LYT-200

Hematological malignancies, such as acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), and locally advanced/metastatic solid tumors, including head and neck cancers

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Hematological malignancies, such as acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), and locally advanced/metastatic solid tumors, including head and neck cancers

100% Equity

Phase 1/2

Description

Hematological malignancies, such as acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), and locally advanced/metastatic solid tumors, including head and neck cancers

Puretech Ownership¹

100% Equity

Stage of Development

Phase 1/2

¹ We have an active IND on file with the FDA for LYT-200. The FDA and corresponding regulatory authorities will ultimately review our clinical results and determine whether our wholly-owned therapeutic candidates are safe and effective. No regulatory agency has made any such determination that LYT-200 is safe or effective for use by the general public for any indication.

Hematological malignancies, such as acute myeloid leukemia and high-risk myelodysplastic syndrome, and locally advanced/metastatic solid tumors, including head and neck cancers

LYT-200 is being developed for the treatment of hematological malignancies, such as acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS), as well as locally advanced/metastatic solid tumors, including head and neck cancers. It is a fully human IgG4 monoclonal antibody targeting galectin-9, a potent oncogenic driver in leukemia cells and an immunosuppresive protein expressed by tumors and immune cells and shown to suppress the immune system from recognizing and destroying cancer cells. A wide variety of preclinical data support the potential clinical efficacy of LYT-200 and the importance of galectin-9 as a target and suggests a potential opportunity for biomarker development.

Key Points of Innovation & Differentiation
- Galectin-9 promotes and facilitates multiple immunosuppressive pathways by expanding regulatory T cells, shifting macrophages from the M1 to M2 phenotype, and inducing apoptosis of activated CD4+ and CD8+ T cells. High expression of galectin-9 is evident in solid tumors and in hematological malignancies, both in patients’ tumors and blood, and correlates with poor survival outcomes and aggressive disease. Our preclinical work demonstrates single agent 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 a standard B16F10 melanoma model as a single agent. LYT-200 also synergizes with anti-PD-1 in activating CD4 and CD8 T cells in melanoma and pancreatic in vivo models. We are advancing LYT-200 to inhibit the multiple effects of galectin-9 and thereby potentially removing a key immunosuppressive barrier that would enable the immune system to attack and destroy the tumor.
- A 2021 study published in Nature Communications proposed that the molecular mechanism by which PD-1 and galectin-9 interact to shield tumors from the immune system demonstrates for the first time that galectin-9 is a ligand for PD-1 and emphasizes its importance as a promising target for immunotherapy³. This provided further evidence that galectin-9 acts as a key regulator of the immune response to tumors and supports its importance as a potential target for cancer treatment.
- We believe that LYT-200 is the most advanced clinical program against this target. It has the potential to be used as a single agent and safely in combination with checkpoint inhibitors and other anti-cancer therapies, depending on the cancer type, treatment setting and line of treatment. Additionally, targeting galectin-9 gives LYT-200 the potential to address a high unmet need for more effective therapies with improved tolerability for acute myeloid leukemia (AML), a devastating disease in which prognosis is poor.
Program Discovery Process by the PureTech Team
- In order to identify approaches with the potential to provide significant therapeutic benefit to cancer patients, we opportunistically identified a foundational immunosuppressive mechanism involving galectin-9, which was the basis of certain intellectual property that we licensed from New York University prior to its publication in Nature Medicine.
Patient Need & Market Potential
- AML
  - The National Cancer Institute estimates that about 60,000 new cases of leukemia are diagnosed each year,⁶ including about 20,000 in AML.⁷ More than 50% of AML patients either don’t respond to initial treatment or experience relapse or death after responding to initial treatment¹ and a median survival time of less than six months.² The poor overall survival highlights the need for more effective therapies for patients with relapsed and refractory AML.
- Metastatic/locally advanced solid tumors
  - In the US, there are approximately 82,000 new cases of bladder cancer each year³
  - In the US, there are approximately 66,000 people diagnosed with head and neck cancers each year.⁴ At diagnosis, ~10% of patients have metastatic disease though an additional 20-30% will develop metastases during the course of their disease. The prognosis for metastatic disease is unfavorable with a median survival of about 10 months.⁵
Milestones Achieved & Development Status
- AML
  - In December 2024, we presented data from the dose escalation phase of the Phase 1b trial evaluating LYT-200 in patients with relapsed or refractory acute AML and MDS at the 2024 American Society of Hematology (ASH) Annual Meeting. 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. 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. 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.
  - In February 2024, the FDA granted Orphan Drug Designation to LYT-200 for the treatment of AML. The FDA grants orphan drug designation to novel drug and biologic products for the treatment, diagnosis, or prevention of conditions affecting fewer than 200,000 persons in the U.S. Orphan drug designation qualifies PureTech for incentives under the Orphan Drug Act, including tax credits for some clinical trials and eligibility for seven years of market exclusivity in the U.S., if the drug is approved for AML.
  - In December 2023, we announced in the ongoing Phase 1b trial evaluating LYT-200 as a single agent in relapsed/refractory AML and MDS patients, three dose escalation cohorts have completed to date at weekly doses of 2 mg/kg (cohort 1), 4 mg/kg (cohort 2) and 7.5 mg/kg (cohort 3). In a heavily pre-treated patient population, the early data demonstrates a favorable safety and tolerability profile of LYT-200 with no dose limiting toxicities. In the first cohort, disease stabilization was observed in two of the five patients treated, with one patient achieving red blood cell transfusion independence. In the second cohort, disease stabilization was observed in two of the four patients treated. In the third cohort, disease stabilization was observed in all four of the patients treated, with a reduction in bone marrow blasts observed in two of the four patients and the clearance of peripheral blasts observed in one patient. Two patients achieved more than 50 percent bone marrow blast reduction, with one of these patients observing an increase in platelet count without transfusions. The fourth cohort, evaluating a weekly regimen of LYT-200 at the 12 mg/kg dose, is still ongoing, and additional data are expected to be shared in a scientific forum.
  - In December 2022, a poster describing new preclinical data supporting the clinical potential of LYT-200 for the treatment of leukemia was presented at the American Society of Hematology (ASH) 64th Annual Meeting. In all models used, LYT-200 demonstrated significant anti-tumor activity and in addition to its established effects on the immune system in solid tumor models, it also notably induced direct apoptosis or cell death across all leukemia cell types. Based on this and other compelling preclinical data generated with LYT-200 in blood cancers, we initiated a clinical trial to evaluate LYT-200 as a single agent for the treatment of AML.
- Metastatic/locally advanced solid tumors
  - In March 2024, the FDA granted Fast Track designation for LYT-200 in combination with anti-PD1 therapy for the treatment of recurrent/metastatic head and neck cancers. Fast Track designation is a process designed to streamline the development and accelerate the assessment of drugs that target serious conditions with unmet need.
  - In December 2023, initial data from the Phase 1 portion of the Phase 1/2 dose escalation and expansion clinical trial of LYT-200 was announced. LYT-200 is being evaluated as a monotherapy and in combination with tislelizumab, an anti-PD-1 antibody being developed by BeiGene, in metastatic solid tumors, including head and neck cancers. The initial data, which was presented at the ESMO Immuno-Oncology, demonstrate that LYT-200 has a favorable safety profile in all cohorts, including the monotherapy and combination arms, and shows disease control and suggestion of anti-tumor activity in combination with tislelizumab. In the combination cohort, anti-tumor activity was observed in patients with relapsed or refractory head and neck squamous cell carcinoma, a patient population that has historically demonstrated a low response rate to anti-PD-1 agents of around 20 percent and 10 percent with chemotherapy.⁸
  - In the first quarter of 2023, we initiated a Phase 1b trial of LYT-200 in combination with tislelizumab in head and neck cancers.
  - In December 2022, we announced results from the monotherapy dose escalation portion of the Phase 1 program of LYT-200 as a potential treatment for metastatic solid tumors. No dose-limiting toxicities were reported, and the full results are planned for presentation in a scientific forum in 2023.
Expected Milestones
- Based on the Phase 1b data evaluating LYT-200 in relapsed/refractory AML and MDS, LYT-200 will continue development towards a Phase 2 clinical trial.
- The Phase 1b trial of LYT-200 in combination with tislelizumab in head and neck cancers is ongoing. Additional data are expected in the fourth quarter of 2024.
Intellectual Property
- LYT-200 has broad intellectual property coverage for these antibody-based immunotherapy technologies. As of December 31, 2023, there are 15 families of intellectual property within this patent portfolio, including eight families of patent filings that are co-owned with and/or exclusively licensed from New York University which cover antibodies that target galectin-9, including LYT-200, and methods of using these antibodies in various immuno-oncology technologies and treatment methods. In addition, the intellectual property portfolio includes six families of company-owned patent applications covering the use of anti-galectin-9 antibodies in the diagnosis and treatment of various cancers, including solid tumors and hematological cancers and one family of patent applications co-owned with BeiGene directed to combination therapies for the treatment of solid tumors. This intellectual property portfolio comprises four issued U.S. patents which are expected to expire in 2038, 12 pending U.S. patent applications, which if issued, are expected to expire 2037 through 2044, two international PCT applications, 54 pending foreign applications and 12 issued patents in foreign jurisdictions.

¹ Walter, R. B., Othus, M., Burnett, A. K., Löwenberg, B., Kantarjian, H. M., Ossenkoppele, G. J., Hills, R. K., Ravandi, F., Pabst, T., Evans, A., Pierce, S., Vekemans, M.,
Appelbaum, F. R., & Estey, E. H. (2015). Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center. Leukemia, 29(2), 312–320. https://doi.org/10.1038/leu.2014.242.

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 Cancer of the Urinary Bladder – Cancer Stat Facts. (n.d.). National Cancer Institute. https://seer.cancer.gov/statfacts/html/urinb.html.

⁴ Head and Neck Cancer – Statistics. (2022, December 16). Cancer.Net. https://www.cancer.net/cancer-types/head-and-neck-cancer/statistics.

⁵ Pisani, P., Airoldi, M., Allais, A., Valletti, P. A., Battista, M., Benazzo, M., Briatore, R., Cacciola, S., Cocuzza, S., Colombo, A., Conti, B., Costanzo, A., Della Vecchia, L., Russi, E. G., Fantozzi, C., Galizia, D., Garzaro, M., Genta, I., Iasi, G. A., . . . Zigliani, A. (2020). Metastatic disease in head & neck oncology. Acta Otorhinolaryngologica Italica, 40(SUPPL. 1), S1–S86. https://doi.org/10.14639/0392-100x-suppl.1-40-2020.

⁶ Leukemia – Cancer Stat Facts. (n.d.). National Cancer Institute. https://seer.cancer.gov/statfacts/html/leuks.html.

⁷ Acute Myeloid Leukemia – Cancer Stat Facts. (n.d.). National Cancer Institute. https://seer.cancer.gov/statfacts/html/amyl.html.

⁸ Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008 Sep 11;359(11):1116-27. doi: 10.1056/NEJMoa0802656. PMID: 18784101.

Given its design to inhibit the activity of galectin-9, LYT-200 is being advanced to potentially remove a key immunosuppressive barrier that would enable the immune system to attack and destroy the tumor. Our fully human monoclonal antibody candidate has potential both as a single agent and in combination with existing therapies such as checkpoint inhibitors and chemotherapeutics.