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 final prospectus filed with the Securities and Exchange Commission, or SEC, on May 20, 2016 relating to our Registration Statement on Form F-1, 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

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 initiating Phase 1 clinical development (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 202.4m cash and equivalents (as of Q3 2017) Cash runway into Q1 2020* *Extension attributable to a revised financial forecast, including expected savings in CMC spend

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

5 Robust Pipeline Targeting Solid and Hematological Tumors Program Targets Indication/drug combination Pre- IND/CTA Phase 1 Phase 2 Partner Merus rights MCLA-128 HER2, HER3 Breast (HER2) Herceptin worldwide 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 US Undisclosed Autoimmune disease No product rights *Phase 1/2

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 Unique Biclonics Technology Platform A unique combination 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: 4.a5 g/l achieved- 2000L Standard IgG formulation

8 % normalized cell growth Functional screening for differentiated product leads Cell-based functional screening of large diverse and Biclonics collections supports the discovery of product leads with novel modes of action Functional Screening of 750 different EGFRxHER3 Biclonics Growth of a tumor cell line _ 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).

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

10 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

11 Percent survival MCLA-128 unique mechanism of action Dock on HER2, abundantly expressed on tumor cells Block HER3 signaling, even under high heregulin stress NK Cell Macrophage Enhanced ADCC - efficient recruitment of immune killer cells In preclinical studies, more effective than Herceptin (H) Perjeta (P) in inhibiting the growth of cell lines resistant to HER2-targeted therapies MCLA-128 heregulin vehicle H P HER2 HER3 Days

12 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

13 Fluorescence intensity MCLA-128 phase 2 combination trial in HER2 mbc Target population HER2 (2 3 IHC/FISH) metastatic breast cancer Rationale Preclinical studies have shown synergistic activity of MCLA-128 and Herceptin in inhibiting heregulin-driven tumor cell growth HER2 mbc failing 2-4 prior HER2 therapies (including T-DM1) N = ~ Herceptin Ctrl IgG - Doublet MCLA-128 Herceptin Triplet MCLA-128 Herceptin chemo MCLA-128 MCLA-128 Herceptin Concentration (nm)

14 Positioning MCLA-128 in the HER2 mbc treatment landscape Positioning of MCLA-128 in HER2 mbc patients, exposed and progressed to Herceptin/ Perjeta / T-DM1/ chemo Standard of care MCLA-128 positioning - Adjuvant Therapy (& Neo-adjuvant) 1 st Line Therapy Herceptin Perjeta chemo POC 2 nd Line Therapy 3 rd -5 th Line Therapy T-DM1 Herceptin chemo Lapatinib Capecitabine Herceptin MCLA-128 /- chemo

15 Tumor volume (mm 3 ) MCLA-128 phase II combination trial in ER/HER2 low mbc Rationale In preclinical models, blocking HER3 signaling has been shown to synergize with endocrine therapy ER/HER2-low mbc failing 1 prior endocrine therapy / CDK4-6 inhibitor (N = ~60) MCLA-128 Ctrl IgG - MCLA-128 Endocrine therapy fulvestrant MCLA-128 fulvestrant Days post treatment

16 Positioning MCLA-128 in the ER mbc treatment landscape Positioning of MCLA-128 in ER/HER-2 low mbc patients, post endocrine therapy (refractory), post palbociclib Adjuvant Therapy (& Neo-adjuvant) 1 st Line Therapy AI Tamoxifen AI Tamoxifen Fulvestrant Letrazole palbociclib - 2 nd Line Therapy 3 rd Line Therapy and beyond MCLA-128 Endocrine therapy AI Tamoxifen Defined according to previous 2 lines Fulvestrant Letrozole palbociclib Exemestane everolimus

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 2 expansion continues in gastric, ovarian, endometrial and lung cancer

18 MCLA-128 near term milestones Near term clinical milestones 2018 Breast cancer: initiation of MCLA-128 phase 2 combination trial (EU/US): 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 Q1 - Gastric, Ovarian/Endometrium, NSCLC cohorts Formulation of clinical development plans based on data readout from the ongoing Phase 1/2 monotherapy clinical trial Q2

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.

21 MCLA restricted tissue expression CLEC12A CD33/ CD123 Hematopoietic Stem Cell Myeloid Stem Cell CD123 CD33 Granulocyte- Macrophage Stem Cell CD123 CD33 CLEC12A Megakaryocyte- Erythroid Stem Cell Megakaryocytes Lymphoid Stem Cell Monocytes Erythrocytes Platelets T Cells B Cells Natural Killer Cells Neutrophils Eosinophils Basophils Macrophages CLEC12A 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 CLEC12A - tumor tissues Expressed by tumor cells of ~90-95% of patients with AML (> 85% of patients with MDS) Expressed by AML tumor stem cells Bone Marrow Blood Blood and tissues Expression

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

23 CD34: AML Tumor Cells CD34: AML Tumor Cells 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 93% 5% 1% 96% Low level CLEC12A expression on the tumor cells in an AML patient MCLA-117 CD3: T Cells CD3: T Cells T Cell Activation/Expansion and AML Tumor Cell Killing

24 MCLA-117 phase 1 trial build up and near-term clinical milestones Patient population Cohort (# pts) Dose Date Near term clinical milestones AML all subtypes except M3 Treatment naïve >65 & Rel/Ref >18 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 Q H Dose escalation of the phase 1 clinical trial in AML continuing IND application to the U.S. Food and Drug Administration submitted Report on safety and potentially early activity during a major scientific/medical conference Safety, recommended dose

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 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

27 P e r c e n t s u r v i v a l N o r m a l i z e d T u m o r o i d s i z e 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 mabs (e.g. 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 Inhibition of organoid growth in vivo P= PBS Cetuximab MCLA-158 P = Selective killing of tumor vs normal cells 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 g / m l ) D a y s e l a p s e d

28 MCLA-158 milestones Near term milestones Filing of a CTA for a first in human phase1 clinical trial in solid tumors 1Q 2018 Submission of an IND to the FDA Start of a phase 1 clinical trial with MCLA- 158 in Europe

29 Merus Closing in on Cancer with Bispecific Antibodies