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Scandion Oncology
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=== CORIST: A tale of two parts === Scandion Oncology’s Phase II CORIST study is a multi-centre, open-label, dose-escalation study of SCO-101 in combination with FOLFIRI that will enrol up to 50 patients with mCRC. CORIST is targeting last-line mCRC treatment, in which enrolled patients will have failed all prior chemotherapy due to resistance and are in the terminal stages of the disease. Considering the small population of patients at this stage, Edison Investment Research expects the company will look to position SCO-101 in earlier lines of treatment in later studies, provided there are positive results in Phase II. The CORIST study itself consists of two parts. Part 1, a dose escalation (3+3) study that concluded in H121, demonstrated a maximum tolerated dose (MTD) and a good safety profile for SCO-101 in combination with FOLFIRI. Importantly, part 1 identified wild-type RAS (wtRAS) as a potential biomarker for SCO-101 treatment. In this trial, patients with wtRAS tolerated higher doses of the SCO-101/FOLFIRI combination and stayed on treatment longer. Five out of eight patients identified with wtRAS also showed stable disease for more than eight weeks, compared to progressive disease in all mutant RAS patients. Mutations in RAS are common oncogenic drivers that are regularly screened for during cancer diagnosis. Scandion has used this information to inform CORIST part 2, which is underway and will enrol 25 mCRC patients harbouring wtRAS to investigate the efficacy of the SCO-101/FOLFIRI combination at the MTD. Despite this, Scandion indicated in June 2022 that it plans to also pursue the opportunity with SCO-101 in the mutant-RAS population as this could potentially double the addressable patient population for SCO-101. Edison Investment Research anticipates that it investigate starting an additional mCRC trial in mutant RAS patients. The primary endpoint for part 2 will be objective response rate (ORR), defined as complete response (CR) and partial response (PR) using RECIST v 1.1. Secondary endpoints include progression free survival (PFS), duration-of-response, overall survival (OS) and further biomarker analysis. Positive results from CORIST part 2 would provide clinical proof-of-concept for SCO101 use in mCRC and will begin to define how Scandion Oncology will position the drug for further development. Top-line results from CORIST are expected in Q2/Q322 (most likely Q322). ==== Data support FOLFIRI combination ==== First-line therapy for mCRC relies heavily on 5-fluorouracil (5FU)-based chemotherapy regimens, often supplemented with targeted therapies (should a molecular driver be present) and/or biologic agents (eg vascular-endothelial growth factor A, VEGF, targeting monoclonal antibody, bevacizumab). Later lines of therapy will also generally be formed around modification of 5FU-based regimens. A common treatment in this setting is FOLFIRI, a chemotherapy regimen consisting of leucovorin calcium, 5-fluorouracil and irinotecan. One of the active ingredients of this regimen, irinotecan, is a prodrug of the potent topoisomerase I inhibitor SN-38. Drugs of this class kill tumour cells by inhibiting DNA repair processes. The development of resistance to irinotecan chemotherapy through ABCG2 efflux pump overexpression and UTG1A1 activity is well documented, thus Scandion Oncology has identified FOLFIRI as a potentially attractive combination therapy for SCO-101. Indeed, analysis of CORIST patients treated with SCO-101 and irinotecan in Part I of CORIST has shown dramatically increased plasma levels of SN-38 at a 90mg/m2 dose when compared to SN-38 data from treatment with irinotecan at 180 mg/m2 (based on patients outside the CORIST study, Exhibit 6), although Edison Investment Research cautions that there are limitations to comparing data from different studies. '''Exhibit 6: SN-38 plasma concentrations in CORIST patients<ref>Source: Scandion Oncology CMD update.</ref><br />''' [[File:Image7-c31e427382287da7a43068acd0e06507.png|600px]] While plasma concentrations in the CORIST patients were dramatically higher when compared to patients treated only with irinotecan (using data compiled from separate studies), Edison Investment Research notes that high plasma levels of SN-38 do not necessarily correlate with a clinical effect, especially in ABCG2 driven resistance. However, this data does provide support for the SCO-101/FOLFIRI combination with the lower 90mg/m2 CORIST dosing regimen for irinotecan (compared to 180mg/m2 commercial norm). ==== Positioning is key to unlocking SCO-101 value in mCRC ==== Should data from the CORIST clinical trial prove positive, Edison Investment Research expects Scandion to begin positioning SCO-101 in earlier lines of therapy. To this end, the company intends to conduct positioning studies in the second line of treatment for mCRC, likely in combination with FOLFIRI ± VEGF and/or EGFR antibodies, before moving to pivotal Phase III trials. Edison Investment Research believes repositioning SCO-101 to the second line in mCRC could add significant value to SCO-101. Edison Investment Research notes, the small patient group size in CORIST part 2 (n=25) and open-label study design will, in its view, likely require Scandion to perform larger, randomised studies to maximise deal value with potential development partners and/or licensors. The company plans to initiate pivotal Phase II/III trials in second-line mCRC patients in 2023, provided data from Part 2 of CORIST are supportive. Furthermore, as stated previously, in June 2022 management announced its intention to use the proceeds from a rights issue to expand SCO-101 clinical development to RAS-mutant patients.
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