TTI-2341: A Novel Brain-Penetrant, Orally Available, Covalent EGFR Inhibitor for the Treatment of Brain Cancers November 2017
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EGFR is a Drug Target in Brain Cancer Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in the pathogenesis of many cancers Amplification of EGFR locus is the most common genetic aberration in glioblastoma (GBM) 1 Aberrant receptor expression correlates with poor clinical prognosis for GBM patients 2 Pharmacological inactivation of EGFR and mutant variants inhibits tumor growth in GBM models 3 Primary Brain Tumors >50% of GBMs have amplified/mutated EGFR Brain Metastasis Lung and CRC metastasize to brain 1 Parsons et al. Science. 2008 2 Shinojima et al. Cancer Res. 2003 3 Johns et al. Clin Cancer Res. 2007; Karpel-Massler et al. Mol Cancer Res. 2009 3
Approved EGFR Inhibitors Exhibit Poor CNS Penetration EGFR-targeted drugs approved by FDA There are numerous EGFR-targeted drugs on the market; none are FDA approved for CNS tumors HNSCC Cetuximab Pancreatic Erlotinib Lung Erlotinib Gefitinib Afatinib Osimertinib Colorectal Cetuximab Panitumumab Clinical testing of EGFR inhibitors in brain cancers has yielded mixed results Poor blood-brain barrier (BBB) penetration (<5%) limits efficacy of existing agents There is an urgent unmet medical need for novel BBB-penetrant EGFR inhibitors HNSCC: head and neck squamous cell carcinoma 4
Trillium s Innovative Chemistry Platform Creating Differentiated New Medicines with Fluorine Approximately 25% of all marketed drugs contain fluorine Block sites of metabolism to increase halflife and reduce toxicity Electronegativity alters chemical properties to improve binding & potency Lipophilicity improves oral absorption and blood-brain-barrier (BBB) penetration Innovative proprietary chemistry allows access to an unprecedented class of novel fluorinated molecules 5
Our Focus: Covalent EGFR Inhibition First generation EGFR-targeted drugs (gefitinib, erlotinib, lapatinib) are noncovalent inhibitors that compete with ATP for the EGFR active site Approved first generation molecules have reduced activity against certain resistance-associated mutations (e.g., T790M) Covalent inhibitors carry an electrophilic warhead that irreversibly interacts with a conserved, solvent accessible cysteine residue in EGFR Advantages of covalent inhibitors: Highly biochemically efficient Irreversible inhibition confers a longer duration of action Active against T790M mutants 6
TTI-2341, the Lead Covalent EGFR Inhibitor, was Identified Through a Rigorous Screening Process Synthesis of patentable compounds (N=30) (Afatinib, Dacomitinib, chemotypes) Biochemical Assays (EGFR wt and mutants) Cell-based Assays (Proliferation and autophosphorylation) Single dose IV & PO PK (rat, mouse) In Vitro ADME Screen #2 (PgP, metabolic stability, plasma binding protein, CYP inhibition, physicochemical properties) In Vitro ADME Screen #1 (herg, microsome stability, Caco-2) Single Dose Tissue Distribution (Brain & Plasma) 7 Day Tox in Rats (Clinical and CNS observations, PK, histopathology) TTI-2341 Throughout this process novel compounds were compared to the FDA-approved benchmark drug afatinib (Gilotrif TM ), additionally TTI-2341 was compared to FDA-approved osimertinib (Tagrisso TM ) 7
TTI-2341 is a Potent Inhibitor of Wild Type and Mutant EGFR Biochemical kinase assay (RBC): EGFR wt and mutants Compound wt T790M T790M/ L858R C797S d746-750/ C797S d746-750/ T790M/ C797S T790M/ C797S/ L858R TTI-2341 <0.5 2.27 2.93 <0.5 <0.5 62.4 389 Afatinib <0.5 0.57 <0.5 <0.5 <0.5 39.5 176 Osimertinib 1.04 1.03 <0.5 5,810 1,160 584 3,890 Values in table = IC 50 (nm) TTI-2341 displays comparable biochemical activity to afatinib and superior potency to osimertinib against EGFR variants containing the C797S mutation 8
TTI-2341 Exhibits Superior ADME Properties Parameter TTI-2341 Afatinib Osimertinib Conclusion Permeability 1 (Caco-2) PgP Efflux Ratio 2 (MDCK-MDR1) % Brain Tissue Binding (Rat) 1 Papp (A-B) 10-6 cm/s 2 Papp (B-A) / Papp (A-B) 2.43 0.81 0.82 TTI-2341 has 3x higher cell permeability 1.61 5.02 13.4 3 TTI-2341 is not a PgP substrate (efflux ratio < 2) 95.7% 4 99.4% >99.9% TTI-2341 is not highly bound to brain 3 Ballard et al., 2016 4 recent study (No. VRI119-17085-RP) In addition, TTI-2341 exhibits comparable to superior characteristics to afatinib and osimertinib across other key ADME parameters 9
TTI-2341 Exhibits Superior Oral Bioavailability Systemic Exposure of TTI-2341 and Afatinib Following a Single 10 mg/kg Oral Dose in Male SD Rats (n=4) Systemic Exposure of TTI-2341 and Osimertinib Following a Single 4 mg/kg Oral Dose in Male SD Rats (n=3) TTI-2341 Afatinib Osimertinib Bioavailability (F %) 85.6 ± 9.1 43.3 ± 10.8 45% 1 1 Finlay et al., 2014 10
TTI-2341 Exhibits Superior BBB Penetration vs. Afatinib Estimated Unbound Brain Exposure Following a Single 20 mg/kg Oral Dose in Male SD Rats (n=4) TTI-2341 estimated unbound brain exposure (AUC and C max ) values are > 15-fold higher than afatinib TTI-2341 (but not afatinib) was quantifiable in the brain up to 24 hours post 7-day repeat dosing TTI-2341 has >10-fold higher Kpuu (unbound drug brain-to-plasma ratio) than afatinib 11
TTI-2341 Exhibits Superior BBB Penetration vs. Osimertinib Estimated Unbound Brain Exposure Following a Single 4 mg/kg Oral Dose in Male SD Rats (n=3) TTI-2341 estimated unbound brain exposure (AUC and C max ) values are approximately 21-fold higher than osimertinib TTI-2341 has a slightly higher Kpuu (unbound drug brain-to-plasma ratio) than osimertinib 12
Summary TTI-2341 as a Potential Best-in-class Brainpenetrant Covalent EGFR Inhibitor TTI-2341 is a novel covalent inhibitor of wild type and mutant EGFR developed with Trillium s proprietary fluorine chemistry Compared to the benchmark compounds, TTI-2341 exhibits: Similar in vitro potency to EGFR mutant targets Superior in vitro ADME properties Greater oral bioavailability and systemic exposure Enhanced BBB penetration and free brain exposure TTI-2341 is amenable to radiolabeling with 18 F for use as a PET imaging probe Future development steps have been identified, IND submission can be achieved in 12-15 months Additional data are available under confidentiality agreement 13