Oncology Pipeline

Let’s investigate

2-10-2015

Boehringer Ingelheim: A Brief History1885–1948: Innovative beginning

1885Albert Boehringer buys a small tartaricacid factory in Ingelheim, Germany; initially with 28 employees

1948–1988: Going global

1948 European subsidiaries established

1957 First overseas subsidiary set up in Latin America (Brazil)

1961 Nippon Boehringer Ingelheim established in Japan

1971 USA subsidiary founded in Ridgefield, Connecticut

1988–present: Value through innovation

2015

BI is one of the world’s 20 leading pharmaceutical companies operating with 142 affiliates worldwide and more than 47,400 employees

Factory site in Ingelheim, Germany, 1907

Headquarters in Ingelheim, Germany, 2015

Boehringer Ingelheim: Our Innovation Milestones1885–1948: Innovative beginning

1885 Albert Boehringer becomes a pioneer of large-scale biotech production by using bacteria to produce lactic acid

1917 First Scientific Department set up in Ingelheim

1941 Introduction of highly innovative Aludrin® for asthma treatment

1948–1988: Going global

1985 Institute for Molecular Pathology founded in Vienna (Austria) as a joint venture with Genentech, Inc. (USA)

1986 Biotechnology Centre, Biberach, starts operations as first biopharmaceutical production plant in Germany

1988–present: Value through innovation1999 Launch of Micardis® for hypertension

2002 Launch of Spiriva® for COPD

2008 First launches of Pradaxa® in prevention of venous thromboembolism

2010 First launches of Pradaxa® in stroke prevention for atrial fibrillation

2011 First launch of Tradjenta® in type 2 diabetes in USA; approved globally as Trajenta®

2013 Launch of Giotrif® (afatinib) for the treatment of EGFR-TKI-naïve adult patients with locally advanced or metastatic NSCLC with activating EGFR mutation(s)

2014 Approval of Vargatef® (nintedanib) in EU for locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology, after first-line chemotherapy

COPD = chronic obstructive pulmonary disease.

Oncology Pipeline

Research Facilities in ViennaBI Oncology Drug Discovery and Basic Science Institutes

Boehringer Ingelheim RCV

Scientific staff of ≈270 Dedicated site for oncology drug discovery Capabilities in NBE and NCE discovery Strong pipeline with focus on tumour cells and

immune cells Multiple collaborations, alliances and

technology licenses

Research Institute of Molecular Pathology

Scientific staff of ≈220 Dedicated to basic research in

the biomedical sciences: cell biology, molecular genetics, neurosciences and other areas

RCV = Regional Center Vienna

1988

Tumour cell

Effector cell

BI Oncology Drug Discovery – Focus on attractive AreasCurrent Research Areas

Oncology Pipeline

# In the EU, afatinib is approved for use in NSCLC patients with distinct types of EGFR mutations. It is not yet approved in other indications ## Nintedanib is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic orlocally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after 1st-line chemotherapy. * This is aninvestigational compound and has not yet been approved. Its safety and efficacy have not yet been fully established.

Signal transductionSeveral NBEs and NCEs from preclinical to Market including Afatinib#, IGF ligand mAb*, FAK inhibitor*, mTORC1/2 inhibitor*

Tumour angiogenesis Several NBEs and NCEs from preclinical to Marketincluding Nintedanib##

Cell-cycle progressionSeveral NCEs from preclinical to Phase I including BI 6727*

ImmunotherapySeveral NBEs from preclinical to Phase Iincluding CD37 mAb*, CD33 mAb*, BI 1361849*

Regulation of apoptosis

Several NCEs and NBEs from discovery to preclinical

Epigenetic regulation of gene expressionSeveral NCEs from discovery to Phase I

Protein homeostasis

Several NCE discovery projects

Tumour Initiating Cells and Stem Cell Pathways Several NCE and NBE discovery projects

Target Compound

EGFR (ErbB1), HER2 (ErbB2), ErbB3, ErbB4

Afatinib#

NCE po

VEGFR, FGFR, PDGFR Nintedanib##

NCE po

Innate immune systemlung cancer

BI 1361849*NBE id

IGF ligand Solid tumours

BI 836845*NBE iv

CD37Haematology

BI 836826*NBE iv

mTorSolid tumours

BI 860585*NCE po

FAK Solid tumours

BI 853520*NCE po

CD33Haematology

BI 836858*NBE iv

PLK Haematology

BI 6727*NCE iv

Oncology Pipeline

BI Oncology Development Pipeline – Growing More Diverse

HNSCC = head and neck squamous cell carcinoma; CRC = colorectal cancer; RCC = renal cell cancer; HCC = hepatocellular carcinoma; AML =acute myeloid leukaemia; NSCLC = non-small cell lung cancer; OC = ovarian cancer; TKI = tyrosine kinase inhibitor; Mesoth = mesothelioma; MDS = myelodysplastic syndromes; SCC = squamous cell carcinoma. # Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF® and in the U.S. under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications. ## Nintedanib is approved in the European union (EU) under the brand name VARGATEF® for use in combination with docetaxel in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. Registration conditions differ internationally, please refer to locally approved prescribing information. Nintedanib is not approved in other indications. * This is an investigational compound and has not yet been approved. Its safety and efficacy have not yet been fully established. Recruitment status based on cliniclatrials.gov and most recent core team discussions

NCDev Phase I Phase II

✓

✓

✓

✓

✓

✓

✓ ✓ SCC NSCLC (submission) HNSCC

Phase III

mBC CRPC NSCLC✓

✓

Approved NSCLC 1st line

EGFR M+#

✓

NHL CLL✓

✓ NSCLC EGFR M+ NSCLC stage 3

✓ ✓ Mesoth. CRC NSCLC 2nd line##

Solid tumour programs

Multiple products entering broad development in solid tumours and haematology in 2015

Solid tumour programs

Clin Cancer Res. 2013;19:2240-2247.

The relative frequencies of the various mechanisms of acquired resistance for EGFR TKIs therapy in 155 patients with EGFR-mutant lung cancers

Mechanisms of Acquired Resistance to 1st-Gen EGFR TKIsHigh unmet needs after failure of Gefitinib or Erlotinib in NSCLC

BI1482694 (HM61713) in-licensing

3rd generation EGFR TKI

In vitro cell growth inhibition in NSCLC Oral EGFR mutant -specific TKI

Potent and irreversible inhibition of sensitising (Del19, L858R) and resistance (T790M) EGFR mutations

More than 200-fold selectivity over wild type EGFR

BI 1482694 / HM61713: MOA

Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF® and in the U.S. under the brand name GILOTRIF® for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications.

3rd generation EGFR TKI

Inhibition concentration (GI50, nM)

H358 HCC827 H1975

EGFR WT EGFRexon 19 del EGFRL858R/T790M

Erlotinib 449 3.2 2,253

Afatinib 31 1.8 53

BI1482694/ HM61713 2,225 9.2 10

Best response

n=62

ORR (%) 54.8

DCR (%) 95.2

MedianPFS

Not reached

• Robust activity in patients with EGFR TKI-resistant T790M-positive NSCLC

• >70% of responders still continue study treatment

BI 1482694 / HM61713: Activity in T790M+ Patients at 800 mg

3rd generation EGFR TKI

BI’694: Most Frequent (>20%) Related AEs at 800 mg

N=76 All G3*

Diarrhoea 58% 0

Nausea 41% 0

Rash 37% 4%

Pruritus 36% 1%

Dry skin 30% 1%

Palmar-plantar erythrodysaesthesia synd. 29% 3%

Decreased appetite 24% 0

Skin exfoliation 21% 0

*Overall rate of related AE ≥gr3 – 19%; no Gr 4 and Gr 5 related AEs.

Park K et al. ASCO 2015. Abstract 8084.

3rd generation EGFR TKI

BI’694: Clinical Trial Program

Keunchil Park, M.D. Ph.D

Phase I/II dose-escalation study in ≥2 line patients with EGFR M+ NSCLC

Phase II Korean study in 1st line patients with EGFR M+ NSCLC

Phase II global study in ≥2 line patients with EGFRT790M positive NSCLC

Phase III randomised trial of BI1482694 in patients with EGFRT790M NSCLC

Phase III randomised trial of BI1482694 as 1st line treatment in EGFR M+ NSCLC

Hanmi Pharmaceuticals

Boehringer Ingelheim

Recruiting

Recruiting

Completed

Planned

Planned

Phase I study in healthy volunteers in Korea Completed

3rd generation EGFR TKI

BI 1482694: Conclusions

BI1482694 is an oral EGFR mutant-specific TKI with selective activity against sensitising and T790M resistance mutation over wild type EGFR

BI1482694 induces durable responses in patients with T790M(+) NSCLC following failure of EGFR TKI (ORR=55%) at the RP2D of 800 mg

Treatment is well tolerated, and the vast majority of adverse events have mild-to-moderate intensity and are easily managed

Registration program of BI1482694 is under way

3rd generation EGFR TKI

Vaccines in NSCLC

Immune systems play a critical role in protecting the host body against cancer

Active immunotherapeutic approaches have the potential to induce durable antitumour responses with minimal toxicity

Current approaches to cancer vaccination, a type of active immunotherapy, have been rather disappointing

Current unsatisfactory results could be due to a number of factors including the suppressing of antigen-presenting machinery and suboptimal trial design based on less than robust clinical evidence

BI 1361849*: Therapeutic mRNA-based Vaccine

*This is an investigational compound and has not yet been approved. Its safety and efficacy have not yet been fully established.** Messenger ribonucleic acid

Source: Boehringer Ingelheim (data on file)

RNA vaccine

A novel investigational therapeutic mRNA**-based vaccine developed in collaboration with CureVac

Mobilises the patient’s own immune system to fight the tumour with a specific immune response

A self-adjuvanting mRNA vaccine, optimised to enhanced antigens expression by up to 4-5 order of magnitude

The vaccine consists of 2 components: free mRNA and mRNA complexed with the cationic protein protamine

This results in a strong and balanced immune response comprising both humoral and cellular responses against the encoded antigens

Clinical investigation is under way in lung cancer settings

The Antigens Encoded by BI 1361849 (CV9202)

Muc 1:Expressed by 40-95%* of NSCLC

Survivin:Expressed in up to 86%*

of NSCLC

5T4:Expressed in up to 95%* of NSCLC Focally In tumour initating cells

NY-ESO 1:Cancer testis antigenExpressed in 20-39%* of NSCLC samples

Mage C2: Expressed in up to 30%*

of NSCLC samples

Mage C1: Cancer testis antigen, expressed in 30-40%* of NSCLC

*Data from literature- see IB for references.

All antigens are frequently overexpressed by NSCLCNot included in predecessorvaccine CV9201

RNA vaccine

Phase 1b Trial of BI 1361849 Combined With Local Radiation as Consolidation and Maintenance Treatment in Stage IV NSCLC

Sebastian M et al. BMC Cancer. 2014;14:748.

Primary endpoint: Number of patients experiencing >Grade 3 AEs

RNA vaccine

Safety and Immune Response to RNActive® Vaccines in NSCLC

Sebastian M et al. J Clin Oncol 30, 2012 (suppl,abstr 2573).

Safety/tolerability: 46 evaluable patients

No DLTs observed

Adverse events:• Most frequent related AEs were mild to moderate injection site reactions and flu-like symptoms• 3 patients (7) had potentially related grade 3 fatigue, injection site granuloma, asthma attack)• No related SAEs

Immune response:

Antigen specific immune responses against at least one antigen were induced in 65% of pts (39% cellular and 49% humoral).

A significant ≥2 fold increase of pre germinal center B cells (pGCB) was observed in 61% of pts

This increase of pGCB correlated significantly (p=0.0028) with increase of total CD4 effector T cells

RNActive® vaccines + local radiation as consolidation and maintenance therapy (stage IV)

RNA vaccine

IGF ligand

Insulin-like Growth Factor Signalling Role in Cancer

IGF signalling promotes cell survival, growth, and proliferation

Implicated in the development and progression of cancers

Thought to play a role in conferring resistance to existing therapies

IGF pathophysiology is likely due to levels of active ligand, as no amplifications/activating mutations of the signalling receptors are known

Pollak M. Nat Rev Cancer. 2012;12:159-169.Khandwala HM, et al. Endocrine Rev. 2000;21:215-244.

IGF Ligand and ReceptorsLigand Neutralisation Reduces the Effects on the Insulin Receptor

Both IGF-1R and IR-A are capable of transmitting IGF signals

IGF-1R targeted monoclonalantibodies (mAbs) do noteffectively target IR-A signalling

An IGF-1/-2 co-neutralising mAbinhibits IGF-1R and IR-A signalling driven by IGF-1 and IGF-2

Pollak M. Nat Rev Cancer. 2012;12:159-169.

IGF ligand

IGF ligand

Introducing BI 836845*

Fully human affinity optimised IgG1 mAb

Binds to IGF-1 and IGF-2 with high affinity:• IGF-1: KD = 0.07 nM1

• IGF-2: KD = 0.80 nM1

Showed potent anti-proliferative effect against a range of cancer cell lines

Source: Boehringer Ingelheim (Friedbichler K, et al. Mol Cancer Ther. 2014;13:399-409)

1KD values determined by surface plasmon resonance analysis.* This is an investigational compound and has not yet been approved. Its safety and efficacy have not yet been fully established.

Phase I Studies

Study objective:

1) MTD or relevant biological dose in the absence of MTD

2) Safety, PK, PD

Design:

Phase I, open-label, multicentre, dose-escalation study in Taiwan

Treatment:

Weekly iv until PD in patients with advanced solid cancer

Study objective:

1) MTD or relevant biological dose in the absence of MTD

2) Safety, PK, PD

Design:

Phase I, open-label, multicentre, dose-escalation study in the UK

Treatment:

Every 3 weeks iv until PD in patients with advanced solid cancer

IGF ligand

Lin CC et al. ASCO 2014. Abstract 2617Rihawi K et al. ASCO 2014. Abstract 2622.

The 10 Most Common AEs Regardless of Relationship to BI 836845 in Phase I Trials

weekly 3-weeklyN=48 N=33

AE N (%) AE N (%)

Anaemia 6 (12.5) Fatigue 13 (39.4)

Decreased appetite 5 (10.4) Decreased appetite 12 (36.6)

Dizziness 5 (10.4) Diarrhoea 12 (36.6)

Fatigue 5 (10.4) Vomiting 11 (33.3)

Cough 4 (8.3) Nausea 10 (30.3)

Dyspnoea 4 (8.3) Abdominal pain 8 (24.2)

Weight decreased 4 (8.3) Back pain 6 (18.2)

Abdominal distension 3 (6.3) Constipation 6 (18.2)

ALT increased 3 (6.3) Dyspnoea 6 (18.2)

Back pain 3 (6.3) Lethargy 6 (18.2)

IGF ligand

Lin CC et al. ASCO 2014. Abstract 2617Rihawi K et al. ASCO 2014. Abstract 2622.

Ewing Sarcoma

2012-12-20: Before treatment 2013-02-05: after 2 cycles 2013-07-02: after 27 weeks

Ewing sarcoma / Primitive neuroectodermal tumour (PNET); CT scanfemale, 19 years; at 1,050 mg weekly, PR determined after 2 cycles, no related AE

IGF ligand

Phase I Studies BI 836845 showed a well-

tolerated safety profile MTD has not been reached at

1,800 mg/week The relevant biological dose for

monotherapy has been 1,000 mg/week for monotherapy studies

Plasma exposure increased dose-proportionally

Terminal half-life at around 6 days

Antitumor activity with 2 PR: neuroectodermal tumour and NPC

Further development deemed feasible due to good safety profile and observed efficacy

BI 836845 showed a well-tolerated safety profile

MTD has not been reached at 3,600 mg every 3 weeks

The relevant biological dose for monotherapy has been selected at 1,000 mg/week for further exploration in phase II studies

Plasma exposure increased dose-proportionally

Terminal half-life at around 6 days

Expansion cohorts are ongoing Further development deemed

feasible, also in combination with other molecular targeted agents

IGF ligand

Lin CC et al. ASCO 2014. Abstract 2617.Rihawi K et al. ASCO 2014. Abstract 2622.

Thank You for Your Attention