Mitochondrial Diseases

SBT-589 showed mitochondrial protection across models of Friedreich's ataxia SBT-589 displayed cardioprotective effects in aggressive mouse model of FA cardiomyopathy Ongoing studies are expected to build on these insights as SBT-589 progresses through developmental stage-gates NEEDHAM, Mass., March 19, 2024 /PRNewswire/ -- Stealth BioTherapeutics Inc. (the "Company" or "Stealth"), a clinical-stage biotechnology company focused on the discovery, development, and commercialization of novel therapies for diseases involving mitochondrial dysfunction, announced today the presentation of new SBT-589 data demonstrating cardioprotective effects across pre-clinical models of Friedreich's ataxia (FA). The data were presented at the Wellcome Trust Conference on Mitochondrial Medicine – Therapeutic Development, held March 18-20, 2024, in Cambridge, England. FA is a chronic disease of metabolic disruption that is typically diagnosed in childhood or adolescence, is inexorably progressive and usually results in premature death from cardiomyopathy or heart failure. There are no approved therapies for the progressive cardiomyopathy, which is linked to severe mitochondrial dysfunction, and is the leading cause of early death in this devastating disease. SBT-589 is a promising novel molecule that acts on mitochondrial pathways essential for cellular health and energy production that are impaired in FA cardiomyopathy. To evaluate the potential of SBT-589 in FA, a series of studies were conducted in FA patient-derived cells, isolated heart mitochondria, and an aggressive mouse model of FA cardiomyopathy. SBT-589 improved bioenergetics in FA patient-derived cells and mitochondria. In an FA mouse model with prominent cardiac hypertrophy and aggressive mortality, mice treated with once-daily SBT-589 displayed significantly reduced cardiac hypertrophy and a delay in the onset of mortality compared to vehicle-treated mice. "Mitochondrial dysfunction is a central contributor to pathology in Friedreich's ataxia, a disease in which heart failure and sudden cardiac events are among the leading causes of mortality," said David A. Brown, Senior Vice President, Discovery. "Mitigating heart disease in FA is central to Stealth's ongoing efforts to improve the lives of individuals with FA. The new findings presented today support continued development of SBT-589 as a potentially disease-modifying therapy to address the unmet need in cardiomyopathy associated with Friedreich's ataxia." The data were presented by Dr. Laura E. Kropp, Senior Manager of Discovery Biology at Stealth, and recipient of the Keith Michael Andrus Cardiac Award from the Friedreich's Ataxia Research Alliance. About Friedreich's Ataxia Friedreich's ataxia is a rare genetic disease affecting an estimated 1 in 50,000 individuals in the United States. The disease is caused by a defect in the frataxin gene resulting in a relative deficiency of frataxin, leading to mitochondrial iron accumulation and oxidative stress. More than 90% of patients with Friedreich's ataxia experience progressive cardiomyopathy which usually becomes fatal by early adulthood and is the leading cause of early mortality. About Stealth BioTherapeutics Stealth BioTherapeutics is a clinical-stage biotechnology company focused on the discovery, development, and commercialization of novel therapies for age-related and rare genetic diseases involving mitochondrial dysfunction. The Company is initiating Phase 3 clinical trials of elamipretide, its lead investigational product candidate, in dry age-related macular degeneration. Elamipretide is also being tested in a fully enrolled Phase 3 clinical trial in primary mitochondrial myopathy, a rare skeletal myopathic disease caused by nuclear DNA mutations, and is the subject of a New Drug Application for Barth syndrome, an ultra-rare cardioskeletal disease. The Company is evaluating its second-generation clinical-stage candidate, SBT-272, for ophthalmic and neurological disease indications. The Company has a deep pipeline of novel mitochondria-targeted compounds under evaluation as therapeutic product candidates. Several of these lead compounds, including SBT-589, have progressed through pre-clinical development stage-gates and toward IND-enabling studies. Investor Contact Kendall Investor Relations Adam Bero, Ph.D. [email protected] [email protected] Media Contact Anna Stallman Communications Anna Stallman [email protected] SOURCE Stealth BioTherapeutics Inc.

Positive top-line data from Phase 2 dose exploration study of nomlabofusp, which was generally well-tolerated, with dose-dependent increases in tissue frataxin levels observedInitiated discussions with the Food and Drug Administration (FDA) on the potential use of tissue frataxin levels as a novel surrogate endpoint to support a Biologics License Application (“BLA”) submission for accelerated approval targeted for 2H 2025In January 2024, initiated open label extension (OLE) study with 25 mg daily dosing of nomlabofusp, with first patient dosed in March 2024; interim data expected in Q4 2024 Recent successful financing that raised $161.6 million extends expected operating runway into 2026. BALA CYNWYD, Pa., March 14, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today reported its fourth quarter and full year 2023 operating and financial results. “This year we made tremendous progress across key clinical and regulatory milestones for our nomlabofusp program. We were thrilled to recently report positive top-line data and successful completion of our Phase 2 dose exploration study. Nomlabofusp was generally well-tolerated and demonstrated dose-dependent increases in skin and buccal cell frataxin levels. Importantly, skin frataxin levels as a percentage of levels in healthy volunteers more than doubled in all patients after 14 days of daily treatment with 50 mg. The clear dose-response and the magnitude of increase in tissue frataxin levels further reinforces the therapeutic potential of nomlabofusp to address frataxin deficiency, the known root cause of disease in patients with Friedreich’s ataxia (FA),” said Carole Ben-Maimon, MD, President, and Chief Executive Officer of Larimar. “Additionally, the first patient in our OLE study has been dosed. The OLE study will inform on the long-term safety profile and long-term tissue frataxin levels. We remain on track to report interim data from the OLE study in the fourth quarter of 2024.” Dr. Ben-Maimon continued, “On the regulatory front, we are continuing discussions with the FDA on the potential use of frataxin as a novel surrogate endpoint to support accelerated approval. We are also beginning to plan for a global double-blind placebo-controlled confirmatory study expected to be initiated prior to a potential BLA submission. The BLA submission is targeted for the second half of 2025. We believe our clinical datasets supporting nomlabofusp’s differentiated mechanism of action, coupled with our strengthened balance sheet and expected runway into 2026, strongly position us for execution of our upcoming pivotal milestones designed to help address the urgent unmet needs of the FA community.” Recent Highlights In February 2024, Larimar announced positive top-line data and successful completion of its four-week, placebo-controlled Phase 2 dose exploration study of nomlabofusp (CTI-1601) in patients with FA. Nomlabofusp was generally well-tolerated up to 4-weeks, had a predictable pharmacokinetic profile, and led to dose-dependent increases in frataxin in skin and buccal cells after daily dosing of 14 days followed by every other day dosing until day 28 in the 25 mg and 50 mg cohorts. Increases in frataxin levels in skin cells were seen in all treated patients, and in buccal cells for the majority of patients. At Day 14, all patients (with quantifiable levels at baseline and Day 14) treated with 50 mg of nomlabofusp achieved frataxin levels in skin cells greater than 33% of the average level found in healthy volunteers, with 3 patients achieving levels greater than 50% of the average healthy volunteer level.In February 2024, Larimar announced that it had initiated discussions with the FDA on use of tissue frataxin levels as a potential novel surrogate endpoint. Larimar received FDA acknowledgement that frataxin 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 with a BLA submission targeted for 2H 2025.In February 2024, Larimar raised net proceeds of approximately $161.6 million through a public offering of common stock. In March 2024, the first patient in the OLE study evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver was dosed. Participants who completed treatment in the Phase 2 dose exploration trial, or who previously completed a prior clinical trial of nomlabofusp, are potentially eligible to screen for the OLE study. The OLE study will evaluate the safety and tolerability, pharmacokinetics, and frataxin levels in peripheral tissues as well as other exploratory pharmacodynamic markers (lipid profiles and gene expression data) following long-term subcutaneous administration of nomlabofusp. Clinical assessments collected during the trial will be compared to data from a matched control arm derived from participants in the Friedreich’s Ataxia Clinical Outcome Measures Study (FACOMS) database. Interim data is expected in Q4 2024. To potentially escalate dose in the OLE study, data from the 50 mg cohort of the Phase 2 study, as well as available data from the 25 mg dose in the OLE study will be submitted for FDA review due to continued partial clinical hold. Fourth Quarter and Full Year 2023 Financial Results As of December 31, 2023, the Company had cash, cash equivalents and marketable securities totaling $86.8 million. As noted above, in February 2024, we raised approximately $161.6 million in net proceeds through a public offering of common stock. The Company reported a net loss for the fourth quarter of 2023 of $13.0 million, or $0.30 per share, compared to a net loss of $9.4 million, or $0.21 per share, for the fourth quarter of 2022. Research and development expenses for the fourth quarter of 2023 were $10.6 million compared to $7.2 million for the fourth quarter of 2022. The increase in research and development expenses compared to the prior year period was primarily driven by an increase of $1.1 million in drug manufacturing costs, an increase of $0.8 million in consulting expenditures, an increase of $0.7 million in personnel expense, an increase of $0.4 million in clinical costs related to an increase in the OLE study partially offset by a decrease in clinical costs associated with the Phase 2 nomlabofusp trial discussed above. General and administrative expenses for the fourth quarter of 2023 were $3.5 million compared to $3.2 million for the fourth quarter of 2022. The increase in general and administrative expense was primarily driven by an increase of $0.2 million in stock-based compensation expense associated with stock option grants made in 2023, an increase of $0.1 million in personnel expense and an increase of $0.1 million in operational costs primarily related to technology, partially offset by a decrease of $0.2 million in legal fees. For the full year 2023, the Company reported a net loss of $36.9 million, or $0.84 per share, compared to a net loss of $35.4 million, or $1.37 per share for the same period in 2022. Research and development expenses for the full year 2023 were $27.7 million compared to $24.3 million for the same period in 2022. The increase in research and development expenses compared to the prior year period was primarily driven by an increase of $1.9 million in personnel expense, an increase of $1.3 million in clinical expense, an increase of $1.1 million in consulting expenditures, an increase of $0.5 million in nonclinical development costs, an increase of $0.5 million in internal lab costs, and an increase of $0.3 million in stock-based compensation expense associated with stock option grants made in 2022 and 2023, partially offset by a decrease of $2.0 million in drug manufacturing costs and a decrease of $0.2 million in royalty fees associated with the milestone achieved in 2022. General and administrative expenses for the full year 2023 were $14.1 million compared to $12.3 million for the same period in 2022. The increase in general and administrative expense was primarily driven by an increase of $0.7 million in stock-based compensation expense associated with stock option grants made in 2022 and 2023, an increase of $0.5 million in personnel expense, an increase of $0.5 million in operational costs primarily related to technology and an increase of $0.4 million in professional fees primarily related to legal, accounting and consulting services, partially offset by a decrease of $0.3 million in insurance expense. About Larimar TherapeuticsLarimar Therapeutics, Inc. (Nasdaq: LRMR), is a clinical-stage biotechnology company focused on developing treatments for complex rare diseases. Larimar’s lead compound, nomlabofusp, is being developed as a potential treatment for Friedreich's ataxia. Larimar also plans to use its intracellular delivery platform to design other fusion proteins to target additional rare diseases characterized by deficiencies in intracellular bioactive compounds. For more information, please visit: https://larimartx.com. Forward-Looking StatementsThis press release contains forward-looking statements that are based on Larimar’s management’s beliefs and assumptions and on information currently available to management. All statements contained in this release other than statements of historical fact are forward-looking statements, including but not limited to statements regarding Larimar’s ability to develop and commercialize nomlabofusp (also known as CTI-1601) and other planned product candidates, Larimar’s planned research and development efforts, including the timing of its nomlabofusp clinical trials, interactions with the FDA and overall development plan and other matters regarding Larimar’s business strategies, ability to raise capital, use of capital, results of operations and financial position, and plans and objectives for future operations. In some cases, you can identify forward-looking statements by the words “may,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “anticipate,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “ongoing” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. These statements involve risks, uncertainties and other factors that may cause actual results, performance, or achievements to be materially different from the information expressed or implied by these forward-looking statements. These risks, uncertainties and other factors include, among others, the success, cost and timing of Larimar’s product development activities, nonclinical studies and clinical trials, including nomlabofusp clinical milestones and continued interactions with the FDA; that preliminary clinical trial results may differ from final clinical trial results, that earlier non-clinical and clinical data and testing of nomlabofusp may not be predictive of the results or success of later clinical trials, and assessments; that the FDA may not ultimately agree with Larimar’s nomlabofusp development strategy; the potential impact of public health crises on Larimar’s future clinical trials, manufacturing, regulatory, nonclinical study timelines and operations, and general economic conditions; Larimar’s ability and the ability of third-party manufacturers Larimar engages, to optimize and scale nomlabofusp’s manufacturing process; Larimar’s ability to obtain regulatory approvals for nomlabofusp and future product candidates; Larimar’s ability to develop sales and marketing capabilities, whether alone or with potential future collaborators, and to successfully commercialize any approved product candidates; Larimar’s ability to raise the necessary capital to conduct its product development activities; and other risks described in the filings made by Larimar with the Securities and Exchange Commission (SEC), including but not limited to Larimar’s periodic reports, including the annual report on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K, filed with or furnished to the SEC and available at www.sec.gov. These forward-looking statements are based on a combination of facts and factors currently known by Larimar and its projections of the future, about which it cannot be certain. As a result, the forward-looking statements may not prove to be accurate. The forward-looking statements in this press release represent Larimar’s management’s views only as of the date hereof. Larimar undertakes no obligation to update any forward-looking statements for any reason, except as required by law. Investor Contact: Joyce Allaire LifeSci Advisors jallaire@lifesciadvisors.com (212) 915-2569 Company Contact:Michael Celano Chief Financial Officermcelano@larimartx.com(484) 414-2715 Larimar Therapeutics, Inc.Consolidated Balance Sheet(dollars in thousands except share and per share data) December 31, December 31, 2023 2022 Assets Current assets: Cash and cash equivalents $26,749 $26,825 Marketable securities 60,041 91,603 Prepaid expenses and other current assets 3,385 2,311 Total current assets 90,175 120,739 Property and equipment, net 684 831 Operating lease right-of-use assets 3,078 2,858 Restricted cash 1,339 1,339 Other assets 659 638 Total assets $95,935 $126,405 Liabilities and Stockholders’ Equity Current liabilities: Accounts payable $1,283 $1,686 Accrued expenses 7,386 8,408 Operating lease liabilities, current 837 611 Total current liabilities 9,506 10,705 Operating lease liabilities 4,709 4,797 Total liabilities 14,215 15,502 Commitments and contingencies (See Note 8) Stockholders’ equity: Preferred stock; $0.001 par value per share; 5,000,000 shares authorized as of December 31, 2023 and December 31, 2022; no shares issued and outstanding as of December 31, 2023 and December 31, 2022 — — Common stock, $0.001 par value per share; 115,000,000 shares authorized as of December 31, 2023 and December 31, 2022; 43,909,069 and 43,269,200 shares issued and outstanding as of December 31, 2023 and December 31, 2022, respectively 43 43 Additional paid-in capital 270,150 262,496 Accumulated deficit (188,554) (151,605) Accumulated other comprehensive loss 81 (31) Total stockholders’ equity 81,720 110,903 Total liabilities and stockholders’ equity $95,935 $126,405 Larimar Therapeutics, Inc.Consolidated Statements of Operations(In thousands, except share and per share data) Three Months Ended December 31, Year Ended December 31, 2023 2022 2023 2022 Operating expenses: Research and development $10,648 $7,218 $27,670 $24,250 General and administrative 3,514 3,221 14,088 12,276 Total operating expenses 14,162 10,439 41,758 36,526 Loss from operations (14,162) (10,439) (41,758) (36,526)Other income, net 1,169 1,014 4,809 1,171 Net loss $(12,993) $(9,425) $(36,949) $(35,355)Net loss per share, basic and diluted $(0.30) $(0.21) $(0.84) $(1.37)Weighted average common shares outstanding, basic and diluted 43,905,903 43,897,603 43,901,241 25,761,394

Developing novel therapeutics which enhance the removal of dysfunctional mitochondria, promoting cell health and function MTX325 is a potentially disease-modifying treatment for Parkinson's Disease with clinical trial due to start imminently Backed by blue chip international investors CAMBRIDGE, England, March 14, 2024 /PRNewswire/ -- Mission Therapeutics ("Mission" or the "Company"), a clinical-stage biotech developing first-in-class therapeutics that enhance mitophagy to promote cell/organ health, today announces it has raised £25.2 million to progress the clinical development of its drug candidates. The financing was jointly led by existing investors Pfizer Venture Investments, Sofinnova Partners, Roche Venture Fund, SR One, IP Group, and Rosetta Capital. Mission plans to use the funds to accelerate development of its lead drug candidates, MTX325 and MTX652, through clinical trials. MTX325 and MTX652 both inhibit USP30, a mitochondrial de-ubiquitylating enzyme (DUB), increasing damage-associated mitochondrial ubiquitylation to promote mitophagy – the essential process cells use to rid themselves of dysfunctional mitochondria. A growing body of scientific evidence has linked a build-up of dysfunctional mitochondria in cells to a range of diseases, including Parkinson's Disease (PD), Kidney Disease, Heart Failure, and Duchenne's Muscular Dystrophy (DMD). MTX325, a CNS penetrant which is a potential disease-modifying treatment for Parkinson's Disease, is about to enter Phase I trials; while peripherally-restricted MTX652 is currently in Phase II investigating acute kidney injury (AKI) associated with cardiac surgery. Dr Anker Lundemose, Chief Executive Officer of Mission Therapeutics, said: "Mission Therapeutics has made huge strides in developing its pipeline, first progressing MTX652 into Phase II, then obtaining robust preclinical proof-of-concept data for its Parkinson's candidate MTX325 - published in Nature Communications - followed by regulatory approval for MTX325 clinical trials in the UK. Thanks to this additional £25.2m from our investors, we can now make the next vital steps, progressing with essential clinical trials." Dr James B. Summers, Acting Chairman of Mission Therapeutics, said: "Mission's laser focus on mitophagy has resulted in a promising suite of drugs that tackle a range of hard-to-treat diseases in a unique and novel way. This latest financing round is a sign of our investors' confidence in the Company and the enormous potential of our clinical assets." The Nature Communications paper, published last November by scientists at Cambridge University, Harvard University and Mission Therapeutics, provided key experimental evidence to support the thesis that MTX325 can modify the course of Parkinson's by targeting USP30. By first using a USP30 knockout mouse model, and then a pharmacological strategy deploying MTX325, they found USP30 inhibition led to protection against loss of dopamine and dopaminergic neurons induced by alpha-synuclein in vivo. USP30 inhibition also reduced potential biomarkers of PD including phosphorylated alpha-synuclein and glial cell activation. In December, the sister publication Nature Reviews Drug Discovery commented that restoring mitophagy to accelerate the removal of damaged mitochondria was "an appealing disease-modifying therapeutic strategy" for Parkinson's Disease. The same month, Mission gained clearance from the US FDA to commence a Phase II trial of MTX652, after the Company received official approval of its Investigational New Drug (IND) application for the candidate drug. About Mission Therapeutics Mission Therapeutics is a world leader in discovering and developing novel therapeutics which promote the removal of dysfunctional mitochondria, promoting cell health and function. Mitochondria are energy producing organelles which require lifetime quality control through a ubiquitin-mediated clearance mechanism known as mitophagy. In certain situations, such as cellular stress, cell injury, and/or defects of the mitophagy process, the mitochondria can become dysfunctional and damaging to the cell, leading to reduced energy production, oxidative stress, inflammation and potentially cell death. Dysfunctional mitochondria are significant drivers of disease pathophysiology in acute kidney injury (AKI), Parkinson's Disease (PD), heart failure, Duchenne's Muscular Dystrophy, IPF, mitochondrial diseases and Alzheimer's. USP30 is a deubiquitylating enzyme that constantly removes ubiquitin from mitochondria, providing a potential brake on clearance of dysfunctional mitochondria. Mission is currently developing two small molecule drugs, MTX652 (peripheral) and MTX325 (targeting the CNS) which, through inhibition of the mitochondrial DUB enzyme USP30, will promote clearance of dysfunctional mitochondria – consequently improving overall cellular health. Mission's USP30 inhibitors MTX652 and MTX325 could potentially be used to treat any disease or condition driven by mitochondrial dysfunction. Mission is backed by blue chip investors including Pfizer Venture Investments, Sofinnova Partners, Roche Venture Fund, SR One, IP Group and Rosetta Capital. SOURCE Mission Therapeutics