LYT-200

LYT-200 is generally safe and well-tolerated as a single agent as well as in combination with standard-of-care venetoclax and hypomethylating agents LYT-200 demonstrates clinical benefit as a single agent, with two partial responses and 59% of evaluable patients achieving stable disease or better In combination, two complete responses were seen and 80% of evaluable patients achieved stable disease or better 1 Data support LYT-200 as a potential first-line treatment for AML/MDS patients BOSTON, MA, USA I December 09, 2024 I PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) (“PureTech” or the “Company”), a clinical-stage biotherapeutics company dedicated to changing the lives of patients with devastating diseases, presented data from the dose escalation phase of its ongoing Phase 1b trial evaluating LYT-200, a first-in-class anti-galectin-9 monoclonal antibody, in patients with relapsed or refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) at the 2024 American Society of Hematology (ASH) Annual Meeting in San Diego, California. LYT-200 is currently being evaluated both as a monotherapy and in combination with the standard-of-care venetoclax and hypomethylating agents (HMA) for patients whose disease is relapsed/refractory to at least one line of prior treatment. It targets galectin-9, a glycan-binding protein that is significantly upregulated in AML and MDS and plays a key role in disease development, progression, immune interference and drug resistance. Initial results show a favorable safety profile across both arms and all dose levels with no dose limiting toxicities, as well as evidence of response, hematological improvement and sustained disease management. “Relapsed/refractory acute myeloid leukemia is one of the most dire cancer diagnoses, with 50% of patients non-responsive to or relapsing after initial treatment and a median survival time of less than six months, 2 ” said Luba Greenwood, J.D., Entrepreneur-in-Residence at PureTech who is leading the Gallop Oncology work. “We are encouraged to see that LYT-200 achieved responses as well as long-term disease stabilization in heavily pre-treated patients, and we look forward to progressing LYT-200 as a critical therapeutic option with the potential to treat most AML patients.” In the monotherapy arm, patients received LYT-200 at five dose levels (2.0 mg/kg to 16.0 mg/kg). Across all dose levels, LYT-200 induced clinical benefit and responses in heavily pre-treated, relapsed/refractory AML/MDS patients, even in those with complex cytogenetics and mutations such as KRAS, NRAS, BRAF as well as patients previously fully refractory to standard of care. Out of 22 evaluable patients who received monotherapy, 59% achieved stable disease or better with two partial responses. The mean duration on treatment is greater than two months, which exceeds the standard overall survival of approximately 1.7 months in venetoclax/HMA-refractory patients. 3 When administered in combination with venetoclax/HMA, results demonstrate that LYT-200 may enhance the efficacy of standard-of-care therapies, even in relapsed or refractory patients. In the combination arm, patients received LYT-200 across three dose levels (4.0 mg/kg to 12.0 mg/kg) with venetoclax/HMA. Out of 15 evaluable patients who received combination therapy, 80% achieved stable disease or better, with two experiencing complete responses and one patient achieving a morphologic leukemia free state (MLFS). 1 The combination regimen has also demonstrated clinical benefit in patients with KRAS/NRAS mutations and the mean duration on treatment up until the point of data cut-off is greater than two months. “Galectin-9 is an essential driver of both disease proliferation and immune suppression in AML that has not yet been addressed therapeutically,” said Aleksandra Filipovic, M.D., Ph.D., Head of Oncology at PureTech. “LYT-200 represents a novel approach for treating AML via a two-gear mode of action that kills cancer cells directly via apoptosis and DNA damage, as well as by re-activating central anti-cancer effectors of the immune system. We are excited by these Phase 1 data that demonstrate the transformative potential of this dual mechanism of LYT-200, both as a single agent and in combination with existing standard-of-care treatments.” Pharmacodynamic assessments of treated patients, using gene and protein analyses of patient cells, validate the LYT-200 dual mode of action, and reveal AML cellular pathways as well as specific immune cell types which may be most critical for response. Based on these data, LYT-200 will continue development in relapsed/refractory AML/MDS towards a Phase 2 clinical trial. PureTech previously announced that it intends to advance LYT-200 via its Founded Entity, Gallop Oncology. About LYT-200 LYT-200 is a fully human IgG4 monoclonal antibody targeting a foundational oncogenic and immunosuppressive protein, galectin-9, for the potential treatment of hematological malignancies and locally advanced metastatic solid tumors, including head and neck cancers, with otherwise poor survival rates. A wide variety of preclinical data support the potential clinical efficacy of LYT-200 and the importance of galectin-9 as a target and suggest a potential opportunity for biomarker development. PureTech has presented data demonstrating high expression of galectin-9 across various solid tumor types and blood cancers and has found that, in several cancers, galectin-9 levels correlate with shorter time to disease relapse and poor survival. Preclinical work also demonstrates single mechanistic and anti-tumor efficacy of LYT-200 in multiple animal and patient-derived tumor cell models. For example, LYT-200 outperforms anti-PD-1 in preclinical models as a single agent. LYT-200 also synergizes with anti-PD-1 in activating CD4 and CD8 T cells in in vivo cancer models. LYT-200 is currently being evaluated in two ongoing Phase 1/2 adaptive design trials for the potential treatment of AML/MDS and head and neck cancers. About PureTech Health PureTech is a clinical-stage biotherapeutics company dedicated to giving life to new classes of medicine to change the lives of patients with devastating diseases. The Company has created a broad and deep pipeline through its experienced research and development team and its extensive network of scientists, clinicians and industry leaders that is being advanced both internally and through its Founded Entities. PureTech’s R&D engine has resulted in the development of 29 therapeutics and therapeutic candidates, including three that have been approved by the U.S. Food and Drug Administration. A number of these programs are being advanced by PureTech or its Founded Entities in various indications and stages of clinical development, including registration-enabling studies. All of the underlying programs and platforms that resulted in this pipeline of therapeutic candidates were initially identified or discovered and then advanced by the PureTech team through key validation points. For more information, visit www.puretechhealth.com or connect with us on X (formerly Twitter) @puretechh. 1 Data as of November 4, 2024, were presented at ASH 2024. Figure reflects additional data generated through November 20, 2024. 2 Miyamoto K, Minami Y. Cutting Edge Molecular Therapy for Acute Myeloid Leukemia. Int J Mol Sci . 2020;21(14):5114. Published 2020 Jul 20. doi:10.3390/ijms21145114 3 Maiti A, Rausch CR, Cortes JE, et al. Outcomes of relapsed or refractory acute myeloid leukemia after frontline hypomethylating agent and venetoclax regimens. Haematologica . 2021;106(3):894-898. Published 2021 Mar 1. doi:10.3324/haematol.2020.252569 SOURCE: PureTech

BOSTON--( BUSINESS WIRE )-- PureTech Health plc (Nasdaq: PRTC, LSE: PRTC) (“PureTech” or the “Company”), a clinical-stage biotherapeutics company dedicated to changing the lives of patients with devastating diseases, today announced that KarXT (xanomeline and trospium chloride), which was initially invented and advanced by PureTech, has received U.S. Food and Drug Administration (“FDA”) approval for the treatment of schizophrenia in adults. The FDA approval triggers two separate milestone payments to PureTech totaling $29 million under agreements with Royalty Pharma and PureTech’s Founded Entity, Karuna Therapeutics, which was acquired by Bristol Myers Squibb (NYSE: BMY) (“BMS”) in March of 2024 . Under these agreements, PureTech is also entitled to potential future payments related to additional milestones as well as approximately 2% royalties on net annual sales over $2 billion. Following the acquisition of Karuna, KarXT is now under the stewardship of BMS and will be marketed as Cobenfy. Cobenfy was invented at PureTech by combining two biologically active molecules – xanomeline and trospium chloride – to address a tolerability challenge that had held back a potential new class of medicines for the treatment of neuropsychiatric conditions, such as schizophrenia. Consistent with its unique model of drug development, PureTech advanced Cobenfy by founding Karuna Therapeutics, which later became a publicly traded company on Nasdaq. Eric Elenko, PhD, Co-founder and President of PureTech said: “ The FDA approval of Cobenfy is a significant milestone in our mission to transform the lives of patients with devastating diseases. Our initial hypothesis was that we could overcome the tolerability issues that had hindered the development of an otherwise promising drug, xanomeline, and we were able to test and validate this concept early on. We are immensely proud that our dedication to this program has led to the first major innovation in decades for those living with schizophrenia, and I am equally pleased that our unique approach to R&D has delivered yet another novel therapeutic to patients. Congratulations to the teams at Karuna and BMS on this historic accomplishment.” The FDA approval of Cobenfy is further validation of PureTech’s model and a hallmark of how it creates value both clinically and financially. PureTech’s monetization of equity holdings in Karuna, including gross proceeds from the BMS acquisition of Karuna, and a strategic royalty agreement with Royalty Pharma have enabled PureTech to generate approximately $1.1 billion to date after directing $18.5 million toward Karuna’s founding and Cobenfy’s development. PureTech’s business model is designed to repeat and scale this type of outcome, and proceeds from the success of Cobenfy have enabled PureTech to self-fund the advancement of several programs – including LYT-100 (deupirfenidone), LYT-200 (anti-galectin-9 mAb), and the Glyph TM platform supporting the pipeline of Seaport Therapeutics. Bharatt Chowrira, PhD, JD, Chief Executive Officer of PureTech said: “ Congratulations to the Karuna and BMS teams for delivering a groundbreaking treatment to people with schizophrenia. The FDA approval of Cobenfy is a testament to our unique R&D engine, which has now produced three FDA approved therapeutics. We've applied this approach across our portfolio, from our late-stage Internal Program LYT-100 (deupirfenidone) to our newly launched Founded Entity, Seaport Therapeutics, and we will continue to leverage this successful drug development model as we enter our next phase of innovation.” PureTech’s next wave of innovation continues to focus on validated biologic and small molecule modalities with human clinical data in diseases with significant unmet need. LYT-100 (deupirfenidone) is PureTech’s wholly-owned program in development for the treatment of idiopathic pulmonary fibrosis (IPF), a rare progressive lung disease with no cure. The LYT-100 program leverages extensive prior clinical data and follows the same blueprint used with Cobenfy to unlock the full therapeutic potential of an efficacious but poorly tolerated medicine. PureTech anticipates topline data from the Phase 2b clinical trial of LYT-100 in patients with IPF by the end of the year, as well as additional readouts from its oncology program, LYT-200 (anti-galectin-9 monoclonal antibody). Important Safety Information CONTRAINDICATIONS COBENFY is contraindicated in patients with: urinary retention moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment gastric retention history of hypersensitivity to COBENFY or trospium chloride. Angioedema has been reported with COBENFY and trospium chloride. untreated narrow-angle glaucoma WARNINGS AND PRECAUTIONS Risk of Urinary Retention: COBENFY can cause urinary retention. Geriatric patients and patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia (BPH), diabetic cystopathy) may be at increased risk of urinary retention. COBENFY is contraindicated in patients with pre-existing urinary retention and is not recommended in patients with moderate or severe renal impairment. In patients taking COBENFY, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria. Instruct patients to be aware of the risk and promptly report symptoms of urinary retention to their healthcare provider. Urinary retention is a known risk factor for urinary tract infections. In patients with symptoms of urinary retention, consider reducing the dose of COBENFY, discontinuing COBENFY, or referring patients for urologic evaluation as clinically indicated. Risk of Use in Patients with Hepatic Impairment: Patients with hepatic impairment have higher systemic exposures of xanomeline, a component of COBENFY, compared to patients with normal hepatic function, which may result in increased incidence of COBENFY-related adverse reactions. COBENFY is contraindicated in patients with moderate or severe hepatic impairment. COBENFY is not recommended in patients with mild hepatic impairment. Assess liver enzymes prior to initiating COBENFY and as clinically indicated during treatment. Risk of Use in Patients with Biliary Disease: In clinical studies with COBENFY, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage. COBENFY is not recommended for patients with active biliary disease such as symptomatic gallstones. Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment. The occurrence of symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should prompt assessment for gallbladder disorders, biliary disorders, and pancreatitis, as clinically indicated. Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times baseline values. Decreased Gastrointestinal Motility: COBENFY contains trospium chloride. Trospium chloride, like other antimuscarinic agents, may decrease gastrointestinal motility. Administer COBENFY with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Use COBENFY with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis. Risk of Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with COBENFY and trospium chloride, a component of COBENFY. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue COBENFY and initiate appropriate therapy and/or measures necessary to ensure a patent airway. COBENFY is contraindicated in patients with a history of hypersensitivity to trospium chloride. Risk of Use in Patients with Narrow-angle Glaucoma: Pupillary dilation may occur due to the anticholinergic effects of COBENFY. This may trigger an acute angle closure attack in patients with anatomically narrow angles. In patients known to have anatomically narrow angles, COBENFY should only be used if the potential benefits outweigh the risks and with careful monitoring. Increases in Heart Rate: COBENFY can increase heart rate. Assess heart rate at baseline and as clinically indicated during treatment with COBENFY. Anticholinergic Adverse Reactions in Patients with Renal Impairment: Trospium chloride, a component of COBENFY, is substantially excreted by the kidney. COBENFY is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <60 mL/min). Systemic exposure of trospium chloride is higher in patients with moderate and severe renal impairment. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate and severe renal impairment. Central Nervous System Effects: Trospium chloride, a component of COBENFY, is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported with trospium chloride, including dizziness, confusion, hallucinations, and somnolence. Monitor patients for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how COBENFY affects them. If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation. Most Common Adverse Reactions (≥5% and at least twice placebo): nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease. Use in Specific Populations: Moderate or Severe Renal Impairment: Not recommended Mild Hepatic Impairment: Not recommended COBENFY (xanomeline and trospium chloride) is available in 50mg/20mg, 100mg/20mg, and 125mg/30mg capsules. Please see U.S. Full Prescribing Information , including Patient Information . About PureTech Health PureTech is a clinical-stage biotherapeutics company dedicated to giving life to new classes of medicine to change the lives of patients with devastating diseases. The Company has created a broad and deep pipeline through its experienced research and development team and its extensive network of scientists, clinicians and industry leaders that is being advanced both internally and through its Founded Entities. PureTech's R&D engine has resulted in the development of 29 therapeutics and therapeutic candidates, including three that have been approved by the U.S. Food and Drug Administration. A number of these programs are being advanced by PureTech or its Founded Entities in various indications and stages of clinical development, including registration enabling studies. All of the underlying programs and platforms that resulted in this pipeline of therapeutic candidates were initially identified or discovered and then advanced by the PureTech team through key validation points. For more information, visit www.puretechhealth.com or connect with us on X (formerly Twitter) @puretechh. Cautionary Note Regarding Forward-Looking Statements This press release contains statements that are or may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation those related to additional milestones or royalties potentially due to PureTech in relation to KarXT/Cobenfy, PureTech’s development plans and the timing of data readouts, including as related to LYT-100 and LYT-200, and our future prospects, developments and strategies. The forward-looking statements are based on current expectations and are subject to known and unknown risks, uncertainties and other important factors that could cause actual results, performance and achievements to differ materially from current expectations, including, but not limited to, those risks, uncertainties and other important factors described under the caption "Risk Factors" in our Annual Report on Form 20-F for the year ended December 31, 2023, filed with the SEC and in our other regulatory filings. These forward-looking statements are based on assumptions regarding the present and future business strategies of the Company and the environment in which it will operate in the future. Each forward-looking statement speaks only as at the date of this press release. Except as required by law and regulatory requirements, we disclaim any obligation to update or revise these forward-looking statements, whether as a result of new information, future events or otherwise. _____________________________ 1 Cobenfy is a trademark of Bristol Myers Squibb.