Merus. Closing in on Cancer with Bispecific Antibodies

Transcription

1 Merus Closing in on Cancer with Bispecific Antibodies

2 Disclaimer This presentation (including any oral commentary that accompanies this presentation) contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of All statements contained in this presentation that do not relate to matters of historical fact should be considered forward-looking statements, including without limitation statements regarding the impact our Biclonics platform can have on cancer, our product candidates' potential to treat certain types of tumors, the timing of regulatory filings and the timing and anticipated results from our clinical trials. These forward-looking statements are based on management's current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: we have incurred significant losses, are not currently profitable and may never become profitable; our need for additional funding, which may not be available and which may require us to restrict out operations or require us to relinquish rights to our technologies or bispecific antibody candidates; potential delays in regulatory approval, which would impact our ability to commercialize our product candidates and affect our ability to generate revenue; the unproven approach to therapeutic intervention of our Biclonics technology; our limited operating history; economic, political, regulatory and other risks involved with international operations; the lengthy and expensive process of clinical drug development, which has an uncertain outcome; the unpredictable nature of our early stage development efforts for marketable drugs; potential adverse public reaction to the use of cancer immunotherapies; potential delays in enrollment of patients, which could affect the receipt of necessary regulatory approvals; failure to obtain marketing approval internationally; failure to compete successfully against other drug companies; potential competition from other drug companies if we fail to obtain orphan drug designation or maintain orphan drug exclusivity for our products; our reliance on third parties to conduct our clinical trials and the potential for those third parties to not perform satisfactorily; our reliance on third parties to manufacture our product candidates, which may delay, prevent or impair our development and commercialization efforts; protection of our proprietary technology; our patents being found invalid or unenforceable; potential lawsuits for infringement of third-party intellectual property; our ability to attract and retain key personnel; managing our growth could result in difficulties; and we may lose our foreign private issuer status and incur significant expenses as a result. These and other important factors discussed under the caption Risk Factors in our Annual Report on Form 20-F filed with the Securities and Exchange Commission, or SEC, on April 30, 2018, and our other reports filed with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this presentation. Any such forward-looking statements represent management's estimates as of the date of this presentation. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change 2

3 Company highlights Oncology focus Proprietary pipeline Unique technology platform Productive discovery engine Strong financials Differentiated pipeline of bispecific antibodies that target cancer (stem) cells, enhance tumor immunity or modulate the tumor micro-environment MCLA in Phase 2 (mbc), Phase 1 (other solid tumors) MCLA in Phase 1 clinical development (AML) MCLA-158 in Phase 1 clinical development (solid tumors with an initial focus on mcrc) MCLA-145 IND enabling studies (multiple solid tumors) Biclonics Platform - full length IgG human bispecific antibodies for functional screening, reliable manufacturing and predictable behavior in patients In-format functional screening interrogating target combinations for novel biology and modes of action fuels a rich pipeline of differentiated Biclonics 224.1m cash, cash equivalents and investments as of June 30, 2018 Gross proceeds from private placement of $55.8 million for 3.1 million shares completed in in February 2018 Expected cash runway based on current operating plan: end of

4 Closing in on Cancer Develop differentiated cancer therapeutics based on the unique properties of bispecific antibodies Engage T lymphocytes to kill tumor cells Biclonics - a full length IgG format... Activate/Revive Exhausted Tumor Killer Cells T Cell Tumor Cell CD-137 OX-40 PD-L1 PD-1 TIM-3 T cell LAG-3 Unlock novel biology based on target combinations Tumor (stem) Cell NK Cell Macrophage...for target combinations with differentiated modes of action Target combinations Cancer (stem) cells Immune cells Tumor stromal cells 4

5 Robust Pipeline Targeting Solid and Hematological Tumors Program Targets Indication/drug combination Pre- IND/CTA Phase 1 Phase 2 Collaborator Merus rights MCLA-128 HER2, HER3 Breast (HER2+) + Herceptin + chemo worldwide Breast (ER+) + hormone therapy worldwide Solid tumors (monotherapy)* worldwide MCLA-117 CD3, CLEC12A AML worldwide MCLA-158 EGFR, Lgr5 Solid tumors worldwide MCLA-145 PD-L1, undiscl. Solid tumors Incyte US Undisclosed Autoimmune disease ONO Pharmaceutical No product rights *Phase 1/2 5

6 Biclonics Technology Platform The full-length IgG format Functional screening bispecific antibodies that kill tumor cells with novel and differentiated modes of action

7 Biclonics Technology Platform the full length IgG format A distinctive suite of proprietary technologies supports the discovery and development of bispecific antibodies with differentiated modes of action Human antibodies MeMo transgenic mouse for large panels of diverse and high quality common light chain antibodies Predictable in vivo behavior IgG-like half life Low immunogenicity In patients Biclonics Full length IgG human bispecific antibodies common light chain Dependable IgG format with true platform characteristics Functional flexibility CH3 engineered for essentially pure Biclonics from single cells Fc silencing for added safety Enhanced ADCC for higher potency Manufacturability 80-99% Biclonics in crude cell harvest Stability: > 60 passages Yield: Up to 4.5 g/l achieved L Standard IgG formulation 7

8 Functional screening for differentiated product leads Cell-based functional screening of large diverse and Biclonics collections yields product leads with novel modes of action Functional Screening of 750 different EGFRxHER3 Biclonics Growth of a tumor cell line + _ % normalized cell growth Assay in the absence ( ) and presence ( ) of heregulin superior growth inhibition + and - heregulin. Control antibodies BxPC3 ligand independent assay BxPC3 EGF + HRG dependent assay Functional screening of WNT x HER Biclonics % apoptotic nuclei Organoids: ex vivo patientderived tissue (tumor). 8

9 Platform deals 2017/18 - highlights Incyte (2017) Total $200m up-front Platform license: $120m Equity investment at premium: $80m Up to 11 bispecific antibody programs in oncology Merus retains US rights on 1 program and opt-in rights on 2 programs For programs without retained product rights, Incyte pays R&D costs, up to $350m in milestones per program, and royalties Simcere (2018) An exclusive license to develop and commercialize in China, 3 bispecific antibodies in immuno-oncology Merus retains all rights outside of China Upfront payment, potential development / commercial milestones and tiered royalty payments on sales in China from Simcere Platform validation Substantial cash component Product rights and opt ins for more value creation Platform validation Substantial product rights Access to China CMC and data Access to treatment naïve patients 9

10 Partnerships highlights Ono (2014/2018) Exercised option under 2014 agreement Developing bispecific derived from Biclonics platform for the treatment of autoimmune diseases Built on success of existing collaboration Unmet medical need VHIO (2018) Builds upon existing relationship with MRUS Trial site for MCLA-128 MBC study; MCLA-158 preclinical development VHIO s strong preclinical and clinical research capabilities to help accelerate pipeline developments Translational and biological insights Support development of existing and future pipeline 10

11 MCLA-128 Biclonics that potently inhibits the HER3 pathway - a driver of tumor growth and survival

12 MCLA-128 targeting the HER3 pathway Heregulin-driven signalling via the HER2:HER3 heterodimer promotes: primary tumor cell proliferation treatment escape/relapse (HER2 and EGFR blockade, hormone therapy, chemotherapy) HER2:HER3 heterodimer heregulin heregulin paracrine autocrine 12

13 MCLA-128 unique mechanism of action Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade Cecile A.W. Geuijen, Camilla De Nardis, David Maussang, Eric Rovers, Tristan Gallenne, Linda J.A. Hendriks, Therese Visser, Roy Nijhuis, Ton Logtenberg, John de Kruif, Piet Gros, Mark Throsby Dock on HER2, abundantly expressed on tumor cells Block HER3 signaling, even under high heregulin stress Enhanced ADCC - efficient recruitment of immune killer cells NK Cell Macrophage 100 In preclinical studies, more effective than Herceptin (H) + Perjeta (P) in inhibiting the growth of cell lines resistant to HER2-targeted therapies Percent survival 50 MCLA-128 heregulin vehicle H + P HER2 HER3 Days 13

14 MCLA-128 phase 1/2 trial - monotherapy Part 1 dose escalation Part 2 expansion cohorts Attractive safety profile Mild to moderate AEs (G1-2); no DLTs HER2+/amplified HER2 non-amplified Recommended dose 750 mg flat; IV infusion over 2 hour period; q3ws Early signs of activity Breast (n=11) Gastric POC achieved heavily pretreated; 2-5 anti-her therapies visceral involvement: lung, liver, brain 1 PR and 7 SD (4 lasting 5 months) clinical benefit rate 64% Endometrial Ovarian NSCLC Phase 2 combination trial in mbc HER2+ ER+/ HER2 low 14

15 MCLA-128 phase 2 combination trial in HER2+ mbc Target population HER2+ (2+ 3+ IHC/FISH+) metastatic breast cancer Failing 2-4 prior HER2 therapies (including T-DM1) N = ~60 Triplet MCLA Herceptin +/- chemo Fluorescence intensity Rationale Preclinical studies: MCLA-128 and Herceptin synergize in inhibiting heregulin-driven tumor cell growth Herceptin Ctrl IgG MCLA-128 MCLA Herceptin Concentration (nm) 1 st line 2 nd line 3 nd -5 th line Positioning HER2+ mbc patients, progressed to Herceptin/ Perjeta / chemo/ T-DM1 Herceptin + Perjeta + chemo T-DM1 Herceptin + chemo Lapatinib + Capecitabine POC Herceptin + MCLA-128 +/- chemo 15

16 MCLA-128 phase 2 combination trial in ER+/HER2 low mbc Target population ER+/HER2-low metastatic breast cancer (N = ~60) Rationale In preclinical models, blocking HER3 signaling has been shown to synergize with endocrine therapy Positioning ER+/HER-2low mbc patients, post endocrine therapy (refractory), post palbociclib Failing 1 prior endocrine therapy / CDK4-6 inhibitor (N = ~60) MCLA Endocrine therapy Tumor volume (mm 3 ) Days post treatment MCLA-128 Ctrl IgG fulvestrant MCLA fulvestrant 1 st line 2 nd line 3 nd - 5 th line MCLA Endocrine therapy AI Tamoxifen AI Tamoxifen Fulvestrant Letrazole + palbociclib Fulvestrant Letrozole + palbociclib Exemestane + everolimus Defined according to previous 2 lines 16

17 MCLA-128 summary and conclusions NK Cell Macrophage Single agent activity established in mbc synergistic activity with trastuzumab supports phase 2 clinical trial design in HER2+ mbc pts preclinical data showing restoration of sensitivity to hormone therapy after blocking HER3 signaling supports combination trial in ER+ mbc patients heregulin Safe and very well-tolerated most drug-related AEs are mild to moderate (G1/G2) no grade 3-4 related GI AEs no clinically relevant decrease on LVEF low incidence of in fusion-related reactions to date, no relevant anti-drug antibodies observed HER2 HER3 Single agent activity in other solid tumors: in progress phase 1/2 expansion continues in gastric, ovarian, endometrial and lung cancer 17

18 MCLA-128 near term milestones Near term clinical milestones Breast cancer: MCLA-128 phase 2 combination trial (EU/US) initiated MCLA-128 with Herceptin +/- chemotherapy in HER2+ mbc failing 2-4 prior HER2 therapies (including T-DM1) MCLA-128 with endocrine therapy in ER+/HER2 low mbc failing 1 prior endocrine therapies / CDK4-6 inhibitor MCLA-128: Phase 1/2 data from gastric cohort will be presented at ESMO in October 2018 MCLA 128: Update planned for ovarian/endometrium and NSCLC cohorts of single-agent activity Q4 18

19 MCLA-117 CD3 x CLEC12A T cell engager Biclonics binding a first-in-class target expressed on acute myeloid leukemia (stem) cells

20 MCLA-117 a unique T cell engager for AML Efficacy and Safety Low affinity anti-cd3 Fab arm for controlled T cell activation in the presence of tumor cells Safety Silenced Fc region to prevent binding to FcγR+ cells while retaining long half life by binding to FcRn Specificity High affinity anti-clec12a arm for efficient tumor targeting and subsequent T cell-mediated killing Developability Efficient Fc hetero-dimerization in CHO cells maintaining stability and high yield through patented CH3 engineering. 20

21 MCLA restricted tissue expression of CLEC12A CLEC 12A expression CD123/CD33 Common myeloid progenitor Hematopoietic stem cell CLEC12A Common lymphoid progenitor Normal tissues Not expressed on normal tissues outside of the hematopoietic system Only on certain myeloid cells of the hematopoietic system More restricted expression than CD33 and CD123 Megakaryocyte/erythroid stem cell Erythrocyte Platelet Basophil Granulocye/macrophage stem cell Neutrophil Eosinophil Monocyte Tumor tissues Expressed by tumor cells of ~90-95% of patients with AML (> 85% of patients with MDS) Expressed by AML tumor stem cells 21

22 MCLA a first in class target for AML tumor (stem) cells % CLEC12A Stem cells CLEC12A expression on AML but not normal hematopoietic stem cells % Specific lysis (%) MCLA-117 specifically kills CLEC12A+ blood mononuclear cells NK cells - CLEC12A- B cells Monocytes - CLEC12A+ 0 AML BM Normal BM Van Rhenen et al., Blood 110, 2659 (2007) [ng/ml] 22

23 MCLA-117 ex vivo killing of tumor cells in primary AML samples Efficient lysis of large numbers of tumor cells by low numbers of T cells in primary samples from AML patients MCLA-117 Mediated Activation of T Cells and Killing of Tumor Cells Day 0 Day 10 MCLA-117 T cell-mediated killing is independent of the level of CLEC12A expression CLEC12A Control CD34: AML Tumor Cells CD3: T Cells 93% 5% + MCLA-117 CD34: AML Tumor Cells CD3: T Cells 1% 96% Low level CLEC12A expression on the tumor cells in an AML patient T Cell Activation/Expansion and AML Tumor Cell Killing 23

24 MCLA-117 phase 1 trial build up and near-term clinical milestones Patient population AML all subtypes except M3 Treatment naïve >65 & Rel/Ref >18 Cohort (# pts) Dose Date 1 (2) Q (2) 3 (3) 4 (3) 5 (3) 6 (3) 7 (3,6) 8 (3,6) 9 (3,6) Intercohort Intrapatient Dose escalation Q1 17 Near term clinical milestones Dose escalation of the phase 1 clinical trial in AML continuing IND application to the U.S. Food and Drug Administration approved 2018 An update is planned in Q Safety, recommended dose 24

25 MCLA-158 Biclonics that potently blocks EGFR signaling in Wnt-activated solid tumors

26 MCLA-158 unique mechanism of action Unmet Medical Need Differentiated Mode of Action Designed to eliminate cancer stem cells that persist in various solid tumors and cause relapse and metastasis RAS-mutant colorectal cancer represents approximately 50% of disease Potently blocks EGFR signaling in Wnt activated tumors Induces apoptosis in cancer (stem) cells Enhanced ADCC for immune effector cell recruitment EGFR Lgr5 NK cell Macrophages Enhanced ADCC Cancer Stem Cell Cancer Stem Cell Apoptosis Cancer Stem Cell 26

27 MCLA-158 differentiated mode of action MCLA-158 is a cancer stem cell targeting Biclonics that, in preclinical studies, has shown: higher potency than EGFR targeting mab, Cetuximab to effectively eliminate tumor stem cells in vitro and in vivo (KRAS WT and KRAS Mut ) lack of skin toxicity (rash) in cynomolgous monkey studies P e r c e n t s u r v i v a l Inhibition of organoid growth in vivo P= PBS Cetuximab MCLA-158 P = Selective killing of tumor vs normal cells N o r m a l i z e d T u m o r o i d s i z e T u m o r C o l o n p t C 5 5 N o r m a l C o l o n p t C 5 5 M C L A C 5 5 T C e t u x i m a b C 5 5 T > 100-fold M C L A C 5 5 N Tumor colon C e t u x i m a b C 5 5 N MCLA-158 Cetuximab Normal colon MCLA-158 Cetuximab D o s e ( l o g µ g /m l) D a y s e l a p s e d 27

28 MCLA-158 milestones Near term milestones CTA for a first in human phase 1 clinical trial in solid tumors in the EU approved IND submitted to and accepted by the FDA First patient dosed (May 2018) 28

29 Financial Overview million Cash, cash equivalents and investments as of June 30, 2018 $55.8 million Gross proceeds from private placement completed in February 2017 for 3.1 million shares End of 2020 Expected cash runway based on current operating plan 29

30 Merus Closing in on Cancer with Bispecific Antibodies