Targeting Cancer. June 5, 2014

Transcription

1 Targeting Cancer June 5, 2014

2 Forward-Looking Statements 2 These slides and the accompanying oral presentation contain "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of These statements may be identified by the use of forward looking terminology such as "anticipate", "believe", "continue", "could", "estimate", "expect", "intend", "may", "might", "plan", "potential", "predict", "should" or "will" and include statements regarding Threshold's product candidates and clinical trial progress and results. These forward-looking statements are based on our current expectations, speak only of the date of this presentation and involve risks and uncertainties, many of which are outside of our control, that can cause actual results to differ materially from those in the forward-looking statements. Potential risks and uncertainties include, but are not limited to, our ability to complete our anticipated clinical trials, the time and expense required to conduct such clinical trials, the ability to manufacture clinical or commercial product, issues arising in the regulatory process and the results of such clinical trials (including product safety issues and efficacy results). Further information is included in Threshold s periodic reports filed with the SEC at We disclaim any duty to update any forward-looking statements.

3 The Threshold Opportunity (Nasdaq: THLD) 3 Building a broad therapeutic platform in cancer Based upon selectively targeting tumor hypoxia A fundamental property of solid tumors as well as some hematologic cancers A significant unmet medical need And including the HX4 hypoxia PET imaging platform acquired from Siemens Discovered and developing TH-302 Industry s most advanced hypoxia targeted anti-cancer compound in active development Partnered with Merck KGaA Pivotal studies underway in 2 indications Phase 3 in soft tissue sarcoma Phase 3 in pancreatic cancer Earlier stage studies underway in a variety of indications

4 IFOS TH-302 Overview deactivating cyp oxidation 4 ng dation O O Cl P TH-302 is Na small molecule prodrug that releases the potent DNAalkylating agent, Br-IPM, via reductases under hypoxic H N conditions. poor substrate for cyp oxidation, primary metabolism is reductive activation O 2 N TH-302 N H C N Hypoxia Trigger O P HN Cl TH-302 (inert prodrug) O N H Br Br Normoxia Oxygen Gradient activating cyp oxidation 5% O 2 0.5% O 2 >1000 patients have been treated with TH-302 in clinical H trials to date C O demonstrating antitumor activity: N P across multiple tumor types (solid tumors and hematological malignancies) N as a single agent and in combination with chemotherapy/antiangiogenics HN with a consistent safety profile and manageable toxicity O 2 N IFOS H TH O N P N H O N H deactivating cyp oxidatio Br-IPM (active cytotoxin) Br Cl Br Cl Hypoxia poor substrate for cyp oxidation, primary metabolism is reductive activation O H Br

5 TH-302 Clinical Development 5 Trial TH-CR- _ Phase 1 Phase 1/2 Phase 2b Phase / 402 / 403 Initial clinical studies (mono / combo) 404 Pancreatic Cancer (+ gemcitabine) 406 Soft Tissue Sarcoma (+ doxorubicin) MAESTRO Pancreatic Cancer (+ gemcitabine) 415 ns-non-small Cell Lung Cancer 413 Melanoma: monotherapy (PETimaging) 414 QT Study: monotherapy EMR-002 Japanese Phase 1 (mono + gem 407 Advanced leukemias: monotherapy 408 Multiple Myeloma (+/- bortezomib) EMR-006 Pancreatic Cancer (+ Gem / Abraxane) 410 RCC & GIST (+ sunitinib) IST IST IST Glioblastoma (+ bevacizumab) Various solid tumors (+ pazopanib) HCC (+ sorafenib) sponsored sponsored Investigator sponsored = ongoing = enrollment completed

6 TH-302 Clinical Development 6 Trial TH-CR- _ Phase 1 Phase 1/2 Phase 2b Phase / 402 / 403 Initial clinical studies (mono / combo) 404 Pancreatic Cancer (+ gemcitabine) 406 Soft Tissue Sarcoma (+ doxorubicin) MAESTRO Pancreatic Cancer (+ gemcitabine) 415 ns-non-small Cell Lung Cancer P 413 Melanoma: monotherapy (PETimaging) 414 QT Study: monotherapy EMR-002 Japanese Phase 1 (mono + gem 407 Advanced leukemias: monotherapy 408 Multiple Myeloma (+/- bortezomib) EMR-006 Pancreatic Cancer (+ Gem / Abraxane) 410 RCC & GIST (+ sunitinib) IST IST IST Glioblastoma (+ bevacizumab) Various solid tumors (+ pazopanib) HCC (+ sorafenib) sponsored sponsored Investigator sponsored = ongoing = enrollment completed

7 TH-302 Clinical Development 7 Trial TH-CR- _ Phase 1 Phase 1/2 Phase 2b Phase / 402 / 403 Initial clinical studies (mono / combo) 404 Pancreatic Cancer (+ gemcitabine) 406 Soft Tissue Sarcoma (+ doxorubicin) MAESTRO Pancreatic Cancer (+ gemcitabine) 415 ns-non-small Cell Lung Cancer 413 Melanoma: monotherapy (PETimaging) P P 414 QT Study: monotherapy EMR-002 Japanese Phase 1 (mono + gem 407 Advanced leukemias: monotherapy 408 Multiple Myeloma (+/- bortezomib) EMR-006 Pancreatic Cancer (+ Gem / Abraxane) 410 RCC & GIST (+ sunitinib) IST IST IST Glioblastoma (+ bevacizumab) Various solid tumors (+ pazopanib) HCC (+ sorafenib) sponsored sponsored Investigator sponsored = ongoing = enrollment completed

8 TH-302 Clinical Development 8 Trial TH-CR- _ Phase 1 Phase 1/2 Phase 2b Phase / 402 / 403 Initial clinical studies (mono / combo) 404 Pancreatic Cancer (+ gemcitabine) 406 Soft Tissue Sarcoma (+ doxorubicin) MAESTRO Pancreatic Cancer (+ gemcitabine) 415 ns-non-small Cell Lung Cancer 413 Melanoma: monotherapy (PETimaging) P P 414 QT Study: monotherapy EMR-002 Japanese Phase 1 (mono + gem 407 Advanced leukemias: monotherapy 408 Multiple Myeloma (+/- bortezomib) EMR-006 Pancreatic Cancer (+ Gem / Abraxane) 410 RCC & GIST (+ sunitinib) IST Glioblastoma (+ bevacizumab) IST Various solid tumors (+ pazopanib) P P IST HCC (+ sorafenib) sponsored sponsored Investigator sponsored = ongoing = enrollment completed

9 Soft Tissue Sarcoma (STS) 9 Group of aggressive cancers originating in supporting tissues e.g. muscle, fat, blood vessels or in any other tissue that surrounds and protects the organs of the body Doxorubicin is the only approved front-line therapy Median overall survival rate of ~ 8 to 12 months Overall response rate of ~15% Use limited due to cumulative cardiotoxicity ~ 36,000 new cases of STS in the U.S. and EU in 2013

10 Hypoxia is Associated with a Worse Prognosis in Patients with Soft Tissue Sarcoma Survival (%) 10 STS patients with less hypoxic tumors have better outcomes po 2? 19 mmhg 2 (n = 14) po > 19 mmhg (n = 14) Time (months) po po 2 < 2 19 < 19 mmhg (n = 14) (n = 14) Brizel DM, et al. Can Res 1996 Nordsmark M, et al. BJC 2001

11 Study TH-CR-403 Soft Tissue Sarcoma Open-Label Single-Arm Phase 2 Study 11 TH doxorubicin (N=89 evaluable) Median Progression-free Survival Median Overall Survival Survival at 1 year 6.7 months (95% CI: 6.2 to 8.1 months) 21.5 months (95% CI: 16.0 to 27.6 months) 73% (95% CI: 63% to 82%) Survival at 2 years 44% Best Overall Response (Partial + 2 Complete Responses) 36% Treatment with TH doxorubicin is associated with longer time to progression or death, increased survival, and higher response rates versus historical treatment with doxorubicin alone. Source: Ganjoo KN, et al. CTOS 2012

12 Phase 3 Pivotal Trial in Front-Line Soft Tissue Sarcoma TH-CR 406: commenced 9/11 12 Eligible (N~620) Randomize 1:1 Doxorubicin + TH-302 No Crossover Doxorubicin Patients Metastatic or locally advanced unresectable front-line soft tissue sarcoma Primary Endpoint Overall survival (OS); 85% power to detect 33% improvement (434 events) Secondary Endpoints Overall response rate, progression free survival, duration of response, EFS Under Special Protocol Assessment (SPA) & Partnership with SARC Enrollment of 620 patients completed December 2013 Interim efficacy data Sept. 2014, top-line data mid-2015

13 Phase 3 STS Trial Positive Endpoints OS Required for Statistical Significance Assuming Different Control OS s OS Treatment Arm (mos) HR= OS Control Arm (mos) OS (med) Dox Dox

14 Pancreatic Ductal Adenocarcinoma (PDAC) 14 Originates in cells lining the pancreatic duct; majority of pancreatic cancers >100,000 new cases in 2013 (U.S. & EU) Treatment of unresectable/metastatic disease with good performance status Gemcitabine-based combinations are mainstay of therapy FOLFIRINOX used in healthiest subset of patients Nab-paclitaxel approved by US FDA (Sept 6, 2013) as first line treatment for patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine Approval based on a 861-patient phase 3 trial in chemotherapy-naïve patients with metastatic pancreatic cancer 2.1 month median OS benefit

15 Phase 2b Study in Pancreatic Cancer (TH-CR-404) 15 Advanced Pancreatic Cancer (N=214) Randomize 1:1:1 Gemcitabine + TH-302 (240 mg/m 2 ) Gemcitabine + TH-302 (340 mg/m 2 ) Gemcitabine (1000 mg/m 2 ) Crossover (randomized to one of Gemcitabine plus TH-302 dose groups) Gemcitabine + TH-302 (240 or 340 mg/m 2 ) Stratification Stage: Unresectable locally advanced vs. distant metastases Primary Endpoint Progression free survival (PFS); 80% power to detect 50% improvement Secondary Endpoints Overall response rate (ORR), overall survival (OS), CA 19-9 response rate as well as various safety parameters

16 Study TH-CR-404 Pancreas Cancer (n=214) All Endpoints Trended Positive 16 TH-302 adds to the efficacy of gemcitabine alone with a clear dose response at 240 mg/m 2 and 340 mg/m 2 TH-302 PFS median (mos) 1 o Endpoint Gem Alone (N=69) Gem + TH mg/m 2 (N=71) D=2.0 (HR=0.65; p=0.060) ORR (%) Mean change in CA 19-9 nadir (U/L) ,669-5,385 # Cycles median Mos Survival (%) Mos Survival (%) Overall Survival, median (mos) D=1.8 (HR=0.96; p=0.827) Gem + TH mg/m 2 (N=74) 6.0 D=2.4 (HR=0.59; p=0.008) 9.2 D=2.3* (HR=0.955; p=0.800) *Crossover diminished the apparent survival benefit of TH-302

17 Phase 3 Pivotal Trial in Front-Line Pancreas Cancer MAESTRO: Commenced December Advanced Pancreatic Cancer (N~660) Randomize 1:1 Gemcitabine + TH-302 (340 mg/m 2 ) Gemcitabine (1000 mg/m 2 ) + placebo Patients Primary Endpoint Secondary Endpoints Metastatic or locally advanced unresectable pancreatic cancer Overall survival (OS) Overall response rate, progression free survival, CA19-9, QOL, pain, safety Under Special Protocol Assessment (SPA) Enrollment on track

18 Multiple Myeloma 18 Hematological cancer associated with malignant plasma cells which crowd the bone marrow, hindering normal blood cell production; attacks cortical bone, produces excess serum monoclonal antibody (M protein, paraprotein, observed in almost all cases) >65,000 new cases of multiple myeloma in the U.S. & EU in 2013 Currently approved treatments steroids Chemotherapy (alkylators) proteasome inhibitors immunomodulatory drugs (IMiDs) stem cell transplantation Opportunity for a novel approach to treat multiple myeloma via targeting tumor hypoxia

19 Hypoxia in Multiple Myeloma 5T33vt Syngeneic Mouse Model 19 Control bone marrow Myeloma bone marrow Pimonidazole HIF-1α Immunohistochemistry staining of exogenous hypoxia marker and endogenous hypoxia marker in BM sections of naive and 5T33vtMM mice. Hypoxia was determined by the accumulation of pimonidazole and HIF-1α. Hu et al. Blood, September 2010

20 TH-CR-408 Relapsed/Refractory Multiple Myeloma Dana Farber Cancer Institute Three-part study Part A: Dose escalation TH-302 plus low-dose dexamethasone: completed Part B: Dose expansion at the maximum tolerated dose: fully enrolled Part C: TH-302 plus low-dose dexamethasone with bortezomib: start in June TH dexamethasone schedule patients (23 evaluable) initiated therapy who had received a median of 6.5 prior therapies All were heavily pre-treated Laubach et al., 2014 ASCO 100% received bortezomib-containing regimen 100% received lenalidomide/thalidomide-containing regimen 92% received alkylator-containing regimen

21 Best Overall Response 21 Laubach et al., 2014 ASCO

22 Maximum Change in Paraprotein All Patients (n=24) at All Doses ( mg m 2 ) of TH Laubach et al., 2014 ASCO = ongoing PD SD MR PR NA

23 Phase 1/2 Multiple Myeloma Data TH-302 compares favorably to early POM and CFZ data 23 Stage TH dex Ph 1 dose esc. & exp Carfilzomib (single agent) Ph 1 dose esc. & exp. Pomalidomide + dex Ph 1 dose esc. N Dose & Schedule mg/m 2 Bi-weekly mg/m 2 Bi-weekly 2-5 mg/day Med Prior Lines 6.5 n/a 6 ORR ( PR) 17% 19% 21% CBR ( MR) 26% 27% 42% Subsequent Studies Based Upon Ph 1 Data TBD Registration Ph 2b & Ex-US Ph 3 Registration Ph 2b & Ex-US Ph 3 Current Status Ph 1 dose exp. complete US Approved US & EU Approved Sources: Alsina Clinical Cancer Research 2012, Richardson Blood 2012, Siegel Blood 2013, Siegel Blood 2012, Laubach ASCO 2014

24 Phase 1/2 Multiple Myeloma Data TH-302 compares favorably to early POM and CFZ data 24 Stage TH dex Ph 1 dose esc. & exp Carfilzomib (single agent) Ph 1 dose esc. & exp. Pomalidomide + dex Ph 1 dose esc. N Dose & Schedule mg/m 2 Bi-weekly mg/m 2 Bi-weekly 2-5 mg/day Med Prior Lines 6.5 n/a 6 ORR ( PR) 17% 19% 21% CBR ( MR) 26% 27% 42% Subsequent Studies Based Upon Ph 1 Data TBD Registration Ph 2b & Ex-US Ph 3 Registration Ph 2b & Ex-US Ph 3 Current Status Ph 1 dose exp. complete US Approved US & EU Approved Sources: Alsina Clinical Cancer Research 2012, Richardson Blood 2012, Siegel Blood 2013, Siegel Blood 2012, Laubach ASCO 2014

25 Phase 1/2 Multiple Myeloma Status and Next Steps 25 Enrollment completed at the previously established TH-302 maximumtolerated dose (340 mg/m 2 ) An additional 8 patients enrolled but not yet assessed (25 340) Combination regimen of TH-302 and proteasome inhibitor bortezomib (Velcade ) to be investigated in final stage of ongoing trial

26 Glioblastoma (GBM) 26 Most common and most aggressive of the primary malignant brain tumors in adults (Grade IV astrocytoma) Median survival is ~15 months Five-year survival rate is ~3% ~30,000 new cases per year in the U.S. & EU

27 GBM: Current Treatment and Outcomes 27 Treatment Setting Therapy Median PFS Median OS Newly Diagnosed First-line setting, after surgical resection temozolomide (TMZ) + radiation (RT) followed by maintenance TMZ a ~7 months ~15 months TMZ + RT provides D2.5 months benefit over RT alone First Recurrence Second-line setting bevacizumab ~4 months b ~9 months b Bevacizumabrefractory Salvage setting Another bevacizumabcontaining regimen ~38 days c 82 days c a) Stupp R. N Engl J Med. 2005;352(10): b) Friedman HS. J Clin Oncol. 2009;27: c) Quant EC. Neuro-Oncology 2009;11:

28 Hypoxia is a Hallmark of GBM Visualization with PET Imaging 28 Tumor tissue 55-y-old woman with a bifrontal GBM imaged after a biopsy: A) MRI T1Gd showing a large contrast-enhancing irregular ringshaped tumor with a necrotic center Hypoxic tissue B) FMISO PET image through the same plane Spence AM, Clin Cancer Res May 1;14(9): FMISO=[18F]fluoromisonidazole hypoxia tracer

29 Rationale for Combining Antiangiogenics + TH-302 Tumor Hypoxia is Increased by Antiangiogenics 29 Vehicle Vehicle Vehicle Vehicle Vehicle Bevacizumab (a-vegf-a) Sunitinib (VEGFR2/3, PDGFR) Sorafenib (VEGFR2/3, PDGFR)) Motesanib (VEGFR, PDGFR) DC101 (a-vegfr2) U251-HRE glioma model Rapisarda et al Rip-Tag PNET model Paes-Ribas et al O RCC model Chang et al UM-SCC1 (HN-SCC) model Kruser et al MDA-MB-231 (breast ca) model Francoet al Addition of TH-302 to antiangiogenic therapies may improve their efficacy

30 Ph1/2 Trial: TH BEV in BEV-Refractory Recurrent GBM Cancer Therapy Research Center, University of Texas, San Antonio 30 Primary Objectives To assess the safety of TH-302 in combination with BEV in patients with GBM To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TH-302 in combination with BEV in patients with GBM Secondary Objective To determine the progression-free survival (PFS) for patients with GBM treated with combination BEV and TH-302 following recurrence on single agent BEV

31 Best Objective Response According to Response Assessment Neuro-Oncology (RANO) Criteria 31 24% Overall Response Rate (1 CR + 3 PR) TH-302 Dose (mg/m 2 ) CR PR SD PD Total Total

32 Change in Tumor Volume (N=17) 32

33 Salvage Therapy Outcomes in Recurrent GBM Following Bevacizumab Failure 33 Treatment Regimen Number Patients ORR (%) Median PFS, months (95% CI) BEV + TH (2.1, 4.0) BEV + carboplatin + irinotecan (1.8, 3.6) Various chemo 3 19 NA 2.0 (1.2, 3.3) BEV + various chemo (NA) BEV + temsirolimus (NA) BEV + TMZ or (1.0, 2.1) BEV + etoposide BEV + chemo 7 54 (35 GBM) (1.2, 1.5) BEV + irinotecan (NA) BEV + dasatinib ( ) MPC Brenner 2014 ASCO 2. Reardon 2011 Cancer 3. Iwamoto 2009 Neurology 4. Norden 2008 Neurology 5. Lassen 2013 Anticancer Res 6. Reardon 2011 J. Neurooncol 7. Quant 2009 Neuro Oncol 8. Kreisl 2009 JCO 9. Lu-Emerson 2011 Neurooncol 10. Grimm 2010 SNO NA = not available

34 Progression-Free Survival on Prior Therapeutic Regimens and TH-302 Plus BEV 34

35 Progression-free Survival (PFS) (N=17) 35 BEV-refractory patients treated with TH BEV demonstrated longer than the historically reported median PFS of 1 to 2 months following administration of a second BEV regimen 1,2 PFS (N=17) PFS (historical) Median, Months 3.1 ( ) ~1.2 3-Month PFS(95% CI) 46% (95% CI: 18% to 74%) ~16% 1. Quant EC, et al. Neuro-Oncology 11: , Reardon DA, et al. Cancer 117(23): , 2011.

36 Summary In Patients with Bevacizumab-Refractory Recurrent Glioblastoma 36 TH-302 has a manageable safety profile when used in combination with BEV Early signals of activity were observed (N=17 evaluable patients) 24% objective response rate (1 CR, 3 PR) Median PFS 3.1 months in TH-302/BEV combination Longer than median PFS 2.4 mos on first BEV regimen in same patients Longer than the historically reported median PFS of ~1.2 months following administration of a second BEV regimen Next steps Expand enrollment at 670 mg/m 2 TH-302 dose in a multi-center study in this BEV-refractory patient population Work towards a front-line setting in temozolomide-resistant patients

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38 Selected Financial Data 38 As of March 31, 2014 Cash, cash equivalents, and marketable securities Shares outstanding Exercisable warrants $2.05; $2.46) $86.4 M 59.3 M 8.3 M Merck KGaA Contractual Milestones Received as of 3/31/2014 Additional development and regulatory milestones Commercial milestones TOTAL $110 M $170 M $245 M $525 M

39 Threshold Pharmaceuticals The Opportunity 39 TH-302, the most advanced drug candidate in development that targets tumor hypoxia, has demonstrated remarkable consistency of activity and safety across a variety of cancers and combinations Interim efficacy analysis of Ph 3 soft tissue sarcoma trial, designed for early stoppage, in mid-september, 2014 Data from 2 pivotal trials in 2015/2016 Multiple other indications in active clinical development Key partnership with a top-20 global pharmaceutical company Cash to last through 2015