AXL is a receptor tyrosine kinase

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1 AXL receptor tyrosine kinase Key driver of tumour plasticity, heterogeneity and immune evasion High AXL expression is correlated with poor survival in most cancers Strong AXL expression correlates with poor survival rate Broad evidence of AXL linked with poor prognosis AXL is an innate immune checkpoint & drives tumour intrinsic cell plasticity. AXL is innate immune checkpoint Unique marker of inflammation and cellular stress Immunesuppressive signalling M2 macrophage polarisation Inhibits DC interferon response Reduced antigen presentation & immunosuppressive cytokine profile M2 NK DC 2. AXL drives tumour cell plasticity tumour cell Therapy resistance Immune escape Metastasis M2: M2 macrophage (immune suppressive), NK: Natural Killer cell, DC: Dendritic cell AXL is a receptor tyrosine kinase Gas6, single high affinity ligand Low expression in normal tissues; upregulated by inflammation and cellular stress Unique signal transduction drives Survival Drug resistance Immune suppression / evasion Metastasis Interest in AXL as a key target for aggressive disease is increasing rapidly Gas6 AXL Benefits of selective AXL inhibition with Selectivity Selective over other kinases and other TAM family members (MerTK, Tyro) specifically Allows for rational combinations while reducing the risk of additive toxicity Safety AXL knockout mice are phenotypically normal AXL is the TAM receptor that is specifically upregulated in aggressive disease is well tolerated across BerGenBio combination studies Efficacy Single agent activity in AML and NSCLC Increased clinical benefit in combination with chemo in NSCLC Reverses acquired resistance to erlotinib in NSCLC Increases efficacy of checkpoint inhibitors in NSCLC AXL is detected on patient tumour tissue and adjacent immune cells by BerGenBio proprietary immunohistochemistry method (IHC) AXL expression in NSCLC patient tumour sample AXL expression in tumour adjacent alveolar macrophages

2 Bemcentinib First-in-class, highly selective and orally bioavailable AXL inhibitor capsule >2.5 fold

3 Bemcentinib preclinical data P

4 2 BGBC3 BGBC4 BGBIL6 BGBC7 BGBC8 saxl levels CD vs C2D in all samples log2 Clinical Trial ID BGBC3 BGBC4 BGBIL6 BGBC7 BGBC8 soluble AXL AXL ligand Gas6 sheddase Figure adapted from Miller et al CCR (27) Yes No Adapted from Cook et al., Nature Reviews Drug Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No No Yes No Patient benefit Yes Expressed on tumour and immune cells driving tumour survival programme and immune evasion Negative prognostic factor in AML Companion Diagnostic for personalised medicine What is Precision Medicine? Why Precision Medicine? Companion Diagnostic Advanced Responder - Treat NSCLC, exhausted all treatment options up to 3 pts any prior treatment Non Responder Likelihood of success (Phase I to approval) 3% 25.9% Single arm 25% Safety Initial read-out expected 2H 28 2% BGB324 mg/d Docetaxel 65% mg/m2 % 5% % 8.4% ORR, PFS, OS, PK, Selecting patients most likely to benefit from treatment assessments Improving probability of Without With approval biomarker biomarker Increase reimbursement rates BerGenBio biomarker programme Designed in line with established and emerging techniques: Standard (tissue) and emerging (blood) pathology techniques are used to diagnose cancer and determine optimal, personalised treatment. Pre-treatment soluble AXL levels in plasma are predictive of patient benefit in AML/MDS &'"-:'"*)",)-#./-5""#-#-&*)7",)-8","97)-7,-8;8<==> Liquid biopsy emerging technology BGBC3 BGBC4 BGBIL5 BGBIL6 BGBC7 BGBC8 Example cut-off for patient stratification Pre-treatment saxl levels (ng/ml) Tissue AXL levels correlate with response in /pembrolizumab combo trial Tumour tissue biopsy the main way cancer is diagnosed BGBIL6 BGBC7 BGBC8 H&E staining Anti-AXL IHC Shown is a fresh tissue biopsy from a partial responder to pembrolizumab. Anti-AXL staining of tumour cells was observed (open arrowheads). Additionally a mainly weak to moderate cytoplasmic staining of stromal cells was seen (arrows). Pharmacodynamics AXL drives a tumour survival programme that is increased by reduced receptor shedding Plasma Concentration (log2 Baseline Normalised) Plasma Concentration (log2 Baseline Normalised) higher plasma AXL levels AXL receptor tyrosine kinase reduced signalling physiological AXL signalling AXL expressing tumour or immune cell AXL addicted tumour sustained signalling lower plasma AXL levels AXL receptor tyrosine kinase: baseline normalised saxl levels CD vs C2D in patients showing clinical benefit (log2 baseline normalised). Patients not demonstrating treatment benefit show no significant alteration of saxl levels following treatment.

5 year old white male screen ECOG of 2 no known mutations line of previous therapy with best response of SD liver metastases present biomarker espression, TPS (%) AXL: 25% PD-L: % weeks 9 In collaboration with Bemcentinib and KEYTRUDA in NSCLC Keytruda monotherapy showed % response rate in previously treated NSCLC patients (Keynote ). The BGBC8 trial is designed to test the hypothesis whether AXL inhibition can BGBC8: Phase II trial in NSCLC, with KEYTRUDA Enhance responses to immunotherapy when given in combination with KEYTRUDA in previously treated, immunotherapy-naïve NSCLC patients. Clinical collaboration with Merck & Co. (MSD) 2nd line advanced adeno NSCLC 33 dose escalation & expansion Single arm IO naive, Safety Prior platinum 2mg daily measurable disease fresh tissue biopsy KEYTRUDA, PDL ve and -ve 2mg q3wks AXL ve and -ve Interim analysis Final analysis BGBC8: Interim clinical data Phase II trial in NSCLC of with KEYTRUDA Best response % change in sum target lesions biomarker expression AXL PD-L best response * Best overall response according to biomarker expression at time of data cut-off (analysis includes ongoing patients) PR SD PD N ORR (%) DCR (%) All PD-L < % AXL % previous Tx pembrolizumab UNK PD PR SD PR SD PD SD SD SD PD SD SD PR PD PD PD PD SD SD SD SD SD SD SD SD PR MR PR PR % TPS < % TPS to be determined PR: partial response, MR: mixed response (new lesion), SD: stable disease, PD: progressive disease Biomarkers Patient case study: AXL biomarker correlated with patient benefit. Patient characteristics H&E staining Plasma soluble AXL levels increase upon treatment with KEYTRUDA Best response on KEYTRUDA: partial response Anti-AXL IHC Anti-AXL staining of tumour cells was observed (open arrowheads). Additionally a mainly weak to moderate cytoplasmic staining of stromal cells was seen (arrows). Sum target lesions (cm) screen 2 days

6 In collaboration with Bemcentinib and KEYTRUDA in TNBC A Ph II study of the selective AXL inhibitor in combination with pembrolizumab in patients with previously treated, locally advanced and unresectable or metastatic triple negative breast cancer (TNBC) or triple negative inflammatory breast cancer (TN-IB) The BGBC7 trial is designed to test the hypothesis whether AXL inhibition with can Phase II Study of the selective AXL inhibitor in combination with KEYTRUDA enhance responses to immunotherapy when given in combination with pembrolizumab in previously treated, immunotherapy-naïve TNBC patients. 2nd line advanced TNBC or TN-IBC Prior taxane &/or anthracycline measurable disease fresh tissue biopsy PDL ve and -ve AXL ve and -ve Single arm 2mg daily pembrolizumab 2mg 3-weekly Interim analysis Final analysis Clinical collaboration with Merck & Co. (MSD) Study Objectives & Endpoints Primary objective: Anti-tumour activity of and pembrolizumab in combination Secondary objectives: Safety of and pembrolizumab when given in combination Anti-tumour activity of the combination of and pembrolizumab Pharmacokinetic profile of when given with pembrolizumab Explorative: Assessment of relevant biomarkers Primary endpoint: Objective Response Rate Secondary endpoints: Duration of Response Disease Control Rate Time to progression Survival at 2 months Response by biomarker expression Translational Analyses Immunohistochemistry PD-L AXL Liquid biomarkers / PBMCs Major Inclusion & Exclusion Criteria Key Inclusion Criteria Histopathologically or cytologically documented TNBC or TN-IBC Locally advanced and unresectable or metastatic TNBC or triple negative inflammatory breast cancer. Received one or more prior therapies for TNBC or inflammatory breast cancer in the metastatic setting Prior treatment (metastatic or (neo) adjuvant) must have included a prior taxane and/or anthracycline-based therapy Renal and hepatic and cardiac function within normal ranges Measurable disease as defined by RECIST.2 Provision of suitable tumour tissue for the analysis of AXL kinase expression and PD-L expression Eastern Cooperative Oncology Group (ECOG) performance score or Key Exclusion Criteria Has disease suitable for local therapy administered with curative intent Has received more than three previous lines of therapy in the metastatic setting Has received prior therapy with an immunomodulatory agent Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis Indigestion remedies Recent or ongoing systemic steroid therapy AXL signalling pathway Soluble AXL MAP Kinase pathway signalling Immune cell populations AKT signalling pathway Pharmacokinetics pembrolizumab Participating Countries Conclusion USA Spain United Kingdom Norway Enrollment opened: July 27 Total Study Sites 2 Total Study Countries 4 4 out of 8 patients analysed were negative for AXL 2 out of 5 patients analysed were negative for PD-L Of 8 patients analysed, had a partial response

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8 33 : mg/2mg qd trametinib/dabrafenib n = 6-2 pts saxl BGBM6 No CD C2D Yes CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease 2 4 BGBM4 BGBM7 CD No C2D Yes BGBM5 BGBM8 CD No C2D Yes Bemcentinib in combination with SoC in metastatic melanoma Although responses to TKIs are rapid, resistance ultimately emerges. Monotherapy checkpoint inhibitor responses can be further improved. The BGBIL6 trial is designed to test the hypothesis whether AXL inhibition can Enhance responses to immunotherapy Enhance responses to targeted therapy when given in combination with pembrolizumab or dabrafenib/trametinib in treatment naïve melanoma patients Ph I/II randomised trial of selective AXL inhibitor in melanoma patients Three part randomised design enrolling up to 92 patients BRAF positive High tumour load BRAF positive Low tumour load BRAF negative Part : Dose finding Part 2: st RP2D Part 3: 2nd RP2D Dose escalation: RP2D 2: expansion 2: erlotinib 2: Dabrafenib/trametinib Dabrafenib/trametinib Dabrafenib/trametinib Dabrafenib/trametinib PK, biomarkers Safety/Efficacy trametinib/dabrafenib /- Safety/Efficacy pembrolizumab /- Assessments - efficacy & safety Response assessed q9 wks per RECIST v. & irc Adverse events assessed by CTCAE v4. Safety-evaluable: dose of study treatment as of cut-off Biomarker analysis Initial read-out expected 2H 28 Soluble protein biomarkers by liquid biopsy PD-L and AXL expression per IHC Immune cell popoulations by CyTOF Endpoints Primary: ORR Secondary: PFS DoR OS Exploratory: response per irc response by biomarker expression QoL Interim clinical data Phase II trial in metastatic melanoma Example CR on dabrafenib/trametinib A 68 year old male was randomised to receive 2 mg/daily standard dabrafenib/trametinib. At screening the patient had multiple metastases to the liver and the lungs. At cycle 2, he had a complete response. Best response 4 Best percentage change from baseline in target lesions in RECIST evaluable patients to date Best overall response PD PD SD SD SD SD SD PR PR SD PR PD PR PR PR PR PR CR CR CT (liver) at screen % change in sum target lesions % % - 8 Treatment pembro pembro monotherapy D/T D/T Biomarkers Cycle 2 (36 weeks): complete response Pharmacodynamics: Serum AXL, serum biomarker BGBM4 and serum biomarker BGBM5 levels increase upon treatment with Predictive: Pre-treatment levels of soluble AXL serum biomarker BGBM7 and serum biomarker BGBM8 associated with benefit from treatment Sample Timepoint Sample Timepoint Sample Timepoint Response assessment Response assessment Response assessment

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10 Bemcentinib docetaxel in NSCLC NSCLC, treatment options Safety Initial read-out expected 2H 28 up to 3 pts any prior treatment Docetaxel 6 mg/m2 ORR, PFS, OS, PK, assessments Sponsor Investigator: Dr David Gerber, UTSW Dallas While it is still early, to date 3 of 7 evaluable cases have demonstrated radiographic partial responses, which we cautiously hope may represent a real improvement over the 7-% response rate seen with docetaxel chemotherapy in this disease setting Duration of treatment (days) Pt 4 characteristics Pt 4 tumour shrinkage (weeks) Gender, age Female, 64 years old Etnicity Caucasian Histologic diagnosis NSCLC Stage IV Mutations Previous lines of treatment Dose EGFR wild-type, ALK negative. Carboplatin / Paclitaxel SD 2. Carboplatin / pemetrexed PD 3. PD Starting dose 75mg/m 2 docetaxel, mg. Cycle 2 day docetaxel reduced to 6mg/m 2

11 HEART. Congestive heart failure 2. Endomyocardial fibrosis 3. Myocardial infarction LIVER. NASH 2. ASH 3. Schistosomiasis 4. Idiopathic portal hypertension 5. Congenital hepatic fibrosis 6. HCV/HBV 7. Autoimmune hepatitis 8. Primary sclerosing cholangitis 9. Primary biliary cirrhosis INTESTINE. Inflammatory bowel diseases 2. Post-surgical adhesions LATOGENIC FIBROSIS. Surgery 2. Radiation therapy 3. Chemotherapy SYSTEMIC. Systemic sclerosis 2. Atherosclerosis 3. Nephrogenic systemic fibrosis Onset of Disease Onset of Sysmptoms Doagnosis Death yr Vehicle Nintendanib Bemcentinib Naive EYES. Glaucoma 2. Diabetic retinopathy 3. Diabetic macular edema 4. Dry eye disease 5. Tracoma 6. AMD LUNG. IPF 2. Asthma 3. COPD 4. ARDS 5. PAH 6. RA-ILD KIDNEY. FSGS 2. Diabetic nephropathy 3. Transplant nephropathy 4. IgA nephropathy 5. Lupus nephritis SKIN. Hypertrophic scars 2. Scleroderma 3. Eosinophilic fasciitis 4. Depuytren s constracture 5. Dermatomyositis 6. Keloids Sub-clinical Period 2 yr 3 yr 4 yr 5 yr 6 yr Hidroxyproline Histology Gene Expression Pre-diagnosis Period Post-diagnosis Period Normal Rapid IPF Slow IPF Normal IPF.. Normal Slow-IPF IPF Rapid IPF Fatty change Perivenular fibrosis (7) Barcena EASL 28 Exposure Abstinence Continued exposure Fibrosis Hyperplastic nodules Abstinence Abstinence Severe exposure Repeated attacks Severe Exposure Liver cell necrosis Inflamation Mallory bodies Fatty change 3 2 CTRL BEMCENTINIB HFCD HFCDBGB HFCD = high-fat, choline deficient diet Leads to NASH in animal models AXL in fibrosis Pre-clinical evidence suggests a promising role for selective AXL inhibition in fibrotic diseases Background The importance of AXL in fibrosis Fibrosis ~45% of all morbidity and mortality of NCDs Contributes to a broad range of fibrotic diseases and remodeling pathologies Fibrosis can affect all organs Fibrotic pathologies remain diseases of unmet medical need Cells contributing to the development of fibrosis Epithelial cells Pericyte Fibroblast Smooth Muscle cells Resident cells ECM deposition Growth factor secretion Proliferation and migration Apoptosis Endothelial cells FIBROSIS Fibrocytes BMDC Infiltrating cells MYFOIBROBLASTS Regulates and modulates key fibrogenic pathways TGFb signaling 2 Mechanosensing Hippo pathway 3 PPAR 4 AXL regulates cellular plasticity implicated in fibrotic pathologies AXL required for hepatic stellate cell (HCS) activation AXL required for HCS ECM expression5 Pharmacological modulation of AXL inhibits development of fibrosis several pre-clinical models Gilbane ART 25; 2 Reichl Hep. 25; 3 Gibault ChemMed 27; 4 Zhu AJTR 26; 5 Barcena J. Hep 25 Idiopathic Pulmonary Fibrosis (IPF) Healthy IPF Alveolar remodeling Bronchiole Fibrocyte Dilated bronchi Alveolus Fibrosis Alveolus O 2 Scarred interstitium CO 2 O 2 Interstitium CO 2 Blood vessel Rare disease Only two licensed anti-fibrotic therapies: Nintedanib Pirfenidone Market size estimated to grow to $3.5B by 225 AXL in Non Alcoholic Steatohepatitis (NASH) STEATOSIS NORMAL LIVER CIRRHOSIS HEPATITIS Non-alcoholic fatty liver disease (NAFLD) affects 75- million Americans Approximately 5% (6 million) Americans currently believed to have NASH Market: >$25B in 226 Patients with advanced fibrosis (F3 and F4) or cirrhosis saxl and GAS6 in circulation,2 saxl accurate biomarker for liver fibrosis and cirrhosis 3 IPF splits into fast and slower progressors Disease Progression A B C Axl expression predicts rapid decliners Bemcentinib modulates the IPF fibroblast fibrogenic phenotype GAS6 -/- mice protected from lung fibrosis AXL is biomarker for liver fibrosis and cirrhosis, inhibits NASH in vivo Serum leves saxl Time Bemcentinib is active in a humanised mouse model of IPF, and is significantly more active than nintedanib 6 (6) Espindola 28 AXL & Gas6 expression is increased in IPF, levels of activated AXL (paxl) increased in rapid IPF IPF Fibroblasts Humanized SCID IPF Model Fold Change (above Normal Lung) S-AXL Fold Change (above Normal Lung) Axl CTRL STEATOSIS FIBROSIS CIRRHOSIS Serum AXL elevated in NASH, selective AXL inhibition active in vivo 7 Bemcentinib reduces Bemcentinib reduces fibrosis in a CCL4-induced fibrosis in a diet induced model of NASH model of NASH Vehicle CCL4 Vehicle AXL inhibitor Hydroxiproline (%) # Hydroxyproline (μg/mg of protein) TAM receptors inhibitors Vehicle, R428, BIBF-2 Day (p.o. 5x week) Day 35 Fold Change (above Normal Lung) Gas6 Fold Change (above Normal Lung) p-axl * Vehicle Bemcentinib SoC Naive