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Scandion Oncology
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== Combatting chemotherapy resistance == The rapidly dividing nature of cancer cells means chemotherapeutic resistance is commonly observed in oncology. The mechanisms are varied and resistance is a widely recognised problem when treating cancer, so much so that the company asserts 90% of cancer deaths are caused by chemotherapy resistance. The development of drug-resistant cancer will almost inevitably lead to more aggressive tumours and poor prognosis. Resistance can be classified as intrinsic or acquired based on the point at which resistance develops. Intrinsically resistant cancers have developed chemotherapeutic resistance before treatment has been administered, whereas acquired resistance is built up over time and is driven by exposure to a specific chemotherapeutic regimen. === Drug-resistance mechanisms are commonly reported === Cancer drug resistance is a complicated process that can occur through a variety of underlying biological mechanisms. Exhibit 4 presents a selection of common drug resistance types seen in oncology. {| class="wikitable" |+Exhibit 4: Examples of chemotherapy resistance types<ref name=":1">Source: Edison Investment Research.</ref> !Resistance type !Underlying mechanism (example) !Effect !Common drugs affected |- |Multi-drug resistance |Up-regulation of ATP Binding Cassette membrane proteins (ABC). |Increased removal of chemotherapy from tumour cells. |Doxorubicin, vinblastine, paclitaxel, irinotecan |- |Inhibition of cell death |Down-regulation of pro-cell death proteins (eg p53). Up-regulation of anti-cell death proteins (eg Bcl-2/xl). |Increased tumour cell survival, even in the presence of toxic agents. |Cisplatin, doxorubicin |- |Altered drug metabolism |Altered activity of UGT enzymes. Increased activity of cytochrome P450 enzymes. |Increased metabolism of active agents reduces effectiveness of chemotherapy. |Docetaxel, gemcitabine, cytarabine |- |Enhanced DNA repair |Increased activity of nucleotide excision repair system and homologous recombination repair mechanisms. |Repair of damaged DNA causes increase in tumour cell survival. |Cisplatin, doxorubicin |} In addition to these mechanisms, chemotherapeutic resistance can arise due to alterations to a drug’s target, gene amplifications and epigenetic alterations. Modern approaches to overcoming resistance have focused on developing new, targeted drugs and immunotherapies (for example PD-(L)1 and CTLA4 monoclonal antibodies). However, drug resistance in chemotherapy continues to be recognised as an area of unmet medical need. === SCO-101 has a dual mechanism of action === With its lead asset SCO-101, Scandion Oncology is targeting two mechanisms of drug resistance in oncology, multi-drug resistance and altered drug metabolism. Scandion claims that SCO-101 is a first-in-class chemosensitiser, a class of compounds that when used in combination with traditional chemotherapy agents may re-sensitise resistant cancer cells to treatment. Specifically, SCO-101 is a potent inhibitor of the ATP Binding Cassette G2 (ABCG2) efflux pump and UTG1A1 enzyme. As a member of the ABC superfamily of transmembrane efflux pumps, ABCG2 (also known as the breast cancer resistance protein, BCRP) is important in the development of chemotherapeutic resistance. In normal tissues, ABCG2 is involved in a range of functions including cell protection (in the brain and placenta), homeostasis, nutrient absorption, and hormone regulation. However, when overexpressed in tumour cells, ABCG2 mediates drug resistance through the increased removal of cytotoxic agents from the cell interior (Exhibit 5). Furthermore, many classes of chemotherapeutics are proven substrates for ABCG2. Examples include topoisomerase I and II inhibitors (irinotecan and doxorubicin, respectively), DNA intercalators, nucleoside analogues (clofarabine), thymidylate synthase inhibitors (5-fluorouracil), EGFR inhibitors (erlotinib) and PARP inhibitors (rucaparib), among others. In Edison Investment Research's view, the prevalence of ABCG2-mediated drug resistance highlights the opportunity for SCO-101 in combination with chemotherapies other than FOLFIRI. '''Exhibit 5: SCO-101 dual mechanism of action<ref>Source: Scandion Oncology corporate presentation.</ref>''' [[File:Image6-b18deb263878259b652ac43cea6d3088.png|600px]] Additionally, as stated above, SCO-101 inhibits the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) to block the metabolism of chemotherapy drugs and increase systemic levels. The UGT family of enzymes work by modifying a chemotherapy drug with glucuronic acid, therefore making it more water soluble and easier to eliminate from the body. There is a body of clinical evidence that supports the role of UGTs in the development of drug resistance in multiple classes of chemotherapy agents, including alkylating agents, targeted therapies, antiangiogenics and hormonal therapies. Altogether, SCO-101’s dual mechanism acts to reverse drug resistance by increasing the level of chemotherapy drug in the body (through UGT1A1 inhibition) while simultaneously decreasing the ABCG2 mediated removal of the drug from the cell. === 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. === PANTAX: Resistance in pancreatic cancer === Scandion Oncology’s second clinical trial, PANTAX, is investigating SCO-101 in the treatment of unresectable or metastatic PC. PANTAX is a Phase Ib, open-label, dose-escalation (3+3) study to establish the safety profile and MTD of SCO-101 in combination with nab-paclitaxel and gemcitabine. The study aims to enrol 18 patients and in addition to primary outcome measurements (safety, MTD) will assess multiple secondary endpoints including, ORR, PFS, OS and pharmacokinetic profile. There remain significant unmet medical needs in the treatment of PC. If diagnosed as unresectable or metastatic, therapy options are limited for patients. Surgery and radiation therapy may be used to manage symptoms, but chemotherapy is usually the only option to improve survival. Gemcitabine is a common first-line therapy and is often used in combination with other drugs such as erlotinib, cisplatin or nab-paclitaxel. Despite this survival rates remain low. Hence, Edison Investment Research sees PC as a potentially valuable indication for SCO-101 but caveat that it is still in early development. Top-line results from PANTAX are expected in Q2/Q322 (likely Q322). Assuming positive Phase Ib results, the company intends to initiate randomised Phase II trials in PC in 2023. ==== SCO-101 works in synergy with nab-paclitaxel ==== Preclinical data presented by Scandion Oncology at the British Association for Cancer Research (BACR) in September 2021 demonstrate the potential of SCO-101 in combination with nab-paclitaxel (Exhibit 7). In these mouse model data, a paclitaxel/SCO-101 combination demonstrated a 63% reduction in tumour volume compared to control, and paclitaxel alone reduced volume by 28%. In Edison Investment Research's view, these preclinical data support the rationale for the combination of SCO-101 and nab-paclitaxel with gemcitabine in the treatment of PC. Nevertheless, Edison Investment Research notes that interpretation of preclinical results is not a reliable indicator of clinical utility. '''Exhibit 7: Preclinical SCO-101 data in combination with paclitaxel'''<ref>Source: Scandion Oncology BACR presentation September 2021.</ref> [[File:Image8-d2f0ab9ac32701491636345b4497b7bb.png|600px]] === SCO-101 could be first in class in chemotherapy resistance === In the past, attention in combatting chemotherapy resistance has focused on repurposing existing therapeutics to serve as add-on treatments to help combat chemotherapy resistance. Specifically, many kinase inhibitors have been investigated as potential combinations to enhance irinotecan response. These include sorafenib, imatinib mesylate, sunitinib, nilotinib and dasatinib. However, to date, none have been approved for use in this setting, due mainly to a lack of efficacy or unfavourable safety profiles. As a direct comparison to SCO-101 in mCRC, Edison Investment Research draws attention to recent data from the Phase Ib/II trial of onvansertib (Cardiff Oncology) in combination with FOLFIRI and bevacizumab in second-line mCRC patients. These data demonstrate a 35% ORR and 9.4-month mPFS (vs 13% ORR and 5.6-month mPFS historically) in KRAS mutant mCRC patients. While onvansertib works through PLK1 inhibition not ABCG2/UTG1A1 inhibition, Edison Investment Research sees these results as a meaningful comparison for SCO-101. As Scandion intends to pursue both wild-type and mutant RAS mCRC populations, Edison Investment Research believes onvansertib could represent a market competitor in mutant-KRAS mCRC patients (potentially 50%) if both drugs are approved. There are no approved chemosensitisers on the market. Still, interest in the field means there are drugs in development that may be competition for SCO-101 in future, if approved. Here Edison Investment Research highlights two comparators. Firstly, bemcentinib, an AXL-inhibitor being developed by BerGenBio for the treatment of non-small cell lung cancer, is hypothesised to restore sensitivity to anti-PD-1 immune checkpoint inhibitors. Bemcentinib is estimated for approval in 2023 and to reach worldwide sales of $140m by 2026 (source: EvaluatePharma). Edison Investment Research believes a second, earlier-stage comparator for SCO-101 is ORIC-553 (ORIC Pharmaceuticals), a CD37 inhibitor in Phase Ib trials for the treatment of multiple myeloma. === Preclinical pipeline will build future value === In addition to its clinical development programme, Scandion is conducting preclinical studies for the use of SCO-101 in double combination with chemotherapy plus immunoncology. In a setting (oncology) where many higher lines of treatment are dominated by immune checkpoint inhibitors, Edison Investment Research sees this as a natural progression for the company’s development platform. Provided preclinical positive results, Edison Investment Research expects Scandion to work further on developing the SCO-101/immunotherapy combinations. Alongside this, a second oral efflux pump inhibitor, known as SCO-201, is being evaluated in preclinical studies for the treatment of solid tumours.
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