Molecular targeted therapeutics for the treatment of cancer patients. August 1, 2016

Transcription

1 Molecular targeted therapeutics for the treatment of cancer patients August 1, 2016

2 Company overview Experienced team with value creating track record in the field of targeted oncology Validated targets and biomarker selected patients Rational drug design in patentable chemical spaces with less competition Reduced clinical risk / fast to market Two targeted anti-cancer programs NT-113 (cerebanib) oral pan-erbb inhibitor with high brain penetration - >$2B sales opportunity in EGFR/HER2+ NSCLC brain mets and GBM NT-125, differentiated oral PARP inhibitor (partnering opportunity) - $1B sales opportunity Recent composition of matter IP on both programs 2

3 Strong management team and SAB Harry Pedersen President & CEO Jackie Walling, MBChB, PhD Chief Medical Officer Wang Shen, Ph.D. Preclinical & Product Dev. Tim Cloughesy, M.D. Advsior Prof. Johann de Bono, M.D. Advisor Biotech entrepreneur with extensive business development experience in both big pharma and start-ups. Responsible for the discovery program that lead to Velcade while at Hoecsht Marion Roussel In-licensed Phase 2 compound, resulting in Chiron acquisition of Matrix Responsible for business development and clinical development of Synribo while at ChemGenex Negotiated $90 million sale to BioMarin while at Lead Therapeutics; deal driven by Lead PARP inhibitor subsequently sold to Medivation Seasoned oncology clinical development expert. Previously, at Eli Lilly responsible for development of Alimta and Gemzar. More recently, VP clinical development at BioMarin responsible for Vimizim and talazoprib (PARPi). Accomplished chemist with multiple patents/products including Lifitegrast and Venclexta previously working for Abbott, Amgen and Sunesis. Head of Neuro-oncology at UCLA and a key opinion leader in the development of new therapeutics for the treatment of brain tumors. Among many accomplishments, Dr. Cloughesy was the lead investigator for the Avastin recurrent GBM trial and presented the final data to the ODAC committee. Head of experimental therapeutics for Cancer Research UK and is a key opinion leader in the development of new targeted therapeutics for solid tumors including erbb and PARP inhibitors. 3

4 Molecularly targeted anti-cancer therapeutics NT-113 (cerebanib) 3 rd generation irreversible pan erbb (EGFR, HER2 and HER4) inhibitor Up to 8:1 brain to plasma drug concentration x higher ratio than marketed EGFR inhibitors Inhibits downstream p-egfr and p-akt inducing cell death Potential best in class IND 9 months post financing Phase I/II study in patients with lung/breast cancers with brain mets, GBM patients NT nd generation PARP inhibitor Excellent PK and biodistribution compared to other agents in development Large partnering deals in the same space IND 18 months post financing Phase I/II could study patients with BRCA1 and BRCA2 mutated ovarian and breast patients The name cerebanib is subject to approval by World Health Organization s International Nonproprietary Names (INN) and United States Adopted Names for pharmaceuticals 4

5 Current targeted therapies inadequate in preventing or treating brain metastases 150, ,000 patients with brain metastases (BM) diagnosed annually in the U.S. alone Lung (50%) and breast (20%) cancers constitute the majority of BM Erlotinib, gefitinib and afatinib induce responses in EGFR+ NSCLC patients with BM, but: Fail to statistically improve overall survival, potentially because, They do not inhibit p-akt to induce cell death, while NT-113 does Gefitinib or erlotinib treatment do not prevent BM 30% of NSCLC patients with EGFR mutations on gefitinib or erlotini developed BM Afatinib: NSCLC BM occurred after initial response Poor BBB penetration properties may account for lack of benefit 5

6 Glioblastoma has a large unmet medical need 10,000 patients with glioblastoma diagnosed annually in U.S. alone month median survival - 5 year survival is 4.7 % Over-expressed EGFR and/or its mutations are the dominant RTK lesions in GBM (50% of patients) Other receptor tyrosine kinase (RTK) lesions rarely co-exist with EGFR+ (7% of patients) GBM blood brain barrier in tact - Higher penetrant agents needed Limited activity of other EGFR inhibitors in GBM (erlotinib, gefitinib and afatinib) likely due to poor brain penetration 6

7 NT-113, oral irreversible pan-erbb inhibitor Up to 8:1 brain to plasma drug concentration 15 to 20 times higher than marketed reversible EGFR inhibitors in vivo activity with significant survival benefit in multiple glioblastoma PDX intracranial xenograft models EGFRvIII+ and/or EGFR/HER2+ PDX tumor tissue showed that NT-113 can overcome tumor heterogeneity by completely inhibiting both p-egfr and downstream p-akt, inducing cell death Clean off-target profile, 14-day tox study in rats completed IND 9 months post funding Phase I/II designed to generate strong efficacy data in man and produce a large valuation inflection point Approval pathways in EGFR+ NSCLC with brain metastases and/ or EGFR+ glioblastoma with over $1B sales potential in each 7

8 NT-113 selectivity in more sensitive assay IC 50 determined at Reaction Biology Corp Kinases NT EGFR EGFR (T790M) EGFR (d ) EGFR (L858R) EGFR (L858R, T790M) ERBB2/HER ERBB4/HER ABL BLK JAK LCK Of the 130 TKIs examined, only 11 showed >90% to 1uM concentration of NT-113 Highly selective for all erbb receptors Active against all EGFR activated mutants tested U87 EGFRvIII cellular.19 Compounds were tested in a 10-dose IC50 mode with 3-fold serial dilution starting at 1 um. Control Compound was tested in a 10-dose IC50 with 3-fold serial dilution starting at 20 um. All kinase reactions were performed at 10 um ATP. 8

9 Irreversible pan-erbbi IC 50 s (nm) Receptor EGFR HER2 HER4 EGFR (L858R) EGFR (L858R/ T790M) NT Afatinib NA Dacomitinib Neratinib Marketed erbb targeted small molecule drugs Erlotinib Gefitnib Lapatinib NT-113: data generated at Reaction Biology Corp ( 2. Afatinib: Li, et al. Oncogene (2008) 27, Dacomitinib, Erlotinib, Gefitinib: Engelman, et al. Cancer Res. 2007; 67: (24) Neratinib: 5. Lapatinib data: Rusnak Mol Cancer Ther. 2001;1:

10 NT-113 achieves efficacious concentrations in rat Concentration (ng/ml) X of U87-vIII EC 50 BT474 EC 50 = 24 nm N87-HER2 EC 50 = 2.8 nm Brain concentration, NT-113 po, 5mg/kg Plasma concentration, NT-113 po, 5mg/kg 4-8X brain/plasma 183X of U87-vIII EC 50 NT113 has sufficient exposure in rat brain after 5 mg/kg PO dosing At 24 h, brain concentration is at >100x of U87-vIII EC 50, or 1.5X of BT474 EC 50 1 U87-vIII EC 50 = 0.19 nm Hours Drug Species Brain / Plasma Ratio 2015 Sales Reference Afatinib Rats 0% $250M Data on file NewGen Gefitinib Mice 15% $450M Agarwal et al Erlotinib Mice 27% $1,097M Elmeliegy et al NT-113 Rats > 400% N/A Data on file NewGen 10

11 GBM 39: PDX tumor model driven by EGFRvIII Bioluminescence Images Control day 1 NT-113 day 1 20mg/kg/po NT day dosing 14 days once a day oral 20mg/kg/po Control day 14 d14 = 13.9x d1 NT-113 day 14 d14 = 0.22x d1 Eight animals per group Relatively stable body weight, no GI side effects observed Data courtesy of Dr. David James, UCSF PDX (patient derived xenograft) use human tumor tissues and are considered the most predictable models of glioblastoma response to drugs 11

12 Active in GBM12 (EGFR amplified) PDX model PDX intracranial mouse model A GBM12: amplified for wild-type EGFR B Normalized BLI Control NT113 Lapatinib Percent survival C vs. L, P < C vs. N, P < N vs. L, P < Control NT113 Lapatinib Day Day C lapatinib (150 mg/kg b.i.d); NT113 (10 mg/kg/d, po) 12

13 Active in GBM6 (EGFRvIII & HER2 amplified) and U87vIII (EGFRvIIII) After 7 days of treatment GBM6 PDX intracranial mouse models U87vIII Dosing: 10mg/kg/po/daily GBM6 over-expresses viii and HER2, an important regulator of cell growth and differentiation not found in normal adult brains - HER2 is overexpressed in 20-90% of GBM patients U87vIII over-expresses viii, a driving mutation in GBM NT-113 produced statistically significant survival in both studies 13

14 NT-113 kills cancer cells as a single agent NT-113 completely shuts down phosphorylation of EGFR, HER2, HER4 and AKT at 1uM/L NT-113 has been shown to reach drug concentrations of.5-.8 um/l in mice at a dose of 10mg/kg with no toxicities. It has been dosed safely in mice up to 20mg/kg NT-113 is expected to achieve sufficient drug concentrations in man to induce apoptosis and produce tumor shrinkage as a single agent 14

15 NT-113 decreases proliferation, induces apoptosis Control Lapatinib NT113 Ki-67 Activated Caspase 3 NT-113 both decreases cell proliferation and induces apoptosis (cell death) Sample taken from GBM12 IC xenograft studies The ability to induce apoptosis suggests single-agent approval possibility 15

16 NT-113 active in 7 PDX xenograft models Cell Lines GBM39, IC PDX GBM12, IC PDX GBM12, IC PDX U87, IC (viii transfected) PDX GMB6, IC PDX Molecular status Treatment initiation from implantation (days) Dose mg/kg Control/ Reference Results EGFR-vIII untreated P>.001 survival vs untreated EGFR-wt 7 20 & 10 Untreated lapatinib EGFR-wt 21 (large tumor) EGFR viii PTEN null EGFRvIII HER2+ 10 untreated erlotinib untreated erlotinib untreated erlotinib P>.0001 survival vs untreated Superior activity compared to lapatinib P>.0003 survival vs untreated Superior activity compared to erlotinib Superior activity compared erlotinib P>.0001 survival vs untreated (insensitive to Erlotinib) N87 Gastric (HER2+) flank H1975 NSCLC (T790M) flank HER & 30 untreated lapatinib EGFR (T790M) 9 20 untreated erlotinib afatinib Superior activity vs lapatinib Activity equivalent to afatinib 16

17 NT-113 competitive landscape No approved product for EGFR+ NSCLC patients with brain metastases or GBM Despite low blood brain barrier penetration, erlotinib, gefitinib and afatinib have shown responses in NSCLC patients with EGFR mutations, but have failed to significantly improve survival Better brain penetrant irreversible pan-erbb inhibitor needed to completely inhibit p-egfr and downstream p-akt (NT-113 does) Rinopepimut (CellDex) recently failed a pivotal Phase 3 in first line EGFRvIII GBM patients Phase 3 failure may be due to lack of inhibition of amplified EGFR Phase 2 Rinopepimut + bev very small (72 patients in 3 groups, controlled group only 20 patients) DC patient specific vaccines likely to play very limited role in GBM EGFRvIII targeted mab s and ADC s are unlikely to cross the BBB and have efficacy in the brain 17

18 Poly ADP ribose polymerase (PARP) PARP 1, PARP 2 play key role in detection and repair after DNA strand breaks Catalyze polymerization of ADP ribose moieties onto target proteins, using NAD as a substrate PARP inhibitors prevent repair of single strand breaks in DNA Cells deficient in DNA repair pathways (e.g. BRCA deficient) can be sensitive to PARP inhibitors PARP inhibitors potentiate efficacy of DNA damaging drugs and radiation in pre-clinical models Team has extensive experience in the discovery and development of PARP inhibitors Potential indications include BRCA mutated breast, ovarian or head & neck cancers 18

19 In vitro comparative data Sample Structure Mol wt IC50 (nm) Cell IHC (nm) ABT888 (Abbo3) O NH 2 N N H N H Olaparib (AZ) O N N F O N N O NT NT NT NT NT

20 NT-125 xenograft: breast BRCA mutant Tumor volume(mm3) Mean±SEM Vehicle NT-125, 25mg/kg,po,bid NT-125, 50mg/kg,po,bid NT-125, 100mg/kg,po,bid Series of potent PARP inhibitors including NT-125 Third generation PARP inhibitor Oral dosing NT-125 has excellent bioavailability and PK May overcome shortcomings of other agents Single agent activity in xenograft models Patents issuing Days after beginning treatment 20

21 Value proposition Lead program is a risk-reduced approach to treating large, defined patient subpopulation Combination of biomarkers and imaging for precision-medicine NT-113 may be best in class with multiple potential pathways to approval NT-125 hot target with near-term partnering potential Strong team with deep targeted oncology experience supported by top KOLs Potential for liquidity in months 21