Periodic Reporting for period 1 - CB-103 (First effective targeted therapy for T-cell acute lymphoblastic leukemia (T-ALL) and other NOTCH pathway driven cancers) Reporting period: 2019-06-01 to 2019-09-30 Summary of the context and overall objectives of the project NOTCH signalling is a developmental pathway known to play crucial roles in regulating cell fate, cell growth and maintenance. Aberrant activation of this pathway leads to aggressive forms of cancers, such as T-cell acute lymphoblastic leukaemia (T-ALL), and others. Currently, an estimated 250,000 people are afflicted by NOTCH-dependent cancers every year with no targeted effective targeted therapy. For these patients, current treatments are associated with poor survival rates, off-target toxicity, painful side effects and high costs of therapy. With no alternative therapies available, patients, especially those with Relapsed/Refractory (R/R) T-ALL have very low remission rates and a poor quality of life.Cellestia Biotech AG (Cellestia) was founded in 2014 as a spin-off from Ecole Polytechnique Fédérale de Lausanne, Switzerland (EPFL). The company is actively engaged in clinical development of first-in-class targeted therapeutics with untapped mode of action, to address unmet medical need in patients with oncology and immunological disorders. Their mission is to develop the CB-103, a novel, first-in-class, oral pan-NOTCH inhibitor with a unique mode of action for treatment of NOTCH dependent leukaemia, lymphomas and solid tumours. The team is currently working towards establishing clinical safety and efficacy of the drug through phase Ib and phase IIa clinical trials. The key development and commercialisation objectives are to manufacture CB-103 for clinical trials, to successfully perform phase Ia and phase IIb clinical trials and then out-license further stages of pivotal trials and EMA/FDA approval to partner pharma companies. Cellestia undertook the feasibility study to determine whether the precision oncology solution and business model were scalable, cost-effective and profitable, and to identify any strengths and weaknesses moving forward. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far During the project, Cellestia defined the minimum viable development path for positioning CB-103 in T-ALL, including the necessary steps for scale-up activities and clinical trials, evaluated the market opportunity with respect to size, customers and competitors, and finally confirmed the business model and commercialisation strategy. Detailed financial projections after successful out-licensing have been estimated. The Phase 1 feasibility assessment showed that the development plan for CB-103 is technically and commercially viable, and that commercialisation plan of out-licensing to a partner pharma company is the most efficient route to market penetration and should be pursued. SME EIC Accelerator funding could provide the correct amount of funding and support to allow the stated activities to be implemented successfully. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) CB-103 is a novel treatment for T-ALL both in children and adults. The positive results achieved thus far in preclinical studies suggest that CB-103 can significantly increase patients’ survival rate and improve their quality of life. A successful development through clinical validation will advance CB-103 toward market approval and, ultimately, positively impact on the quality of life and survival of patients.Cellestia’s highly disruptive CB-103 pan-NOTCH targeted therapy will offer several medical benefits to Europe and the world. It has been estimated that about 250,000 oncology patients are affected by NOTCH-dependent cancers worldwide. However, the currently available therapies only treat efficiently the few T-ALL cases that are not relapse or refractory, and most of the patients do not respond to conventional treatments, reducing their life expectancy down to 10%, without any available therapies. These patients also have to deal with high costs associated with current treatments. Cancer diagnosis and treatment costs approximately €35,000 per patient and, by 2020, this is expected to rise to €47,000. Blood cancers, in particular, are very expensive to both patients and the healthcare system. CB-103 is expected to have a major impact on the quality of life and survival prospects for all T-ALL patients.