Antibody Targeted Amanitin Conjugates (ATACs) Expanding the ADC Landscape With a New Payload Targeting RNA Polymerase II

Transcription

1 ntibody Targeted manitin Conjugates (TCs) Expanding the DC Landscape With a New Payload Targeting RN Polymerase II

2 Safe Harbor Forward looking statements This communication contains certain forward-looking statements, relating to the Company s business, which can be identified by the use of forward-looking terminology such as estimates, believes, expects, may, will should future, potential or similar expressions or by general discussion of strategy, plans or intentions of the Company. Such forward-looking statements involve known and unknown risks, uncertainties and other factors, which may cause our actual results of operations, financial condition, performance, or achievements, or industry results, to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Such factors include, among others, the following: uncertainties related to results of our clinical trials, the uncertainty of regulatory approval and commercial uncertainty, reimbursement and drug price uncertainty, the absence of sales and marketing experience and limited manufacturing capabilities, attraction and retention of technologically skilled employees, dependence on licenses, patents and proprietary technology, dependence upon collaborators, future capital needs and the uncertainty of additional funding, risks of product liability and limitations of insurance, limitations of supplies, competition from other biopharmaceutical, chemical and pharmaceutical companies, environmental, health and safety matters, availability of licensing arrangements, currency fluctuations, adverse changes in governmental rules and fiscal policies, civil unrest, acts of God, acts of war, and other factors referenced in this communication. Given these uncertainties, prospective investors and partners are cautioned not to place undue reliance on such forwardlooking statements. We disclaim any obligation to update any such forward-looking statements to reflect future events or developments. This material is not intended as an offer or solicitation for the purchase or sale of shares of WILEX G. This material may not be distributed within countries where it may violate applicable law. 2

3 Corporate verview TC Technology Platform Proprietary TC Project HDP-101 Summary & utlook 3

4 Heidelberg Pharma at a Glance Developing new options to address major challenges in cancer therapy ur Company ur Mission ur pproach WILEX G becomes Heidelberg Pharma G Frankfurt Stock Exchange: WL6 Shares outstanding: million Market cap: 40 million Headquarters: Ladenburg, Germany 55 employees (ugust 2017) Improving efficacy vercoming resistance mechanisms Killing dormant tumor cells New options in cancer therapy New mode of action in cancer therapy - ntibody Targeted manitin Conjugates (TCs) Induction of apoptosis by inhibition of RN Polymerase II pplication of innovative payload harnessing DC technology Fully fledged DC company 4

5 Strategic Cornerstones Build proprietary TC pipeline Sign technology licensing collaborations dditional upside potential with partnered non-tc legacy clinical assets Proprietary lead candidate HDP-101 Lead TC HDP-101 TC technology partner TC technology partnering with pharma and biotech TC cooperations & follow-up proprietary TC candidates TC collaboration & pipeline Clinical assets MESUPRN REDECTNE RENCREX WILEX G 5

6 Early Validation and Cash Through Pharma Collaborations + Future High Value Potential with Proprietary Portfolio Partnering target by target ntibodies from partners, license to the partner, development by the partner TC toolbox: customized and target-optimized toxins and linkers Defined payload Linker variations manitin derivates In-licensed antibodies, internal development activities Proprietary 6

7 Early Validation and Cash Through Pharma Collaborations + Future High Value Potential with Proprietary Portfolio Partnering target by target ntibodies from partners, license to the partner, development by the partner TC toolbox: customized and target-optimized toxins and linkers Defined payload Linker variations manitin derivates In-licensed antibodies, internal development activities Proprietary 7

8 Corporate verview TC Technology Platform Proprietary TC Project HDP-101 Summary & utlook 8

9 Innovative potential first-in-human mode of action with compelling clinical potential Unique mode of action of manitin as toxic payload manitin kills dividing ND quiescent tumor cells Most effective and specific inhibitor of eukaryotic transcription (binds and specifically inhibits RN polymerase II) Toxin from Death cap mushroom Low toxicity of free toxin due to low membrane permeability results in potential clinical benefits by Chemical synthesis ntibody Targeted manitin Conjugates (TCs) DC technology harnessed to deliver this new mode of action to patients Strong efficacy in vivo and in vitro models bility to overcome resistance Kill dormant tumor cells causing metastasis & tumor relapse TC 9

10 Therapeutic dvantages of TCs: Effective on Dormant Cells, Breaking through Drug Resistance and Relapse TCs are active in resistant or difficult-to-treat tumors TCs are highly potent on true, nondividing embryonic stem cells 10

11 T u m o r v o lu m e [m m 3 ] T u m o r v o lu m e [m m 3 ] TC Efficacy in Heterogeneous Kadcyla-resistant HER2 1+ Breast Cancer PDX Model HER2 low and heterogeneous PDX model 0 Model is resistant to Kadcyla Complete remission after single dose of HER2 TC D a y s N o n -b in d in g T C [2 m g /k g ] H B TC ra x -1 s tu0 z u m a b - T C [0.5 m g /k g ] T ra s tu z u m a b - T C [2 m g /k g ] D a y s TCs are effective on low expressed targets TCs have a bystander effect D IG T -D T -D 11

12 HDP s MD nderson Collaboration in Nature 2015: p53 Deletion is Payload-specific Predictive Biomarker for TCs Joint HDP Publication with MD nderson in Nature pril 30, 2015 Target of amanitin PLR2 close to TP53 on Chr 17 Passenger deletion 10-fold increased susceptibility to EpCM-manitin-DC of PLR2loss cells in vitro & in vivo 12

13 Predictive Biomarker Potential for Superior Therapeutic Index and ccelerated TC Clinical Development T u m o r v o lu m e [m m 3 ] T u m o r v o lu m e [m m 3 ] HER2 1+ PDX model CNV p53 and PLR2: 2 H B C x -1 0 HER2 1+ PDX model CNV p53 and PLR2: 1 H B C x D a y s N o n -b in d in g T C [2 m g /k g ] T ra s tu z u m a b - T C [0.5 m g /k g ] T ra s tu z u m a b - T C [2 m g /k g ] D IG -D C [2 m g /k g ] D a y s Stratification of patients T -D C [0.5 m g /k g ] Clinical Development of TCs may include 17pDel high-risk cohorts to facilitate accelerated approval T -D C [2 m g /k g ] 13

14 SPPS manitin : Total Chemical Synthesis by Solid Phase H Solid Phase Peptide Synthesis by FMC H 3 C HN CH CH CH CH 2 H C NH CH C NH CH 2 C C H 2 C NH CH 3 PS H N Fmoc-HypH Resin, 3 steps H N C H 2 C CH NH CR C S CH 2 N H CH NH C CH 2 HC H C NH -manitin -manitin CH CH 2 CH 3 R = NH 2 R = H Fmocsn(Tri)H FmocCys(Tri)H Fmoc GlyH FmocIleH FmocGlyH Savige-Fontana Tryptathionylation (B-Ring Formation) & Simultaneous Resin Cleavage Macrolactamisation (-Ring Formation) Deprotection, Linker Introduction H H N + Cl H H DHIL, 10 steps N H H N HPI, 2 steps H Tech Transfer to CDM initiated GMP available in early

15 Corporate verview TC Technology Platform Proprietary TC Project HDP-101 Summary & utlook 15

16 BCM n Ideal Target for TCss BCM is expressed on mature but not on healthy earlier stage plasma cells. BCM is specifically expressed in multiple myeloma (MM), a mature B-cell neoplasm. Upside: approximately 50% of CLL and DLBCL patients express BCM on B-cells and may also profit from BCM-TC therapy BCM BCM 16

17 Lead Proprietary TC Candidate HDP-101: Strong Case for Multiple Myeloma BCM antibody selected under collaboration with Max Delbru ck Center for Molecular Medicine in the Helmholtz ssociation manitin + Linker + BCM antibody = HDP-101 Ideal for multiple myeloma (MM) treatment BCM expression highly restricted in MM, a mature B-cell neoplasm, and malignant CLL / DLBCL BCM plays an important role in progression of multiple myeloma TC/HDP-101: ideal approach to target low expressed BCM on slowly proliferating tumor cells Hematological tumor type = good accessibility to tumor cells Multiple Myeloma: 3rd most prevalent hematopoietic malignancy (about 1% of all cancers worldwide); still considered incurable, with median survival of ~30-60 months dditional indications: Diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) Favorable market: peak sales 1.8 billion EUR for HDP

18 HDP-101: Strong Efficacy in Multiple Myeloma Xenograft Models Complete tumor remission in a subcutaneous multiple myeloma mouse model Subcutaneous NCI-H929 murine xenograft model for multiple myeloma nimals were treated with a placebo (PBS) or a single dose of HDP-101 Very good safety & tolerability profile after multiple dosing in various species No liver toxicity seen t 4 mg/kg a complete remission was achieved for 3 months 18

19 HDP-101: Strong Efficacy in Multiple Myeloma Xenograft Model T o ta l F lu x [p /s ] Intravenous multiple myeloma xenograft model (MM1.S-Luc) Day 40: Control Group Groups treated with ascending doses of HDP mg/kg Highly efficient treatment with HDP-101 E ffic a c y o f T C s in a d is s e m in a tin g iv M M 1.S -L u c M M X e n o g r a ft 0.3 mg/kg P B S [ 1 0 m l/k g ] J IS Y - D C [ 0.1 m g /k g ] J IS Y - D C [ 0.3 m g /k g ] J IS Y - D C [ 1 m g /k g ] J IS Y - D C [ 2 m g /k g ] B a c k g r o u n d L e v e l 1 mg/kg * * 2mg/kg T r e a t m e n t ( s i n g l e d o s e i v ) D a y s P o s t T u m o r C e ll In o c u la tio n * 9 /1 0 a n im a ls : b a c k g r o u n d le v e l 19

20 No Liver Toxicity in Monkeys No signs of liver toxicity in dose escalating and repeat dosing in cynomolgus monkeys 3 animals per group 3 week schedule * Scheduled sacrifice ---- min/mean/max/ values of untreated animals 3 female cynomolgus monkeys were treated with escalating doses of HDP-101 every 3 weeks t 3 mg/kg, regimen was switched to repeated dosing No changes in liver transaminases observed Histopathological examination did not detect any liver abnormalities 20

21 Large Therapeutic Index & Favorable Tolerability Therapeutic index based on UC : 60 3 animals per group 3 week schedule * Scheduled sacrifice ---- min/mean/max/ values of untreated animals No clinical side effects, LDH most sensitive parameter from clinical chemistry ccompanied by transient increase of neutrophils & decrease of monocytes and lymphocytes TI : HNSTD (3mg/kg repeated in NHP) / MED (0.1 mg/kg single in murine disseminating xenograft) 21

22 Pharmakokinetic Profile in Monkeys Dose dependent exposure & Dose Linearity No signs for neutralizing antibodies or Ds Free Linker-Toxin at LLQ 22

23 Corporate verview TC Technology Platform Proprietary TC Project HDP-101 Summary & utlook 23

24 HDP-101: Development Process and Milestones Major milestones in preclinical development of HDP-101 achieved preparation for the clinic ongoing Humanization of therapeutic BCM antibody ptimization of linker payload combination with best efficacy and toxicity profile Conjugation with manitin to generate HDP-101 Preclinical studies in mice showed excellent efficacy (subcutaneous and i.v. MM mouse model) Very good tolerability in non-human primate studies (cynomolgus monkeys) GMP antibody manufacturing started GMP matoxin manufacturing started Regulatory process initiated Preclinical development GLP / GMP / IND enabling Clinical Phase I/II Candidate nomination Scientific dvice PEI/FD GLP tox IND approval GMP TC First signals of efficacy 24

25 TCs: Growing Pipeline of Proprietary and Partnered Programs dditional proprietary TCs in research and preclinical development Targets: PSM, CD19, others Excellent preclinical efficacy in mice Very good tolerability in cynomolgus monkeys Product Target Indication Research Preclinic Clinic Partner I II III HDP-101 BCM Multiple Myeloma (DLBCL/CLL) Proprietary PSM-TC PSM Prostate cancer Proprietary CD19-TC CD19 Hematological tumours Proprietary HuMB 5B1-TC n/a Metastatic pancreatic cancer Mab Vax NN-TCs n/a Leukemias Nordic Nanovector 25

26 Summary manitin Highly potent payload; Unique mode of action Chemical synthesis established. Tech transfer & GMP ongoing Synthetic derivative with improved stability Linker & Conjugation technology Comprehensive linker toolbox established Linker & conjugation technology for different conjugation strategies established Favorable therapeutic index demonstrated in non-human primates Biomarker / Companion Diagnostic First biomarker in DC area, high incidence in advanced tumors Guidance of R&D in target and indication selection Stratification of patients in clinical trials to decrease RR and probability of approval Candidate for Clinical Development HDP-101 (BCM-TC) 26

27 cknowledgements Team of Heidelberg Pharma Torsten Hechler Christoph Müller Christian Lutz Michael Kulke Gudrun Schiedner M. Raab, Multiple Myelom Unit, DKFZ, Heidelberg Hi-Stem, Heidelberg, Germany HEIDELBERG PHRM G PSTL DDRESS Schriesheimer Straße 101 D Ladenburg, Germany Phone: +49 (0) info@hdpharma.com Thank you for your attention 27