skin Baseline, Day 13 Platelets Baseline, Day 4, Day 13 Cohort 2 Sampling Days Buccal Cells Baseline, Day 7, Day 13 Skin Baseline, Day 13 Platelets Baseline, Day 7, Day 13 Cohort 3 Sampling Days Buccal Cells Baseline, Day 7, Day 13 Skin Baseline, Day 13 Platelets Baseline, Day 7, Day 13
Dose Dependent Increases in FXN Levels Observed in Skin and Buccal Cells in Phase 1 *FXN levels measured via detection of peptide derived from mature FXN; FXN concentrations are normalized to total cellular protein content in each sample; Data represent median and 25th and 75th percentiles; FXN levels from Day 4, & Day 13 measurements are shown for data derived from the 25 mg cohort; FXN levels from Day 7 & Day 13 measurements are shown for data derived from the 50 & 100 mg cohorts; FXN* Change from Baseline By Dose Group (Skin Cells) FXN* Change from Baseline By Dose Group (Buccal Cells) Placebo: Participants randomized to placebo in each cohort 25 mg: Dosed daily for 4 days, every third day thereafter 50 mg: Dosed daily for 7 days, every other day thereafter 100 mg: Dosed daily for 13 days
MAD Trial Patient Demographics Parameter Statistic All placebo (n=7) 25 mg CTI-1601 (n=6) 50 mg CTI-1601 (n=7) 100 mg CTI-1601 (n=7) All CTI-1601 (n=20) Overall (n=27) Sex Male n (%) 5 (71.4) 3 ( 50.0) 4 ( 57.1) 3 ( 42.9) 10 ( 50.0) 15 (55.6) Female n (%) 2 (28.6) 3 ( 50.0) 3 ( 42.9) 4 ( 57.1) 10 ( 50.0) 12 (44.4) Age (years) Mean 25.7 39.7 34.7 28.0 33.9 31.7 SD 6.37 16.59 9.03 8.96 12.13 11.40 Median 23 37 36 24 34 28 Min, Max 20,36 21,65 19,47 20,44 19,65 19,65 Race White n (%) 6 ( 85.7) 6 (100.0) 6 ( 85.7) 6 ( 85.7) 18 ( 90.0) 24 (88.9) Asian n (%) 0 0 1 ( 14.3) 1 ( 14.3) 2 ( 10.0) 2 ( 7.4) American Indian n (%) 1 ( 14.3) 0 0 0 0 1 (3.7) Ethnicity Hispanic/Latino n (%) 2 (28.6) 0 0 0 0 2 (7.4) Not Hispanic/Latino n (%) 5 (71.4) 6 (100.0) 7 (100.0) 7 (100.0) 20 (100.0) 25 (92.6) SD: Standard deviation
MAD Trial Patient Disease Characteristics Parameter Statistic All placebo (n=7) 25 mg CTI-1601 (n=6) 50 mg CTI-1601 (n=7) 100 mg CTI-1601 (n=7) All CTI-1601 (n=20) Overall (n=27) Age at Symptom Onset Mean 14.1 24.0 19.3 11.9 18.1 17.1 SD 5.34 14.48 6.21 6.72 10.37 9.39 Median 15.0 18.0 19.0 10.0 18.0 16.0 Min, Max 8,23 12,44 8,28 5,22 5,44 5,44 Age at Diagnosis Mean 18.3 31.5 26.4 15.9 24.3 22.7 SD 7.87 19.88 4.28 8.21 13.24 12.23 Median 20.0 25.5 28.0 13.0 27.0 21.0 Min, Max 9,32 14,64 17,30 5,27 5,64 5,64 Assistive Device Walker n (%) 0 2 (33.3) 3 (42.9) 0 5 (25.0) 5 (18.5) Wheelchair n (%) 4 (57.1) 3 (50.0) 1 (14.3) 6 (85.7) 10 (50.0) 14 (51.9) Other n (%) 1 (14.3) 0 1(14.3) 0 1 (5.0) 2 (7.4) None n (%) 2 (28.6) 1 (16.7) 2 (28.6) 1 (14.3) 4 (20.0) 6 (22.2) SD: Standard deviation
Summary of MAD Trial PK Analyses CTI-1601 was quickly absorbed after subcutaneous administration Dose-proportional increases in exposure observed with increasing doses of CTI-1601 Mean half life of CTI-1601 in plasma was approximately 11 hours CTI-1601 appeared to be at or close to steady state exposure after 13 days of dosing 100 mg once daily PK analyses support evaluating once-daily and every-other-day dosing regimens for CTI-1601
Phase 2 Demographic/ Disease Characteristics and Additional Data
Demographics – Phase 2 Trial 25 mg Cohort 50 mg Cohort Placebo N = 4 Nomlabofusp N = 9 Overall N = 13 Placebo N = 5 Nomlabofusp N = 10 Overall N = 15 Age at Screening (Years) Mean (SD) 34.0 (9.20) 37.8 (14.93) 36.6 (13.16) 28.6 (4.67) 28.1 (11.00) 28.3 (9.17) Median 33 31 31 27 24 26 Q1, Q3 27, 42 27, 42 27, 42 26, 30 21, 32 21, 32 Min, Max 25, 45 25, 69 25, 69 24, 36 19, 54 19, 54 Sex n (%) Male 2 (50.0) 5 (55.6) 7 (53.8) 1 (20.0) 4 ( 40.0) 5 (33.3) Female 2 (50.0) 4 (44.4) 6 (46.2) 4 (80.0) 6 ( 60.0) 10 (66.7) Previously Treated with Nomlabofusp n (%) Yes 1 ( 25.0) 3 ( 33.3) 4 ( 30.8) 0 1 ( 10.0) 1 ( 6.7) No 3 ( 75.0) 6 ( 66.7) 9 ( 69.2) 5 (100.0) 9 ( 90.0) 14 ( 93.3)
Disease Characteristics – Phase 2 Study 25 mg Cohort 50 mg Cohort Placebo N = 4 Nomlabofusp N = 9 Overall N = 13 Placebo N = 5 Nomlabofusp N = 10 Overall N = 15 Age at Symptom Onset (Years) Mean (SD) 14.5 (4.93) 13.0 (10.47) 13.5 (8.77) 15.2 (7.26) 13.7 (8.37) 14.2 (7.78) Median 14.5 10 11 14 12.5 14 Q1, Q3 11, 19 8, 13 9, 15 11, 16 7, 18 7, 18 Min, Max 9, 20 5, 38 5, 38 8, 27 5, 30 5, 30 Age at Diagnosis (Years) Mean (SD) 17.5 (5.57) 18.6 (11.20) 18.2 (9.58) 18.6 (6.80) 16.6 (8.03) 17.3 (7.46) Median 16.5 16 16 19 13.5 14 Q1, Q3 14, 22 14, 20 14, 20 13, 20 10, 21 12, 21 Min, Max 12, 25 5, 42 5, 42 12, 29 9, 30 9, 30 Time Since Diagnosis (Years) Mean (SD) 16.1 (5.97) 18.5 (11.52) 17.8 (9.94) 9.5 (3.72) 11.9 (7.05) 11.1 (6.10) Median 13.42 14.32 13.5 11 11.26 11 Q1, Q3 12.9, 19.3 12.8, 21.6 12.8, 21.6 5.8, 11.3 7.4, 15.3 5.8, 15.2 Min, Max 12.5, 25.0 5.4, 45.0 5.4, 45.0 5.6, 14.0 2.3, 25.1 2.3, 25.1
Absolute Increases in Skin FXN Levels Day 14 Skin FXN Levels Dose Visit Absolute Values (pg/µg) Median Mean 25 mg Baseline 3.70 3.38 Day 14 5.53 6.40 Change from Baseline 2.81 3.02 50 mg Baseline 2.12 2.08 Day 14 7.40 7.32 Change from Baseline 5.57 5.24 Dose response in tissue FXN concentrations and increases from baseline after dosing Only participants with quantifiable levels at baseline and day 14 and day 28 are included in the tables. Day 28 Skin FXN Levels Dose Visit Absolute Values (pg/µg) Median Mean 25 mg Baseline 3.70 3.38 Day 28 4.39 4.80 Change from Baseline 2.28 1.41 50 mg Baseline 2.12 2.08 Day 28 5.23 5.24 Change from Baseline 3.14 3.17
Absolute Increases in Buccal FXN Levels Day 14 Buccal FXN Levels Dose Visit Absolute Values (pg/µg) Median Mean 25 mg Baseline 1.78 1.80 Day 14 2.24 2.22 Change from Baseline 0.56 0.42 50 mg Baseline 1.61 1.69 Day 14 2.44 2.38 Change from Baseline 0.72 0.69 Dose response in tissue FXN concentrations and increases from baseline after dosing Only participants with quantifiable levels at baseline and day 14 and day 28 are included in the tables. Day 28 Buccal FXN Levels Dose Visit Absolute Values (pg/µg) Median Mean 25 mg Baseline 1.70 1.65 Day 28 1.73 1.76 Change from Baseline 0.03 0.11 50 mg Baseline 1.76 1.77 Day 28 2.15 2.15 Change from Baseline 0.48 0.38
Non-Interventional Study Data
CLIN-1601-002: Top-line Non-interventional Study Results Non-interventional study measured FXN in homozygous healthy volunteers FXN concentrations were measured in skin and buccal cells from 60 homozygous healthy volunteers utilizing the same sampling technique and assay as clinical trials of nomlabofusp; FXN levels measured via detection of peptide derived from mature FXN; FXN concentrations normalized to total cellular protein content in each sample. 1. E.C. Deutsch et al. Molecular Genetics and Metabolism 101 (2010) 238–245. 2. Friedreich’s Ataxia Research Alliance Skin cells Buccal cells Median Frataxin Concentration (pg/µg) in Homozygous Healthy Volunteers (n = 60) Most patients with FA only produce ~20-40%1 of normal frataxin levels depending on the tissue, sampling technique, and assay considered Lower FXN levels seen with typical onset2 (5 to 15 years of age) Higher FXN levels seen with late onset2 (after 25 years of age) Heterozygous carriers who show no signs of disease have buccal cell FXN levels of ~50% of unaffected healthy persons1 [13.5, 18.6] IQR [6.2, 9.4] IQR
FDA START Pilot Program
Nomlabofusp Selected by FDA for START Pilot Program Highlights FDA commitment to augment formal meetings with more rapid, ad-hoc communications to accelerate program development of rare diseases START Pilot Program Support for Clinical Trials Advancing Rare Disease Therapeutics A new milestone-driven program launched by the FDA in September 2023 Designed to accelerate development of novel therapies intended to address unmet medical needs in rare diseases 7 novel drugs selected 3 products by CDER (nomlabofusp) for rare neurodegenerative conditions 4 products by CBER for cell and gene therapy FDA: Food and Drug Administration; CDER: Center for Drug Evaluation and Research; CBER: Center for Biologics Evaluation and Research; CMC: Chemistry, Manufacturing, and Controls CDER Selection Based On Demonstrated development program readiness (e.g., sponsors who demonstrate the ability to move the program towards a marketing application) Potential to address serious and unmet medical need in a rare neurodegenerative condition Alignment of CMC development timelines with clinical development plans Proposed plan where enhanced communication can improve efficiency of product development