Basilea reports preclinical data on oncology drug candidates BAL0891, derazantinib and lisavanbulin at AACR Annual Meeting

Basel, Switzerland, April 13, 2022

Basilea Pharmaceutica Ltd. (SIX: BSLN), a commercial-stage biopharmaceutical company committed to meeting the needs of patients with infectious diseases and cancer, reported today that promising preclinical data on the anti-cancer activity of its three oncology drug candidates, BAL0891, derazantinib and lisavanbulin, have been presented at the Annual Meeting of the American Association for Cancer Research (AACR) that took place April 8-13, 2022, in New Orleans, USA.

BAL0891 is a potential first-in-class mitotic checkpoint inhibitor (MCI) that drives aberrant tumor cell division leading to tumor cell death. A first poster showed in-vitro data on the activity of BAL0891 against its targets, threonine tyrosine kinase (TTK) and polo-like-kinase 1 (PLK1). The activity of BAL0891 led to a faster disruption of the mitotic spindle assembly check point (SAC) than TTK- and PLK1-specific inhibitors alone. This was associated with a broad anti-cancer effect across diverse tumor cell lines, including those derived from breast, gastric and colorectal cancer. Data presented on a second poster confirmed the good tolerability and potent single-agent anti-cancer activity of BAL0891 across a panel of patient-derived xenograft (PDX) in-vivo models of triple-negative breast cancer. Complete tumor regressions were observed in a significant number of PDX models and support the further development of BAL0891 for the potential treatment of human cancer. The data on both posters were generated in collaboration with the Dutch precision medicine company, NTRC B.V., from which Basilea in-licensed the drug candidate.

Dr. Laurenz Kellenberger, Chief Scientific Officer of Basilea, said: “The data presented at the AACR Annual Meeting confirm the differentiated profiles of our drug candidates. For BAL0891, the in-vitro an in-vivo data provide additional support for the novel mode of action of our compound and its potent single-agent activity. We are particularly pleased that BAL0891 shows convincing activity in models of human triple-negative breast cancer, a difficult-to-treat cancer with a high medical need.”

Further in-vitro and in-vivo data was also presented for derazantinib, a fibroblast growth factor receptor (FGFR) inhibitor, confirming similar sensitivity of FGFR1-3 and colony stimulating factor 1 receptor (CSF1R) to derazantinib. CSF1R plays an important role in the anti-tumor immune response to PD-L1 checkpoint inhibitors used for cancer therapy. In-vivo tumor models with high CSF1R levels were partially sensitive to derazantinib, but not to another FGFR inhibitor with no activity against CSF1R. The importance of the additional CSF1R inhibition was highlighted by data that showed a synergistic effect of the combination of derazantinib with a PD-L1 antibody in an immunologically competent breast cancer model. As compared to the single agents, this combination increased efficacy against the primary tumor, and liver and lung metastases. The combination also led to a more pronounced activation of the immune microenvironment in the primary tumor.

Finally, preclinical data were presented on avanbulin, the active moiety of Basilea’s tumor checkpoint controller lisavanbulin. In-vitro, avanbulin treatment was associated with high anti-tumor activity in models of diffuse large B cell lymphoma (DLBCL), supporting a potential application of lisavanbulin for the treatment of lymphoma patients. These data were generated in collaboration with Prof. Bertoni (Institute of Oncology Research, USI, Bellinzona, Switzerland).

Posters on Basilea’s oncology candidates presented at AACR Annual Meeting 2022
Abstract #	Authors/title
5646 5645 5501 2575 / 14	E. Zanini, N. Forster-Gross, F. Bachmann, N. Willemsen-Seegers, J. De Man, G. J. R. Zaman, R. C. Buijsman, A. Groner, M. Roceri, K. Burger, P. McSheehy, L Kellenberger, H. A. Lane BAL0891: A novel, small molecule, dual TTK/PLK1 mitotic checkpoint inhibitor (MCI) that drives aberrant tumor cell division H. A. Lane, F. Bachmann, E. Zanini, P. McSheehy, K. Litherland, N. Forster-Gross, L. Bury, D. Vu-Pham, J. de Man, W. E. van Riel, G. J. R. Zaman, R. C. Buijsman, L. Kellenberger BAL0891: A novel dual TTK/PLK1 mitotic checkpoint inhibitor (MCI) that drives aberrant tumor cell division resulting in potent anti-cancer activity M. El Shemerly, L. Kellenberger, E. Zanini, H. Lane, P. McSheehy Derazantinib, an FGFR1-3 inhibitor, inhibits CSF1R in macrophages and tumor cell lines and synergizes with a PDL1-antibody in an FGFR-driven murine syngeneic model F. Spriano, L. Aresu, L. Cascione, A. J. Arribas, N. Forster-Gross, F. Bachmann, H. Lane, F. Bertoni Avanbulin, the active moiety of the tumor checkpoint controller lisavanbulin (BAL101553) has anti-lymphoma activity

For further information please visit https://www.aacr.org/meeting/aacr-annual-meeting-2022/.

About BAL0891

BAL0891 is a first-in-class mitotic checkpoint inhibitor (MCI) that pushes cells through mitosis without adequate time for correct chromosome alignment and segregation. This results in aberrant tumor cell division leading to tumor cell death. The compound is a unique dual inhibitor of threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1). Both kinases collaborate in activating the mitotic spindle assembly checkpoint (SAC), a cell division mechanism regulating correct chromosome alignment and segregation. The dual action of BAL0891 leads to a rapid disruption of the SAC driving cells through mitosis before the chromosomes are properly aligned, leading to premature cell division and tumor cell death. BAL0891 has shown anti-proliferative activity across diverse tumor cell lines in vitro and single agent efficacy in in-vivo models of solid human cancers. Basilea has in-licensed BAL0891 from Dutch precision medicine company NTRC B.V.

About derazantinib

Derazantinib is an investigational orally administered small-molecule FGFR inhibitor with strong activity against FGFR1, 2, and 3.¹ FGFR kinases are key drivers of cell proliferation, differentiation and migration. FGFR genetic aberrations, e.g. gene fusions, mutations or amplifications, have been identified as potentially important therapeutic targets for various cancers, including intrahepatic cholangiocarcinoma (iCCA), urothelial, breast, gastric and lung cancers.² In these cancers, FGFR genetic aberrations are found in a range of 5% to 30%.³
Derazantinib also inhibits the colony-stimulating-factor-1-receptor kinase (CSF1R).^1, 4 CSF1R-mediated signaling is important for the maintenance of tumor-promoting macrophages and therefore has been identified as a potential target for anti-cancer drugs.⁵ Pre-clinical data has shown that tumor macrophage depletion through CSF1R blockade renders tumors more responsive to T-cell checkpoint immunotherapy, including approaches targeting PD-L1/PD-1.^6, 7
Derazantinib has demonstrated antitumor activity and a manageable safety profile in a previous biomarker-driven phase 1/2 study in iCCA patients,⁸ and has received U.S. and EU orphan drug designation for iCCA. Basilea is currently conducting three clinical studies with derazantinib. The first study, FIDES-01, is a phase 2 study in patients with inoperable or advanced iCCA. It comprises one cohort of patients with FGFR2 gene fusions and another cohort of patients with mutations or amplifications.⁹ The second study, FIDES-02, is a phase 1/2 study evaluating derazantinib alone and in combination with Roche's PD-L1 checkpoint inhibitor, atezolizumab, in patients with advanced urothelial cancer, including metastatic, or recurrent surgically unresectable disease, expressing FGFR genetic aberrations.¹⁰ The third study, FIDES-03, is a phase 1/2 study evaluating derazantinib alone and in combination with Lilly’s anti-VEGFR2 antibody ramucirumab and paclitaxel, or with Roche’s PD-L1 checkpoint inhibitor atezolizumab, in patients with advanced gastric cancer with FGFR genetic aberrations.¹¹ Basilea has in-licensed derazantinib from ArQule Inc., a wholly-owned subsidiary of Merck & Co., Inc., Kenilworth, N.J., U.S.A.

About lisavanbulin (BAL101553)

Basilea's oncology drug candidate lisavanbulin (BAL101553, the prodrug of BAL27862)¹²
is currently being developed as a potential therapy for glioblastoma.^13, 14, 15 In preclinical studies, lisavanbulin demonstrated in-vitro and in-vivo activity against diverse treatment-resistant
cancer models, including tumors refractory to conventional approved therapeutics and radiotherapy.^16, 17, 18
Lisavanbulin efficiently distributes to the brain, with anticancer activity in glioblastoma models.^19, 20 In preclinical studies, end-binding protein 1 (EB1) was identified as a potential response-predictive biomarker in glioblastoma models and strong EB1-positivity was shown in about 5% of tissue samples from glioblastoma patients.^21, 22 The strongest expression of EB1 in non-glioblastoma tumors was detected in tissue samples from medulloblastomas and neuroblastomas, which are cancers that occur predominantly in the pediatric population.
EB1-positive staining was also found in tissue samples from metastatic melanoma (skin cancer). Other tumors expressing slightly lower levels of EB1 staining include non-small cell lung cancer, colorectal cancer and triple-negative breast cancer.²⁴ The active moiety BAL27862 binds to the colchicine site of tubulin, with distinct effects on microtubule organization,²³ resulting in the activation of the "spindle assembly checkpoint" which promotes tumor cell death.²⁴

About Basilea

Basilea is a commercial-stage biopharmaceutical company founded in 2000 and headquartered in Switzerland. We are committed to discovering, developing and commercializing innovative drugs to meet the needs of patients with bacterial and fungal infections and cancer. We have successfully launched two hospital brands, Cresemba for the treatment of invasive fungal infections and Zevtera for the treatment of severe bacterial infections. We are conducting clinical studies with two targeted drug candidates for the treatment of a range of cancers and have several preclinical assets in both anti-infectives and cancer in our portfolio. Basilea is listed on the SIX Swiss Exchange (SIX: BSLN). Please visit basilea.com.

Disclaimer

This communication expressly or implicitly contains certain forward-looking statements, such as "believe", "assume", "expect", "forecast", "project", "may", "could", "might", "will" or similar expressions concerning Basilea Pharmaceutica Ltd. and its business, including with respect to the progress, timing and completion of research, development and clinical studies for product candidates. Such statements involve certain known and unknown risks, uncertainties and other factors, which could cause the actual results, financial condition, performance or achievements of Basilea Pharmaceutica Ltd. to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Basilea Pharmaceutica Ltd. is providing this communication as of this date and does not undertake to update any forward-looking statements contained herein as a result of new information, future events or otherwise. Derazantinib, lisavanbulin and BAL0891 and their uses are investigational and have not been approved by a regulatory authority for any use. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in nonclinical/preclinical studies to humans is currently being evaluated.

For further information, please contact:

Peer Nils Schröder, PhD Head of Corporate Communications & Investor Relations
Phone	+41 61 606 1102
E-mail	media_relations@basilea.com investor_relations@basilea.com

This press release can be downloaded from www.basilea.com.

References

1. T. G. Hall, Y. Yu, S. Eathiraj et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS ONE 2016, 11 (9), e0162594
2. R. Porta, R. Borea, A. Coelho et al. FGFR a promising druggable target in cancer: Molecular biology and new drugs. Critical Reviews in Oncology/Hematology 2017 (113), 256-267
3. T. Helsten, S. Elkin, E. Arthur et al. The FGFR landscape in cancer: Analysis of 4,853 tumors by next-generation sequencing. Clinical Cancer Research 2016 (22), 259-267
4. P. McSheehy, F. Bachmann, N. Forster-Gross et al. Derazantinib (DZB): A dual FGFR/CSF1R-inhibitor active in PDX-models of urothelial cancer. Molecular Cancer Therapeutics 2019 (18), 12 supplement, pp. LB-C12
5. M. A. Cannarile, M. Weisser, W. Jacob et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. Journal for ImmunoTherapy of Cancer 2017, 5:53
6. Y. Zhu, B. L. Knolhoff, M. A. Meyer et al. CSF1/CSF1R Blockade reprograms tumor-infiltrating macrophages and improves response to T cell checkpoint immunotherapy in pancreatic cancer models. Cancer Research 2014 (74), 5057-5069
7. E. Peranzoni, J. Lemoine, L. Vimeux et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment. Proceedings of the National Academy of Science of the United States of America 2018 (115), E4041-E4050
8. V. Mazzaferro, B. F. El-Rayes, M. Droz dit Busset et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. British Journal of Cancer 2019 (120), 165-171. ClinicalTrials.gov identifier: NCT01752920
9. FIDES-01: ClinicalTrials.gov identifier: NCT03230318.
10. FIDES-02: ClinicalTrials.gov identifier: NCT04045613
11. FIDES-03: ClinicalTrials.gov identifier: NCT04604132
12. J. Pohlmann, F. Bachmann, A. Schmitt-Hoffmann et al. BAL101553: An optimized prodrug of the microtubule destabilizer BAL27862 with superior antitumor activity. Cancer Research 2011, 71 (8 supplement), abstract 1347
13. ClinicalTrials.gov identifier: NCT02490800; C. Tiu, S. Derby, N. Md. Haris et al. The potential utility of end-binding protein 1 (EB1) as response-predictive biomarker for lisavanbulin: A phase 2 study of lisavanbulin (BAL101553) in adult patients with recurrent glioblastoma. Journal of Clinical Oncology 2021, 39 (15 supplement, TPS2068)
14. ClinicalTrials.gov identifier: NCT03250299
15. ClinicalTrials.gov identifier: NCT02895360
16. A. Sharmq, A. Broggini-Tenzer, V. Vuong et al. The novel microtubule targeting agent BAL101553 in combination with radiotherapy in treatment-refractory tumor models. Radiotherapy Oncology 2017 (124), 433-438
17. G. E. Duran, H. Lane, F. Bachmann et al. In vitro activity of the novel tubulin active agent BAL27862 in MDR1(+) and MDR1(-) human breast and ovarian cancer variants selected for resistance to taxanes. Cancer Research 2010, 70 (8 supplement), abstract 4412
18. F. Bachmann, K. Burger, G. E. Duran et al. BAL101553 (prodrug of BAL27862): A unique microtubule destabilizer active against drug refractory breast cancers alone and in combination with trastuzumab. Cancer Research 2014, 74 (19 supplement), abstract 831
19. A. Schmitt-Hoffmann, D. Klauer, K. Gebhardt et al. BAL27862: a unique microtubule-targeted agent with a potential for the treatment of human brain tumors. Molecular Cancer Therapeutics 2009, 8 (12 supplement), C233
20. A. C. Mladek, J. L. Pokorny, H. Lane et al. The novel tubulin-binding 'tumor checkpoint controller' BAL101553 has anti-cancer activity alone and in combination treatments across a panel of GBM patient-derived xenografts. Cancer Research 2016, 76 (14 supplement), abstract 4781
21. R. Bergès, A. Tchoghandjian, S. Honoré et al. The novel tubulin-binding checkpoint activator BAL101553 inhibits EB1-dependent migration and invasion and promotes differentiation of glioblastoma stem-like cells. Molecular Cancer Therapeutics 2016 (15), 2740-2749
22. M. Skowronska, C. Tiu, A. Tzankov et al. Expression of end-binding protein 1 (EB1), a potential response-predictive biomarker for lisavanbulin, in glioblastoma and various other solid tumor types. Journal of Clinical Oncology 2021, 39 (15 supplement, 3118)
23. A. E. Prota, F. Danel, F. Bachmann et al. The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization. Journal of Molecular Biology 2014 (426), 1848-1860
24. F. Bachmann, K. Burger, H. Lane. BAL101553 (prodrug of BAL27862): the spindle assembly checkpoint is required for anticancer activity. Cancer Research 2015, 75 (15 supplement), abstract 3789

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