Targeted Therapeutics for the Treatment of Cancer

Transcription

1 Targeted Therapeutics for the Treatment of Cancer

2 Company overview Three promising targeted anti-cancer programs Irreversible pan-erbb inhibitor EGFR/HER2/HER4 inhibitor PARP inhibitor Strategy Focus on validated targets Optimized drugs: potency, PK and biodistribution Enriched patient populations = higher probability of clinical success Fast to proof of concept and market Large markets Experienced team

3 Pipeline Discovery Preclinical Phase 1 Phase 2 Phase 3 Irreversible pan-erbb inhibitor: NT-113 Glioblastoma NSCLC with brain mets Breast with brain mets EGFR/HER2/HER4 inhibitor: NT-004 Breast cancer Colon cancer PARP inhibitor: NT-125 Solid tumors Leukemia Epigenetic inhibitor

4 NT-113 Irreversible pan-erbb tyrosine kinase inhibitor

5 Why NT-113? 3rd generation irreversible vs. 1 st generation reversible inhibitors pan-erbb vs. mono-erbb inhibitors Inhibiting the whole family: EGFR, HER2 & HER4 Very high brain penetration and preferential uptake in tumor Erlotinib, gefitinib, lapatinib and afatinib do not Most potent with best spectrum of irreversible pan-erbb inhibition Preclinical anti-tumor activity in EGFRvIII and EGFR amplified intracranial human GBM, resistant NSCLC and HER2+ gastric xenograft mouse models Phase 1 will be enriched with variety of erbb+ solid patients for early evidence of clinical activity across tumor types (eg:bmn-673) Potential for accelerated approval in GBM by 2017 EGFRvIII and high over-expression of EGFRwt

6 Disease driving mutations of EGFR differ in NSCLC and GBM. NT-113 targets both

7 ErbB critical in Glioblastoma: TCGA Data ErbB2 mutations in 91 GBM patients

8 High brain penetrant pan-erbbi s needed

9 Why is this important? ErbB family signaling ErbB receptors drive cell proliferation, migration, metabolism and survival Family includes EGFR (erbb1), HER2 (erbb2), HER3 (erbb3) and HER4 (erbb4) erbbs dimerize to form various homo- and hetrodimers that activate downstream pathways More than 90% of all solid tumors overexpress at least one receptor from the erbb family Overactivation leads to uncontrolled cell proliferation, inhibition of apoptosis and promotion of tumor growth and spread Overexpression of erbb3 and erbb4 (as well as erbb1 and 2) is an independent poor prognostic factor in multiple tumors Inhibiting only one erbb family receptor is insufficient: sustained blockade of multiple targets is likely to lead to improved clinical activity

10 Growing significance of HER2, HER3 and HER4 HER3 appears to be driving mutation in GBM HER4 activation occurs in 16% of GBM patients HER4 is a driving mutation and is overexpressed in 91% of NSCLC patients HER3 appears to be a driving mutation in gastric cancer NT-113 inhibits the spectrum of erbb receptors more effectively than other agents

11 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;1:85-94

12 NT-113 is the most potent in the class NT-113 Relative Potency Receptor EGFR HER2 HER4 EGFR (L858R) Afatinib 1.25x 3.3x --- Dacomitinib 15x 11x 35x Neratinib 230x 14x --- EGFR (L858R/ T790M) NT-113 is the most potent irreversible pan-erbb inhibitor NT-113 is 35X more potent inhibitor of HER4 compared to dacomitinib

13 NT-113 has the best spectrum of potency Multiple of EGFR inhibition Receptor EGFR HER2 HER4 EGFR (L858R) EGFR (L858R/ T790M) NT Afatinib NA Dacomitinib Neratinib The ideal agent should inhibit all targets within a tight range around EGFR NT-113 has the best overall spectrum of potency

14 Inhibitor Effects on EGFR and Downstream Signaling Mediators U87- MG U87 viii Treatment (1 um) EGF (5 nm) P- EGFR 1173 EGFR P- ERK ERK P- Akt Akt B- ac8n DMSO Ctrl Erlo8nib NT DMSO Ctrl Erlo8nib NT

15 NT-113 distributes preferentially into brain Concentration (ng/ml) Brain concentration, NT-113 po, 5mg/kg Plasma concentration, NT-113 po, 5mg/kg Plasma concentration, NT-113 iv, 1mg/kg >4X brain/plasma Drug Gefitinib/ Mice Erlotinib/ Mice Erlotinib/ 4 patients Brain/ Plasma Ratio Reference 0.15 Agarwal et al Elmeliegy et al Togashi et al Hours Afatinib/ Rats NT-113/ Rats 0 Data on file NewGen > 4.0 Data on file NewGen

16 NT-113 potent activity in 6 xenograft models Cell Lines Molecular status Treatment initiation from implantation (days) Dose mg/kg Control/ Reference Results GBM39 intracranial EGFRvIII untreated P>.001 survival vs untreated GBM12 intracranial GBM12 intracranial U87 (EGFRvIII) intracranial H1975 NSCLC (T790M) flank N87 Gastric (HER2+) flank EGFR amplified EGFR amplified EGFR transfected EGFR (T790M) 7 20 & 10 untreated erlotinib lapatinib untreated erlotinib untreated erlotinib 9 20 untreated erlotinib afatinib HER & 30 untreated lapatinib P>.0001 survival vs untreated Superior activity compared to lapatinib P>.0003 survival vs untreated Superior activity compared to erlotinib Superior activity compared erlotinib Activity equivalent to afatinib Superior activity vs lapatinib

17 Potent activity of NT-113 in glioblastoma GBM 39: A tumor driven by EGFRvIII Bioluminescence Images Control day 1 NT-113 day 1 Normalized Luminescense Control NT-113 (20mg/kg/po) Days from initiation of therapy NT day dosing Control day 14 Eight animals per group d14 = 13.9x d1 Relatively stable body weight, no GI or CNS side effects observed Data courtesy of Dr. David James, UCSF NT-113 day 14 d14 = 0.22x d1

18 Highly active against GBM12 (EGFR+)

19 NT113 preferentially accumulates in tumor Tumor / Contralateral Brain Contralateral Brain/ Plasma Tumor / Plasma Mice were treated with 10mg/kg NT113 for 3 days, and samples were collected 2 hours after completion of NT113 treatment. (n = 3)

20 NT-113 decreases proliferation and induces cell death Third Orthopic/Intracranial Xenograft Therapy Response Experiment: GBM12, Amplified wt EGFR Comparison of NT113 vs. Other EGFR Inhibitors Control Lapatinib NT113 Ki-67 T Activated Caspase 3 NT-113 both decreases cell proliferation and induces apoptosis (cell death)

21 Potent activity in HER2+ N87 Gastric Cancer Vehicle Tumor volume(mm3) Mean±SEM NT-113, 15mg/kg,po,qd NT-113, 30mg/kg,po,qd Lapatinib,129.9mg/kg, po,bid Days after beginning treatment NT-113 has superior activity at both doses compared to lapatinib

22 Resistant NSCLC (T790M) H1975 Vehicle Tumor volume(mm3) Mean±SEM 3000 Erlotinib,100mg/kg,po,qd KU113,10mg/kg,po,qd NT-113, 10mg/kg, po,qd KU113,20mg/kg,po,qd NT-113, po,qd KU041,20mg/kg,po,qd Afatinib, po,qd Days after beginning treatment

23 What differentiates NT-113? Highly potent irreversible inhibitor of EGFR, HER2, HER4, EGFR(L858R), EGFR(L858R/T790M) Excellent PK with > 10X superior brain penetration compared to erlotinib, gefitinib or afatinib High brain penetration needed to inhibit p-egfr High unmet need for ErbB+ solid tumors that metastasize to the brain High activity in vivo (intracranial) against three human GBM cell lines including EGFRvIII+ and EGFR amplified High activity in vivo against T790M mutant NSCLC and HER+ human cell lines Profile suggests a development pathway in (at least) NSCLC patients with brain mets and glioma

24 NT-113 options for clinical development Tumor Setting Activity of TKIs NSCLC Glioma Breast Selected pts. with brain mets 1 st or 2 nd line Selected pts. with recurrent disease Pts with brain mets. Prior lapatanib (L)/ trastuzumab (T) or in combination with L or T EGFR inhibitors: 10% in unselected pts. [n = 41 (Ceresoli, 2010)] 70% in pts. with activating mutations [n = 23 (Kim 2009)]. Afatinib superior to chemotherapy in 1 st line in selected patients ( LUX-LUNG3) Low. Three 100 pt. phase II studies of erlotinib have failed to establish benefit HER2 directed agents active. Complete HER2 blockade not established by trastuzumab + lapatinib. EGFR inhibitors have poor activity Medulloblastoma Selected pts. with recurrent disease Phase II study of lapatinib is reported as completed, but data not in public domain Gastric Selected pts. 2 nd line Trastuzumab licensed (OS benefit). Erlotinib 1 st line: 4 responses in 70pts Endometrial Nonendometriod 1 st line Erlotinib: Ph. II: 4PRs / 32. 3/19 in EGFR M Prostate Castrate resistant Prior chemo Gefitinib: Randomized ph II failed to establish benefit. Erlotinib Ph. II: 2PRs in 29 pts.

25 Clinical relevance of inhibiting EGFR in GBM 40% of GBM s harbor mutations EGFR mutant GBM cells are addicted to EGFR Complete suppression of EGFR is required to induce cell death in EGFR mutant GBM cells Lapatinib and CI 1033 are active against glioma cell lines but fail to achieve sufficient intratumoral concentrations in patients with GBM to reach IC50 Potent EGFR inhibitors with better brain penetration should be explored in the clinic Cancer Discovery, May 2012, Viivanco, et al

26 Clinical plans IND-Q Phase 1b proof of concept data in GBM by 2016 Accelerated approval possible

27 NT-113 development pathway Phase 1a dose escalation Unselected patients with known EGFR mutations preferred Goal to determine BED Expansion cohort A Solid tumors with at least one ErbB mutation or amplification NSCLC with or without brain mets 12 patients Expansion cohort B High grade glioma 12 patients At least 6 will have second look surgery Phase 2 NSCLC with brain metastases or Breast cancer with brain metastases Phase 2 High grade glioma Accelerated approval possible

28 Why NT-113? 3rd generation irreversible vs. 1 st generation reversible inhibitors pan-erbb vs. mono-erbb inhibitors Inhibiting the whole family: EGFR, HER2 & HER4 Very high brain penetration and preferential uptake in tumor Erlotinib, gefitinib, lapatinib and afatinib do not Most potent with best spectrum of irreversible pan-erbb inhibition Preclinical anti-tumor activity in EGFRvIII and EGFR amplified intracranial human GBM, resistant NSCLC and HER2+ gastric xenograft mouse models Phase 1 will be enriched with variety of erbb+ solid patients for early evidence of clinical activity across tumor types (eg:bmn-673) Potential for accelerated approval in GBM by 2017 EGFRvIII and high over-expression of EGFRwt

29 NT-004 Reversible EGFR, HER2 and HER4 tyrosine kinase inhibitor

30 NT-004 kinase activity profiling NT004 TK panel profiling NT004 only hits 3 kinases with >65% 1 um: EGFR, HER2, HER4 in the TK panel ( EGFR IC 50 = 14.7 nm HER2 IC 50 = 18.2 nm ~1 x HER4 IC 50 = 17.6 nm NT004 is a reversible, pan-erbb kinase inhibitor Lapatinib reported IC 50 s EGFR IC 50 = 10.8 nm HER2 IC 50 = 9.2 nm HER4 IC 50 = 367 nm ~30 x Rusnak DW, et al. Mol Cancer Ther 2001;1:85-94 HER4 in cancer Up regulated in response to treatment with EGFR or HER2 inhibitors Highly over-expressed in certain types of lymphoma, neuroblastic tumors Ambiguity about HER4 s role in breast cancer

31 NT-004 activity in Her2+ gastric cancer Tumor volume(mm3) Mean±SEM Vehicle NT-004, 40mg/kg, po,bid NT-004, 80mg/kg, po,bid Lapatinib,129.9mg/kg, po,bid Days after beginning treatment NT004 has equivalent activity compared to lapatinib

32 NT-004 activity in Her2+ breast cancer Tumor Volume (mm 3 ) 对 Vehicle 组 KU004 NT-004, 40mg/kg KU004 NT-004, 80mg/kg KU004 NT-004, 120mg/kg lapatinib, 80mg/kg Days after implantation

33 NT-004 summary A potent proprietary EGFR, HER2 and HER4 inhibitor In vitro potency, equal to or superior to lapatinib PK profile, superior to lapatinib Potential once daily dosing in humans In vivo activity: equal to or superior to lapatinib in multiple xenograft models Ready for GLP studies Pilots batches of GMP-like material >99.7%

34 NT-125 PARP inhibitor

35 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

36 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 Days after beginning treatment

37 NT-125 summary Series of potent PARP inhibitors Third generation PARP inhibitor Oral dosing NT-125 shows promising PK Active in xenograft models Provisional patent filed

38 Management Name/Title Harry Pedersen President & CEO Dennis Brown, Ph.D. Chairman Wang Shen, Ph.D. Vice President, R&D Jackie Walling, M.D., Ph.D. CMO Background ChemGenex Matrix Sanofi Aventis ChemGenex Matrix Stanford Kanion/USA Sunesis, Amgen Abbott BioMarin Tularik Eli Lilly

39 Board of directors and SAB Board of Directors Name/Title Harry Pedersen President & CEO Dennis Brown, Ph.D. Chairman Alan Mendelson Secretary Name Background ChemGenex Matrix Sanofi Aventis Marion ChemGenex Matrix Stanford Latham Watkins Scientific Advisory Board Institution Victor Levin, M.D. Howard (Skip) Burris, M..D Timothy Cloughesy, M.D. C. David James, Ph.D. UCSF UCSF M.D. Anderson Centennial Medical Center Sarah Cannon Research Institute UCLA Ronald Reagan UCLA Medical Center Professor Johann de Bono, M.D. Institute for Cancer Research, Royal Marsden Hospital, UK

40 Contact NewGen Therapeutics, Inc. Harry D. Pedersen President & CEO Phone: ext. 101 Corporate Headquarters 3475 Edison Way, Suite R Menlo Park, CA 94025