Basilea reports data from poster presentations at ESMO Virtual Congress 2020

• Gene expression data may explain differences inclinical adverse event profiles ofFGFR inhibitors
• Antitumor activity of derazantinibin preclinical cancer models with FGFR aberrationssupportsplanned gastric cancerstudy
• Full resultsfrom the completed phase 1 study in patients with brain cancer underscores the potential for lisavanbulin to be developed in a targeted patient populationusing end-binding protein 1 (EB1) as a patient selection criterion
  
  

Basel, Switzerland, September22, 2020

Basilea Pharmaceutica Ltd. (SIX: BSLN) today reports on several e-posters with new preclinical and clinical data on its fibroblast growth factor receptor (FGFR) inhibitor derazantinib and its tumor checkpoint controller, lisavanbulin, presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020, which took place from 19-21 September, 2020.

A preclinical study showed that treatment-specific gene expression patterns in tumor models may help elucidating the biological processes driving differences in the clinical adverse event profiles of FGFR inhibitors. Moreover, the results from this study may explain low rates of adverse events reported with derazantinib for retinal events, mucositis and nail toxicities.

Results from a series of preclinical efficacy models of breast, colorectal, head & neck, lung, ovarian and gastric cancer with confirmed FGFR1-3 genetic aberrations, showed that FGFR2-fusion-positive gastric cancer models were particularly sensitive to treatment with derazantinib. In addition, gastric and lung cancer models showed the strongest correlation of FGFR1-3 expression versus the anticancer activity of derazantinib. The results support the planned clinical investigation of derazantinib in gastric cancer as its next indication.

Full results from a phase 1 study with once-daily oral lisavanbulin in adult patients with recurrent glioblastoma (GBM), or high-grade glioma, showed an overall clinical benefit rate of 44% at six months at daily doses of 25-30 mg. There was an exceptional long-lasting response in a patient, whose tumor tissue was positive for end-binding protein 1 (EB1), a previously identified response predictive biomarker for lisavanbulin in preclinical studies. A phase 2 expansion study will be initiated shortly, which will use EB1-positivity as a patient selection criterion.¹ Lisavanbulin is dosed at the recommended phase 2 dose of 25 mg/day in this phase 2 study in patients with recurrent GBM. The prevalence of EB1-positivity in GBM is estimated at 2-5%.

Dr. Marc Engelhardt, Chief Medical Officer, said: “The results presented at ESMO support our differentiation strategy for derazantinib, which is based on its unique kinase inhibition profile and its clinical safety profile. They also provide the preclinical rationale for our decision to initiate a clinical study of derazantinib alone and in combination with other therapies in patients with advanced gastric cancer. The full results from the completed phase 1 study with lisavanbulin underscore its potential to be developed in a targeted patient population. Our initial focus will be on glioblastoma. We may decide to explore other tumor types upon achieving clinical validation of EB1 as a response-predictive biomarker in glioblastoma.”

The following e-posters were presentedat ESMO Virtual Congress 2020:
Presentation #	Title
1960P	Differential induction of gene expression may explain differences in reported adverse event profiles between the FGFR-inhibitors derazantinib and erdafitinib: an analysis in safety relevant normal tissues from urothelial cancer (UC) patient-derived mouse xenograft (PDX) models.
541P	Derazantinib (DZB), an oral Fibroblast Growth Factor Receptor inhibitor (FGFRi), shows promising activity in PDX-tumor models with aberrations in FGFR1-3
382P	The potential utility of end-binding protein 1 (EB1) as response-predictive biomarker for lisavanbulin: Final results from a phase 1 study of lisavanbulin (BAL101553) in adult patients with recurrent glioblastoma (GBM)

For further information, please visit https://www.esmo.org/meetings/esmo-virtual-congress-2020

About derazantinib

Derazantinib is an investigational orally administered small-molecule FGFR kinase inhibitor with strong activity against FGFR1, 2, and 3.² 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.³ In these cancers, FGFR genetic aberrations are found in a range of 5% to 30%.⁴
Derazantinib also inhibits the colony-stimulating-factor-1-receptor kinase (CSF1R).^{2, 5} 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.⁶ Preclinical 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.^7,8
Derazantinib has demonstrated antitumor activity and a manageable safety profile in previous clinical studies, including a biomarker-driven phase 1/2 study in iCCA patients,⁹ and has received U.S. and EU orphan drug designation for iCCA. Basilea is currently conducting two clinical studies with derazantinib. The first study, FIDES-01, is a registrational 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.¹⁰ The second study, FIDES-02, is a phase 1/2 study evaluating derazantinib alone and in combination with Roche's PD-L1-blocking immune-checkpoint inhibitor atezolizumab (Tecentriq^®)¹¹ in patients with advanced urothelial cancer, including metastatic, or recurrent surgically unresectable disease, expressing FGFR genetic aberrations.¹².
Basilea 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)¹³ is being developed as a potential therapy for diverse cancers.^1, 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, 21 In preclinical studies, end-binding protein 1 (EB1) was identified as a potential response-predictive biomarker in glioblastoma models.²¹ The active moiety BAL27862 binds to the colchicine site of tubulin, with distinct effects on microtubule organization,²² resulting in the activation of the "spindle assembly checkpoint" which promotes tumor cell death.²³

About Basilea

Basilea Pharmaceutica Ltd. is a commercial-stage biopharmaceutical company, focused on the development of products that address the medical challenges in the therapeutic areas of oncology and infectious diseases. With two commercialized drugs, the company is committed to discovering, developing and commercializing innovative pharmaceutical products to meet the medical needs of patients with serious and life-threatening conditions. Basilea Pharmaceutica Ltd. is headquartered in Basel, Switzerland and listed on the SIX Swiss Exchange (SIX: BSLN). Additional information can be found at Basilea's website www.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 and its 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. ClinicalTrials.gov identifier: NCT02490800
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. FIDES-01: ClinicalTrials.gov identifier: NCT03230318
11. Tecentriq^® ist eine eingetragene Marke von Hoffmann-La Roche AG.
12. FIDES-02: ClinicalTrials.gov identifier: NCT04045613.
13. J. Pohlmann, F. Bachmann, A. Schmitt-Hoffmann et al. BAL101553: An optimized prodrug of the microtubule destabilizer BAL27862 with superior antitumor activity. American Association for Cancer Research (AACR) annual meeting 2011, abstract 1347; Cancer Research 2011, 71 (8 supplement)
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. American Association for Cancer Research (AACR) annual meeting 2010, abstract 4412; Cancer Research 2010, 70 (8 supplement)
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. American Association for Cancer Research (AACR) annual meeting 2014, abstract 831; Cancer Research 2014, 74 (19 supplement)
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. AACR-NCI-EORTC conference 2009, abstract C233; Molecular Cancer Therapeutics 2009, 8 (12 supplement)
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. American Association for Cancer Research (AACR) annual meeting 2016, abstract 4781; Cancer Research 2016, 76 (14 supplement)
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. 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
23. F. Bachmann, K. Burger, H. Lane. BAL101553 (prodrug of BAL27862): the spindle assembly checkpoint is required for anticancer activity. American Association for Cancer Research (AACR) annual meeting 2015, abstract 3789; Cancer Research 2015, 75 (15 supplement)

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