COMPANY PRESENTATION - MOLOGEN AG · the market • Lefitolimod uniquely positioned as potential...

COMPANY PRESENTATION FEBRUARY 2017

1

www.mologen.com

Disclaimer

Certain statements in this presentation contain formulations or terms referring to the future or future developments, as

well as negations of such formulations or terms, or similar terminology. These are described as forward-looking

statements. In addition, all information in this presentation regarding planned or future results of business segments,

financial classification numbers, developments of the financial situation, or other financial or statistical data contains

such forward-looking statements. The company cautions prospective investors not to rely on such forward-looking

statements as certain prognoses of actual future events and developments. The company is neither responsible nor

liable for these forward-looking statements. It is not responsible for updating such information, which only represents

the state of affairs on the day of publication.

2

Agenda

3

Business overview and „Next Level“ strategy 4

TLR9 agonist product family: Lefitolimod (MGN1703) 10

Market 14

TLR9 agonist product family: EnanDIM® 16

Key financials 17

Appendix 22

MOLOGEN Snapshot

4

• Based in Berlin, Germany; founded 1998

• Approx. 50 employees

• One of the pioneers in immunotherapies

• Focus on family of TLR9 agonists:

• Immunotherapy lefitolimod (MGN1703)

• Next generation technology EnanDIM®

• Highly attractive markets: A multi-billion US$ market

• Close network with scientific institutions & experts

Lefitolimod

EnanDIM®

MOLOGEN summary highlights

5

• Management with clear commercial focus and strong track record of previous

successes

• Leading German research player transitioning to global market ready company

• Strong value-creative pipeline with lead product lefitolimod in two late-stage

trials & two earlier clinical programs as well as follow-up compounds being

qualified for trials in man

Advanced

immunotherapy

player

• Lefitolimod has the potential to re-activate the immune system

• Single-agent potential in oncology as well as infectious diseases

• Combination therapy potential augmenting other existing effective treatments

Safe & well

tolerated lead

product

• mCRC (phase III): sizeable market; immunogenic disease

• SCLC (phase II): highly lethal; limited treatment advances; short survival times,

exploratory study

• Combination treatment in solid tumours (phase I): broad market opportunity

including potential for collaborations

• HIV (phase I): potential to eradicate rather than manage infection

Multi-billion dollar

target markets

• Advance clinical development of Lefitolimod (2 study read-outs in 2017: TEACH &

IMPULSE)

• Progress follow-up compounds

• Adjust organisation to late stage development needs (esp. manufacturing scale-up)

• Propel outlicensing activities

Value-creative

milestones ahead

Legend: HIV human immuno-deficiency virus | mCRC metastatic colorectal cancer I SCLC small cell lung cancer

Executive Board:

Clear commercial focus & successful track record

6

Dr. Mariola Söhngen, CEO Walter Miller, CFO

29 years biotech industry and

corporate leadership

experience as founder and

former MOB of Paion AG

15 key successful out-

licensings at Paion across

the globe

21 years industry as well

as financial expertise from

leadership positions at

Nuvisan and Santhera

Pharmaceuticals AG

Successful IPO of Santhera

• MOLOGEN management brings long-term experience and is focusing on gearing

MOLOGEN towards the commercialisation of its development programs

• Value creating projects are being forcefully pursued and key intellectual capital is

being retained

Legend: MOB Member of Board

Next Level Strategy:

Transition to commercial enterprise

7

Research

driven

Market-

facing

History

Focus on basic research

• Broad pipeline

comprised of three

technology platforms

• Own in-house R&D-

scale production (trials

fully stocked)

Focus on commercial

activities

• Pipeline focus on lead

compound & follow-up

• Streamlined structure,

operational efficiency

• Structured partnering/

licensing activities

• US strategy being defined

Harvest lefitolimod potential

• Enable commercial-

scale production;

transition to CMO

• Focus research on

follow-up compounds;

transition to CRO

• Reduce headcount while

retaining expertise

• Enhance flexibility of

cost structure

Today Outlook

“Next

Level”

Legend: CMO Contract Manufacturing Organization | CRO Contract Research Organization

Advanced immunotherapy pipeline:

Late-stage lefitolimod & follow-up EnanDIM®

8

Indication(1) PC Ph I Ph II Ph III Timeline(2) Exclusivity(3)

Metastatic colorectal

cancer (mCRC)

LPI: Q1 2017

Data: 2019

Filing: 2019/2020

EU: 2030

US: 2028

Small-cell lung cancer

(SCLC)

Data: 2017 EU: 2030

US: 2028

Advanced solid

malignancies

(+ ipilimumab)

LPI: 2018

Data: 2019

EU: 2036

US: 2036

Human immunodeficiency

virus (HIV)

LPI: 2016

Data: 2017

EU: 2036

US: 2036

Cancer/

infect. diseases

Pre-clinical

EU: 2035

US: 2035

Renal cell carcinoma

(RCC)

Ph I / II data

available

Backup compound

EU: 2036

orphan drug status

US: 2038

Lefi

tolim

od

E

nan

DIM

M

GN

1601

Legend: PC Pre-clinical | Ph Phase | LPI last patient in • Notes: (1) Pipeline overview excludes MIDGE platform | (2) Timeline Denotes latest estimated

timeline of upcoming milestones | (3) Exclusivity Denotes estimated minimum market exclusivity horizon based on patent and data protection

IMPALA (MGN)

IMPULSE (MGN)

TEACH (Aarhus)

MD Anderson

ASET (MGN)

Cancer immunotherapy value proposition:

Improve long-term overall survival

Traditional chemotherapy Immunotherapy

9 Source: "Immuno-oncology: The new weapon in the war against cancer”, Alistair Campbell; Berenberg Equity Highlights, February 2014.

Legend: OS overall survival

Immunotherapy

Control

group time

Patients alive in %

Control

group

Chemotherapy

time

Patients alive in %

• Fast effect in many patients

• Effect not lasting

• Needs time to be effective

• Long-lasting effect in a subgroup

of patients

• Immunotherapies target improving OS at the long end of the curve

Safe & well tolerated immunotherapy:

“Best in class“ TLR9 agonist lefitolimod

10

• Immunologic activation and

good safety profile due to

molecular composition

– Safety established in ~400

patients to-date

• High dosing over long periods of

time – as required to trigger

clinical benefit – possible

without major toxic effects

• Clinical strategy optimized for

lefitolimod TLR9 activation

pattern

Light blue area: Motifs recognized by TLR9 receptor

• Lefitolimod is geared to success given its combination of

safety & tolerability by design with large potential for clinical benefit

Molecular structure Commentary

Safe & well tolerated lead product:

Mode of action in oncology

11

• The patient’s immune system generally polices the development of cancer cells

occasionally, cells evade that system, developing into cancer

• Lefitolimod reactivates the patient’s own immune system for anti-cancer surveillance

• Lefitolimod can work safely alongside other treatments leveraging the body’s own

immune surveillance system

Legend: mDC myeloid dendritic cell I NK cell natural killer cell I NKT cell natural killer T cell I pDC plasmacytoid dendritic cell


Mode of action in HIV

12

• Patients on ART are cleared from actively infecting HI virus, but T cells keep the

virus in its latent stage (no immune response against the virus)

• Lefitolimod as “kick & kill” agent kicks the virus from latency into active infection, and

reactivates immune surveillance to kill infected cells by NK cells and CTL

Legend: ART anti-retroviral therapy | HIV human immuno-deficiency virus | pDC plasmacytoid dendritic cell | mDC myeloid dendritic cell | NK cell

natural killer cell | CTL cytotoxic T lymphocytes


Combination therapies represent the next opportunity

13

• Combination treatments aim to

combat a disease through

various synergistic ways

• Expected to play integral role in

future new immunotherapy

approaches or breakthrough

outcomes

• Increased research – and

business development – across

the market

• Lefitolimod uniquely positioned

as potential “combination

partner of choice”

Immunotherapy

Control

group time

Patients alive in %

• Combination therapies are the latest advancement in the fight against

several global diseases including cancer & HIV

Combination therapies

Combination therapy potential Commentary

Source: "Immuno-oncology: The new weapon in the war against cancer”, Alistair Campbell; Berenberg Equity Highlights, Feb 2014

Multi-billion US$ markets in oncology:

Strong fundamentals and significant unmet needs

14

WW Prescription Drugs1 WW Oncology Drugs1

2014 2020

743

987 CAGR

+4.8%

2014 2020

79

153 CAGR

+11.6%

Colorectal Cancer2 Lung Cancer3 SCLC4

8.3 9.4

2013 2020

CAGR

+1.8%

4

13

2010 2020

CAGR

+12.5%

0.2

2.3

2014 2024

CAGR

+27.7%

• Oncology is expected to be

among the largest and

fastest growing therapeutic

areas worldwide

• Cancer immunotherapies

represent a huge market

potential: ~US$ 35 bn

Sales in US$ bn

Source: 1EvaluatePharma 2015 | 2ResearchandMarkets Jan 2015 (5 EU, US, Japan & Canada) | 3MarketsandMarkets Nov 2011 (G7 Countries) | 4GlobalData, Jan 2016 (5 EU, US, Japan) | Legend: CAGR Compound Annual Growth Rate I WW worldwide

AIDS-related deaths (in million) People living with HIV on ART (in million)

• Better diagnostics

• Improved treatment regimens

• Price reductions of medicines

• Growing patient population

• ART represents no cure

• Patients remain infectious

Multi-billion dollar markets in HIV:

Increasing number of patients living with HIV

15

<1

17

30

2000 2015 2020

Source: UNAIDS; “Global AIDS Update” (worldwide), 2016 | ART antiretroviral therapy

1.5

1.1

<0.5

2000 2015 2020

• People living with AIDS have opened a market for drugs like lefitolimod

• Eradicating HIV would prevent risks of further transmission and of viremia,

while improving QOL

Legend: EnanDIM® Enantiomeric DNA-based ImmunoModulator | DNA sequence essential for function (so-called “CG motifs”) |

new structural feature in EnanDIM providing protection against degradation | phosphorothioate backbone (chemical modification)

Follow-up molecules EnanDIM®:

Next generation TLR9 agonists

16

• Linear molecules

– Simple cost-effective

production

• Stability through chemically

modified structure

– Usually unfavorable risk /

benefit ratio

Linear DNA-structure

• Stability through closed,

dumbbell-shaped structure

– Production complexity

• Only natural DNA

components

– Good safety and

tolerability profile

Lefitolimod EnanDIM®

• Linear molecules; stability

through specific feature

– Simple cost-effective

production

• No chemical modifications

– Good safety and

tolerability profile expected

• New family of linear TLR9 agonists, combining safety of molecules containing only

natural DNA components with simple production process of linear molecules

– Allow drug differentiation on molecular level

• Broad immune activation and anti-tumor effect shown in pre-clinical models

• Potential application in cancer and in anti-infective therapies

17

• Slightly increased R&D expenses and related cash outflow due to advanced study program

• Next level strategy including upscaling: increased R&D expenses in the mid- and long-term

• Proceeds from capital increase expected to last into the fourth quarter 2017

Key financials 9M 2016

In € million 9M

2016

9M

2015 ∆

FY

2015

R&D expenses 10.5 10.4 1% 16.8

EBIT -14.3 -13.3 8% -20.5

Cash flows from operating activities -13.9 -9.0 54% -15.1

Cash flows from financing activities -0,5 26.1 -102% 26.2

Monthly cash burn 1.6 1.3 23% 1.4

In € million 30 Sep

2016

31 Dec

2015 ∆

Total assets 11.3 26.4 -57

Cash & cash equivalents 10.2 24.6 -59

Equity ratio 44% 74% -41

Goals 2016

18

• Intensify product development

• Focus on lefitolimod (MGN1703)

- IMPULSE study: start of analyses towards end of 2016

- IMPALA study: finalize patient recruitment in Q1 2017

- Continue TEACH study with extension phase

- Start combination study with ipilimumab (Yervoy®) in patients with

solid cancers in cooperation with MD Anderson

- Evaluation of additional combination study (e.g. preclinical)

• Evaluate and prioritize pipeline

• Continue partnering discussions

19

Refinancing -

Current shareholder structure

Capital measures

Cash reach until the beginning of 2018

29%

5% 4%

4%

58%

Global Derivative Trading GmbH

Deutsche Balaton Aktiengesellschaft

Baloise Holding AG

Deutscher Ring Krankenversicherungsverein a.G.

Freefloat

• Capital increase: Oct 2016 (~11 m new shares to now ~34 m shares) €13.60 m

• Convertible bond: Nov 2016 (8 years, 6% interest rate) €2.54 m

• Convertible bond: Jan 2017 (8 years, 6% interest rate) €4.99 m

Total gross proceeds ~ €21.10 m

Key data of convertible bonds

20

2016/2024 2017/2025

Amount €2.54 million €4.99 million

Issue date 25 Nov 2016 20 Jan 2017

Maturity date 29 Oct 2024 20 Jan 2025

Coupon 6% 6%

Price EUR 10,000 EUR 10

Interest payment date Quarterly Quarterly

Conversion price EUR 1.50 EUR 1.60

ISIN DE000A2BPDY4 DE000A2DANN4

Listing no no

Holder at issuance date Global Derivate Trading

(GDT)

ca. 73% subscribed by GDT

Financial calendar 2017 and contact details

22 March 2017

Full Year Report 2016

28 April 2017

Annual General Meeting

11 May 2017

Quarterly Statement as of 31 March 2017

10 August 2017

Half-Yearly Financial Report as of 30 June 2017

9 November 2017

Quarterly Statement as of 30 September 2017

21

Claudia Nickolaus

Head of Investor Relations &

Corporate Communications

Phone: +49-30-841788-38

Fax: +49-30-841788-50

[email protected]

www.mologen.com

MOLOGEN®, MIDGE®, dSLIM®, and EnanDIM® are registered trademarks of the MOLOGEN AG

Appendix

22

Lefitolimod – Ongoing clinical trials 23

Lefitolimod mode of action 24

Lefitolimod ongoing clinical trials overviews 27

Lefitolimod Phase II data mCRC 41

Oncology competitive landscape 46

MGN1601 RCC clinical trial overview 48

Financial information 54

23

• MOLOGEN is developing its lead compound in various directions

Lefitolimod (MGN1703)

• Pivotal multicenter (122) EU (8 countries) study “IMPALA”

• Status: started Sep-14 targeting 540 patients

• Patient recruitment on track

• Aims: to compare OS vs. local gold-standard treatment &

to enable regulatory approval

• Targets(1): read-out 2019 (event driven), filing 2019/ 2020

mCRC: Phase III

• Multicenter (41) EU (4 countries) study “IMPULSE”

• Status: started Mar-14 with recruitment of 100 patients

completed Oct-15

• Aims: to compare OS vs. local gold-standard treatment,

to inform development pathway in SCLC, to further

support safety data base

• Target(1): read-out 2017

SCLC: Phase II

• Two-stage single-center

“TEACH” trial

– Aarhus Univ. Hospital

(DEN)

• Status: started Jun-2015

– Stage 1 successfully

completed (15 patients)

– Stage 2 first patient Jun-

2016 (target: 15 patients)

• Aim: to define value in kick

and kill concept in HIV /

infectious diseases

• Target: read out 2017

HIV: Phase I

• Single-center proof-of-

concept trial combining

lefitolimod with checkpoint

inhibitor ipilimumab

(Yervoy®)

– MD Anderson (US)

– 50-60 patients envisaged

• Status: started Jul 2016

(first patient in)

• Aim: to inform development

pathway in combination

treatments

• Target: read-out 2019

Solid tumours: Phase I

Multi-billion dollar markets: ongoing clinical trials

Legend: HIV human immune deficiency virus | mCRC metastatic colorectal cancer | SCLC small cell lung cancer

Note: (1) Subject to actual overall survival (amongst others).

24

Days

Weeks

Innate Cellular

cancer cell

Radiation or

Chemotherapy

Adaptive Cellular

B cells

Adaptive Humoral

Weeks to

Months

pDC

mDC

monocytes

NK

NKT

ADCC

Lefitolimod

(MGN1703)

cytotoxic

T lymphocytes

TAA, TSA

Lefitolimod: Oncological mode of action (1/3)


Immune surveillance reactivation (ISR)

25

mCRC program: Phase III (ongoing)

pivotal IMPALA study

27

• Primary endpoint overall survival (OS)

• Open-label, randomized, controlled, two-arm, multinational phase III trial

• 540 patients in around 120 sites in eight European countries, including Top

5 European pharma markets

• Biomarkers used as stratification factors: CEA level and NKT activation

PD

Lefitolimod

(MGN1703)

Trial Treatment Period

Re-Induction

Induction CT

12–30 weeks

Standard first-line

CT for mCRC

PR/CR

Responder

Screening/

Randomization

1:1 Control

group PD

Lefitolimod

(MGN1703)

with

induction CT

Induction

CT

PD

Start of

2nd line

PD

Legend: CEA carcinoembryonic antigen - a tumor marker for colorectal cancer | CT chemotherapy | CR complete response | mCRC metastatic colorectal

cancer | NKT Natural Killer T cells | PD progressive disease | PR partial response

Maintenance

IMPALA: Inclusion & exclusion criteria

28

PD

Legend: CT computed tomography | ECOG eastern cooperative oncology group | RECIST response evaluation criteria in solid tumors | UICC union for

international cancer control

Main inclusion criteria

• Histologically confirmed colorectal cancer with unresectable stage IV (UICC) disease (primary

tumor may be present)

• Complete or partial response (according to RECIST 1.1) within 12-30 weeks from start of

induction treatment with standard first-line chemotherapy with or without biological agents

• ECOG performance status 0 or 1

Main exclusion criteria

• History of other malignant tumors within the last 5 years, except basal cell carcinoma or

curatively excised cervical carcinoma in situ

• Known brain metastases (present or treated)

• Prior allogenic stem cell transplantation or organ transplantation

• Active or uncontrolled infections or undiagnosed febrile condition

• Pre-existing autoimmune or antibody mediated diseases or immune deficiency

• Inadequate pulmonary function according to the investigator’s judgment, history of interstitial

lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease

on baseline chest CT scan

IMPALA: Statistical considerations

29 Legend: OS overall survival | w/o without

PD

Median OS

comparator

[months]

Median OS

treatment

[months]

Hazard ratio Events

needed [#]

Sample size

(w/o drop-

out)

Comments

22 29.5 0.75 365 506 Assumption of 10% drop-out

(by month 10 per patient)

implies sample size of 540

540 patients planned sample size (270 per arm); 365 events required for analysis

• Two-sided stratified log-rank test at a 0.05 significance level

• Targeted power for superiority in OS of 1–β = 0.80% with targeted hazard ratio (HR)

of 0.75

Assumptions:

• Median OS of 29.5 months from randomization in experimental arm vs. 22 months

from randomization in control group, with the gain in OS deemed clinically relevant

• Proportional hazards and exponential distributions

• Key variables at α=0.05 and power of 80% (two-sided log-rank) (original protocol

calculation):

IMPALA: Secondary endpoints

30

• Overall survival (OS) from induction start; OS rates

• Progression-free survival (PFS) on study treatment, until first

progressive disease (PD), after re-introduction, and after first-line

treatment; PFS rates

• Overall response rate (ORR) after randomization

• Toxicity and safety profile of lefitolimod (MGN1703) (adverse events,

AE)

• Quality of Life (QoL) and patient-reported outcomes

• Translational research - Immunological analyses of patient samples

during follow-up (e.g. immune cell activation, cytokine levels)

Legend: AE adverse events | ORR overall response rate | OS overall survival | PD oprogressive disease | PFS progression-free survival |

QoL quality of life

SCLC program: Phase II (ongoing)

randomized IMPULSE study

31

• Primary endpoint overall survival (OS)

• Randomized, controlled, two-arm, multinational trial with 100 patients in

Belgium, Austria, Germany and Spain

• Biomarkers used as stratification factors: NSE level and NKT activation

• Patient enrollment completed: End of October 2015

PD


Maintenance

Induction CT

4 cycles of

platinum-based

therapy

Standard first-line

CT for extensive

disease SCLC

PR/CR

Responder

Screening/

Randomization

3:2

Experimental Group:

5th cycle of platinum based

CT followed by lefitolimod

(MGN1703) maintenance

Control Group:

5th cycle of platinum

based CT followed by

local practice

PD

PD

Start of

2nd line

Legend: CR complete response | CT chemotherapy | NKT Natural Killer T cells | NSE neuron specific enolase - a tumor marker for lung cancer |

PD progressive disease | PR partial response | SCLC small cell lung cancer

IMPULSE: Main inclusion and exclusion

criteria

32 Legend: CR complete response | CT chemotherapy | NKT Natural Killer T cells | NSE neuron specific enolase - a tumor marker for lung cancer |

PD progressive disease | PR partial response | SCLC small cell lung cancer | ECOG eastern cooperative oncology group

Main inclusion criteria

• Extensive disease SCLC confirmed by a pathologist, on the basis of histology of SCLC

or mixed histology of SCLC, or a cytological diagnosis if histology cannot be obtained

• Completion of 4 cycles of first-line therapy with a platinum-based regimen and no other

prior chemotherapy

• Documented evidence of tumor response (PR or CR) as assessed by the investigator at

the end of the fourth cycle of platinum-based first-line chemotherapy using CT or

magnetic resonance imaging (MRI) scan

• ECOG performance status 0 or 1

Main exclusion criteria

• Prior or current other malignancy, except adequately treated superficial bladder cancer,

basal or squamous cell carcinoma of the skin, or other cancer for which the patient has

been disease free for more than 3 years

• History of carcinomatous meningitis

• Prior or current paraneoplastic syndrome related to SCLC

• History of autoimmune disease or immune deficiency

IMPULSE: Secondary endpoints

33

PD

Legend: OS overall survival | PFS progression-free survival | RECIST response evaluation in solid tumors | irRC immune-related response criteria |

AEs adverse events

Efficacy

• OS from the start of the first cycle of induction chemotherapy (OS1)

• Progression-free survival (PFS) from the date of randomization with progression

assessed by response evaluation in solid tumors (RECIST) 1.1 and immune-related

response criteria (irRC)

• PFS from the start of the first cycle of induction chemotherapy (PFS1) assessed by

RECIST 1.1 and irRC

• Best objective response rate (ORR) with clinical response assessed by RECIST 1.1

and irRC

• Quality of life measured by Lung Cancer Symptom Scale at every staging

• Treatment outcome correlation of predefined biomarkers and immune parameters

Safety

• Safety profile of MGN1703 in terms of the incidence of adverse events (AEs) graded

according to National Cancer Institute Common Terminology Criteria for Adverse Events

(NCI CTC Version 4.03)

• Autoimmunity of MGN1703 in terms of antinuclear antibodies

34 Legend: SCLC small cell lung cancer | mOS median overall survival | LPI last patient in

• Patients with extensive disease SCLC after response to platinum-based

chemotherapy are expected to have a median OS of about 9 months with currently

available treatment options

• Primary analysis 12 months after LPI, final analysis 24 months after LPI

• 100 patients

IMPULSE: Statistical considerations


Mode of action in HIV

35

• Patients on ART carry the HI virus which is suppressed by the therapy and invisible to the

immune system (latent infected cells)

• Lefitolimod “kick & kill” approach triggers viral particles to “unhide” so they can be eradicated by

the immune system which is also activated by lefitolimod

KICK via

latency

reversal

KILL via anti-retroviral therapy

KILL via

activated cells

(NK/CD8)

KICK via

immunomodulation

(activation of pDC)

Legend: LRA latency-reversal agent | ART anti-retroviral therapy | NK cell natural killer cell I pDC plasmacytoid dendritic cell

36

• Collaboration agreement with Aarhus University Hospital, DK

• First trial of lefitolimod (MGN1703) in HIV patients

• Aarhus University Hospital conducts the trial; MOLOGEN provides

lefitolimod (MGN1703); funding received from the American Foundation for

AIDS research (amFAR)

• Extension phase: More patients to be treated for 6 months based on broad

activation of immune system induced by lefitolimod as shown in first phase

– Activation of plasmacytoid dendritic cells (pDC), natural killer cells (NK)

and T cells in HIV patients during the antiretroviral therapy (ART)

– Lefitolimod (MGN1703) could play a role in “kick &and kill‘‘ concept of

HIV eradications

– First patients of extension phase enrolled

• Final results expected in mid-2017

HIV program: Phase I (ongoing)

• The HIV program explores potential expansion of applications of

lefitolimod (MGN1703)

Legend: ART antiretroviral therapy | HIV human immuno-deficiency virus | NK cells natural killer cells| pDC plasmacytoid dendritic cells

Grant by Gilead for combination study in

HIV with lefitolimod

37

Aarhus University Hospital received 2.75 US$ from Gilead to fund clinical

study in HIV-positive patients on antiretroviral treatment (ART)

Evaluating combination of lefitolimod with novel virus-neutralizing

antibodies

Rationale for the study

Coordinated mode of action of the compounds could generate a more

effective attack and killing of the HIV reservoir compared to standard

HIV treatment regiments, i.e. ART

Promising potential for the combination of lefitolimod with virus-neutralizing

antibodies

New use of “kick-and-kill” concept with virus-neutralizing antibodies

Combination program: Phase I (ongoing)

lefitolimod (MGN1703) and ipilimumab (Yervoy®)

38

• Collaboration with MD Anderson Cancer Center, Texas, US

• First combination trial of lefitolimod (MGN1703) with checkpoint inhibitor,

commercially available ipilimumab (Yervoy®), manufactured by Bristol-Myers

Squibb Co.

• MD Anderson Cancer Center conducts the trial; MOLOGEN provides

lefitolimod (MGN1703) and funding for the trial

• Phase I trial in 50-60 patients with advanced solid malignancies, mainly

melanoma

The combination program explores further potential expansion of applications

of lefitolimod (MGN1703)

Study outline

• Open-label, single site, phase I trial

• Patients with advanced solid tumors

• Primary endpoints: Safety, toxicity, MTD, and DLTs of combination therapy; dose finding for phase 2

• Dose escalation part followed by three expansion cohorts:

• Dose escalation: Six lefitolimod dose levels (3.75 – 120 mg) with up to 6 patients per dose level to find MTD;

• Once MTD is determined, patients will be enrolled in three expansion cohorts (5-12 patients each) at this dose to further define this dose and to help determine biological endpoints.

• Expansion Cohorts (Malignancy / Variable): (1) Melanoma / lefitolimod SC; (2) Melanoma / lefitolimod IT; (3) Advanced malignant diseases / recent radiation to tumor

Treatment Course

• Lefitolimod (MGN1703) administered weekly, SC (dose escalation and 2 expansion cohorts) or IT (one expansion cohort)

• ipilimumab always administered at 3mg/kg IV every 3 weeks

• Patients will receive treatment for 4 cycles – a total of 12 weeks

• Treatment will be discontinued in case of disease progression

• If patients demonstrate stable disease or a response, they will be eligible to continue to receive lefitolimod for up to a year

39

Combination trial:

Lefitolimod (MGN1703) and ipilimumab (Yervoy®)

Legend: MTD maximum tolerated dose | DLT dose limiting toxicities | SC subcutaneous | IT intratumoral | IV intravenous

Break-through potential for combinations of

lefitolimod with checkpoint inhibitors (CPI)

40

First preclinical confirmation of the combination approach of lefitolimod with

checkpoint inhibitors in treatment of cancer

The mode of action of lefitolimod is ideally suited to enhance the anti-tumor

effect of checkpoint inhibitors

This was confirmed in mouse tumor models where lefitolimod clearly

improved the anti-tumor effect of checkpoint inhibitors anti-PD-1 and anti-

PD-L1:

Combination of lefitolimod and anti-PD-1 was superior to each

monotherapeutic approach which was also in line with ‘in vitro’

experiments

The combination of lefitolimod with anti-PD-L1 further reduced tumor

growth compared to either lefitolimod or anti-PD-L1 monotherapy and

thus prolonged survival

Promising potential for the combination of lefitolimod with checkpoint

inhibitors

mCRC program: Phase II (completed)

IMPACT study design

41


*at investigators’ discretion

Maintenance

Induction CT

4.5-6 months

mCRC patients

treated first-line

with FOLFOX /

XELOX or FOLFIRI

+/- bevacizumab*

At least

SD

Experimental Group:

60mg lefitolimod (MGN1703)

twice weekly s.c.

No maintenance

Placebo

Twice weekly s.c.

Screening / Randomization

2:1

PD**

PD**

** Treatment

after PD at

investigators’

discretion

• Primary endpoint: progression-free survival

• Double-blind, randomized, placebo-controlled, two-arm, multinational

phase II trial with 59 mCRC patients

• Start: June 2010

• Primary completion date: February 2013

Legend: CEA carcinoembryonic antigen - a tumor marker for colorectal cancer | CT chemotherapy | mCRC metastatic colorectal cancer | NKT natural

killer T cells | PD progressive disease | s.c. subcutaneous injection | SD stable disease

4 progression-free patients

still on treatment at end of study


primary endpoint suggests efficacy

42

• PFS from start of maintenance (local assessment)

• ~ 10% long-term responders

Legend: CI confidence interval | HR hazard ratio | mPFS median progression-free survival

Final results MARCH 2013

MGN1703

(n=43)

Placebo

(n=16)

mPFS

[95% CI]

2.8 months

[2.8-4.1]

2.6 months

[2.5-2.8]

HR=0.55 [95% CI: 0.3-1.0]


IMPACT key take-aways (1/2)

43

• Primary endpoint met:

– progression free survival (HR 0.55, p= 0.04)

• Secondary endpoint “Overall Survival“:

– median OS 22.6 months (lefitolimod (MGN1703)) vs. 15.1 months (p=ns),

– in subgroup (relevant patients for phase III: responders (PR, CR) to induction

chemotherapy):

median OS 24.5 months (lefitolimod (MGN1703)) vs. 15.1 months (p=0.069)

• Predictive biomarkers identified:

– tumor reduction by induction therapy

– normalized CEA level

– presence of activated NKTs

Legend: CEA carcinoembryonic antigen - a tumor marker for colorectal cancer | HR Hazard Ratio | NKT Natural Killer T cells | ns not significant


IMPACT key take-aways (2/2)

44

• Long-term treatment with lefitolimod

– Follow-up of four patients who continued MGN1703 monotherapy in

compassionate use programs since no relapse at end of study:

• 3 patients progression-free in excess of 58 months as of June 2016

• Excellent safety and tolerability, also when treated long-term

Legend: CEA carcinoembryonic antigen - a tumor marker for colorectal cancer | HR Hazard Ratio | NKT Natural Killer T cells | ns not significant

Findings from subgroup analyses were used to optimize the phase III

study design


IMPACT sustained efficacy

45

April 2010: Patient 049 – Initial diagnosis

• Colon carcinoma with multiple liver metastases

December 2010: After induction chemotherapy

• 06/2010 - 11/2010: 9 courses of CT (FOLFIRI) +

bevacizumab (biologic)

• 12/2010: Response to induction CT: PR*

March 2015: Under maintenance therapy

• Since 12/2010: Lefitolimod (MGN1703) maintenance

therapy

• New PR(1) after 9 months

• Still ongoing PR

• Good medical condition, mild local skin reactions, no

further severe toxicities

Legend: CT chemotherapy | PR partial response • Note: (1) Confirmed by two independent radiologists

Competitive landscape oncology (1)

46 Note: (1) Mostly in mCRC; limited competing developments in SCLC Legend: mCRC metastatic colorectal cancer I SCLC small cell lung cancer I

Mab monoclonal antibodies

Today

mCRC SCLC

• Chemotherapy

(FOLFOX,

FOLFIRI)

+ biologicals

(“Mab”: anti-

VGEF or anti-

EGFR)

• Chemotherapy

Future

Various approaches in trials (examples)1

• Checkpoint inhibitors

(CTLA4, PD1, PD-L1, …)

• TLR agonists

• Cell therapies

• Vaccines (tumor cell or antigen

based)

Indication-specific competition first-line mCRC & SCLC

Lefitolimod has potential to differentiate by long-term efficacy, good

tolerability, and high safety

47

• Lefitolimod is the sole TLR9 agonist in phase III development in oncology, with

human use safety established and efficacy supported by a significant base of

~400 patients treated

Source: EvaluatePharma, company websites, clinicaltrials.gov; Jan 2017 I NHL non-Hodgkin’s lymphoma

Company Compound Monotherapy Combination

Mologen (GER) Lefitolimod PhIII mCRC, phII SCLC PhI w. ipilimumab in solid tumours

Dynavax (US) SD-101 PhI/II NHL PhIb/II w. pembrolizumab in melanoma

PhI/II w. ipilimumab in B-cell lymphoma

PhIb/II w. ibrutinib in follicular lymphoma

PhI w. MK-1966 in advanced malignancies

Idera (US) IMO-2125 PhII melanoma PhI/II w. ipilimumab in melanoma

Checkmate (US) CMP-001 n/a PhI w. pembrolizumab in aPD1-refractory

melanoma

Innate (FR) MIS416 Preclinical n/a

• Index, Sweden: Kappaproct, is the sole other TLR9 in phase III development across

indications, however in ulcerative colitis with no disclosed development in oncology

– BiolineRX, Israel: BL-7040 is in phase II against ulcerative colitis & in phase II

against IBD

Competitive landscape oncology (2) –

TLR9 agonists across indications

MGN1601: Therapeutic cancer vaccine:

Shipped off the shelf

48

MGN1601:

Cell-based cancer vaccination available off the shelf

49

Either single or small number of tumor

antigens as peptides, loaded dendritic

cells, or clonally selected cell lines; HLA-

restricted response selects against tumors

not expressing the antigen(s), and thereby

driving immune evasion of the tumor

Introduced tumor antigens may not be

processed & presented in a natural way

Long and challenging manufacturing

process of autologous approaches,

individually for each patient

Only moderately immunogenic vaccines

(clonal tumor cells, “loaded” dendritic

cells), lacking sufficient co-stimulatory

signals, use of weak adjuvants

Improved properties to conventional cell-based cancer vaccination strategies

Not clonally selected, allogeneic tumor

cell line presents an abundance of broadly

recognized key tumor antigens, thereby

preventing immune evasion

Unique, allogeneic tumor cell line with

naturally processed and presented

antigens

GMP-production process in place, batch

production and storage established,

off the shelf shipment

First 4-fold gene-modified cell-based

vaccine expressing co-stimulators (CD80,

CD40L) and cytokines, (GM-CSF, IL-7) to

enhance immune recognition, potent TLR9

agonist reactivates immune surveillance

Limitations of previous

cell-based cancer vaccines

Solution provided by the

MGN1601 tumor vaccine

ASET Trial with MGN1601:

Promising data

50

Phase I/II study (12/2010 – 08/2013)

• Open-label, proof-of-principle, multi-center phase I/II trail

• 19 patients with advanced renal cell carcinoma who failed prior systemic

therapies

• Primary endpoint met: Favorable safety and tolerability profile

• Promising overall survival data in subgroup of patients

• Improved function in patient‘s immune cells

• Identification of potential biomarkers

ASET trial with MGN1601:

Study design

51

TPP Extension phase

Patients

with

advanced

renal cell

cancer

No

standard

therapy

available

Trial

inclusion

8 applications

of MGN1601

in 12

weeks i.d.

DC

Max. 5

applications in

week 24, 36, 48,

72 and 120


SD PD**

PD**

** Treatment

after PD at

investigators

discretion 8 applications

of MGN1601

in 12

weeks i.d.

• Primary endpoints met: safety and tolerability

• Open-label, proof-of-principle, multi-center phase I/II trial

• 19 patients with advanced renal cell carcinoma who failed prior systemic therapies

• Orphan drug designation from EMA

• Start: December 2010 – primary completion date: August 2013

Legend: SD Stable disease | EMA European Medicines Agency | i.d. intradermal injection | PD progressive disease | TPP Treatment per protocol


Study results (1/2)

52

• Overall survival benefit

– ITT group (19 patients): all patients who received at least one vaccination

– PP group (10 patients): patients received eight vaccinations within twelve weeks

as planned

– Non-PP group (9 patients): patients dropped out before finalizing the 12 weeks

course of treatment

Legend: ITT intent-to-treat | OS overall survival | PP (treatment) per-protocol

53

• Median OS:

– 24.8 weeks (ITT group) vs. 115.3 weeks (PP group)

• Potential biomarker identified:

– MSKCC Score & NLR may have predictive value for longer overall survival (OS)

– First evidence of cytotoxic antitumor immune response after MGN1601

vaccination (in patient subgroup)

– Significant improvement of cellular immune function during treatment (in patient

subgroup)

• Two patients had no progression after 12 weeks and continued treatment:

– One patient with stable disease progressed after 48 weeks

– One patient had sustained partial response for over 120 weeks


Study results (2/2)

Legend: MSKCC Memorial Sloan–Kettering Cancer Center | NLR neutrophil-lymphocyte ratio | OS overall survival

Quarterly Key Financials

54

[in €

million]

Q3

2016

Q2

2016

Q1

2016

Q4

2015

Q3

2015

Q2

2015

Q1

2015

Q4

2014

Q3

2014

Q2

2014

Q1

2014 2015 2014

R&D

expenses 3.5 3.4 3.7 6.4 5.2 2.8 2.4 2.8 4.6 3.0 2.9 16.8 13.3

EBIT -4.5 -5.3 -4.5 -7.2 -6.4 -3.7 -3.2 -3.8 -5.4 -3.8 -4.1 -20.5 -17.1

CF from

operating

activities

-4.7 -4.8 -4.4 -6.1 -4.3 -2.5 -2.2 -4.1 -5.0 -3.3 -3.2 -15.1 -15.6

CF from

financing

activities

-0.5 0.0 0.0 0.1 0.0 26.8 -0.7 -0.2 - -0.1 14.8 26.2 14.5

Monthly

cash

burn

1.7 1.6 1.5 2.0 1.5 1.4 1.0 1.4 1.7 1.1 1.4 1.4 1.4

COMPANY PRESENTATION FEBRUARY 2017

www.mologen.com

COMPANY PRESENTATION - MOLOGEN AG · the market • Lefitolimod uniquely positioned as potential...

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