• No results found

BY PEOPLE. WITH PEOPLE. FOR PEOPLE. 4SC COMPANY PRESENTATION AMSTERDAM 1 APRIL 2014

N/A
N/A
Protected

Academic year: 2021

Share "BY PEOPLE. WITH PEOPLE. FOR PEOPLE. 4SC COMPANY PRESENTATION AMSTERDAM 1 APRIL 2014"

Copied!
32
0
0

Loading.... (view fulltext now)

Full text

(1)

APRIL 2014

BY PEOPLE. WITH PEOPLE. FOR PEOPLE.

*

Epigenetics: Each and every human cell contains specific genetic information. What happens to a cell is determined by the way this information is processed. Epigenetics is the key to controlling this process. 4SC is one of the pioneers in this field of science. We develop epigenetic anti-cancer drugs.

4SC

COMPANY PRESENTATION

AMSTERDAM

(2)

FORWARD LOOKING STATEMENTS

The information contained in this presentation includes forward-looking statements. Any forward-looking statement applies only on the date of this presentation. By their nature, forward-looking statements are subject to a number of known and unknown risks and uncertainties that may or may not occur in the future and as a result of which the actual results and performance may differ substantially from the expected future results or performance expressed or implied in the forward looking statements. No warranties or representations are made as to the accuracy, achievement or

reasonableness of such statements, estimates or projections, and 4SC AG has no obligation to update any such

information or to correct any inaccuracies or omission which may become apparent. Neither 4SC nor the management, the directors, employees, agents or advisers of 4SC make any representation or warranty, expressed or implied as to the accuracy or completeness of the information contained in this presentation, and nothing contained herein is, or shall be relied upon as, a promise or representation, whether as to the past or the future.

This presentation does not constitute an offer or invitation for the sale of securities of 4SC AG or any interest therein in any jurisdiction and is not intended to provide the basis for any credit, investment or other evaluation or decision.

Important information for the United States: This presentation is only being made available to interested parties on the basis that: (A) if they are United States persons, they are “accredited investors” as defined under Rule 501(a)

promulgated under the United States Securities Act of 1933, as amended; or (B) they are outside the United States (all such person collectively being referred to as “Relevant Persons”). By accepting this document you represent and warrant that you are such a person. This presentation must not be acted on or relied on, and should be returned to 4SC AG, by persons who are not Relevant Persons. Any investment or investment activity to which this presentation relates is available only to Relevant Persons and will be engaged only with Relevant Persons.

(3)

APRIL 2014

OUR VISION – DEVELOP RESMINOSTAT TOWARDS

APPROVAL IN BLOCKBUSTER INDICATION HCC

3

OUR VISION FOR

RESMINOSTAT

Blockbuster potential

in 1

st

and 2

nd

line HCC

(potential peak sales

of > €1 billion)

Promising Phase IIa

efficacy & biomarker

data

Phase II programme

currently in

preparation, to be

followed by Phase III

Phase I/II trial by

Yakult in 1

st

line HCC

in Japan underway

(started May 2013)

MARKET

APPROVAL

DEADLY DISEASE

3

rd

leading cause of cancer-related mortality

 ~700,000 deaths/year

NEXAVAR: ONLY TREATMENT

Only one approved 1

st

-line therapy for

advanced HCC: Sorafenib (Nexavar

®

)

HIGH NEED:

1

ST

& 2

ND

LINE TREATMENT

No approved 2

nd

-line therapy

LIVER

CANCER

(4)

COMMERCIALISATION &

VALUE GENERATION

4SC CORPORATE STRUCTURE & BUSINESS MODEL

4SC GROUP CORPORATE STRUCTURE

4SC AG

Key focus on developing epigenetic

cancer therapies towards the market

4SC Discovery GmbH

Commercialising early-stage

drug discovery in epigenetics, cancer

stem cells and inflammation

Pharma partnerships:

 Joint development towards approval

 Upfront payments

 Milestone payments

 Royalties

Discovery Partnerships:

 Upfront, milestone & royalty payments from early partnering deals

 Constant revenue from research collaborations

 Replenishing 4SC‘s clinical pipeline

 Financing contribution through

revenues from service collaborations

 Long-term value generation from early-stage pharma partnerships

(5)

APRIL 2014 5

STRONG FUNDAMENTAL MARKET DRIVERS FOR 4SC

HIGH MEDICAL NEED AND LARGE MARKET POTENTIAL CHALLENGES FOR BIG PHARMA

 Urgent need for new drugs to compensate for sales reductions due to patent ends

 Massive R&D spending cuts offer chances for research-orientied biotechs to fill the gap

CANCER

 Global oncology market to grow from

today US$ 60 bn to US$ 88 bn in 2016 (IMS Health)

 Blockbuster indication liver cancer (HCC)

AUTOIMMUNE DISEASES

 IBD (Crohn‘s disease & ulcerative colitis): 4 mn patients are expected by 2016 worldwide. Very limited treatment options available.

MEGATREND PERSONALISED MEDICINE MEGATREND EPIGENETICS

 Epigenetics: linking the genotype with the phenotype

 GEN (Oct. 15, 2012): Market for epigenetic cancer drugs expected to grow from US$ 800 mn (2011) to US$ 8 bn (2017)

 Selection and stratification of patients with a

particular benefit from a certain therapy, according to certain genes or biomarkers

 Increasing demand from regulatory authorities, health insurers, and pharma companies

* Source: (Jennifer Cropley, Victor Yang, Cardiac Research Institute)

(6)

Product Indication Research Preclinical Phase I Phase II Phase III Partner ONCOLOGY

Resminostat Hepatocellular Carcinoma (HCC) (Western)

Resminostat HCC (Asia) *

Resminostat Hodgkin’s Lymphoma (HL)

Resminostat Colorectal Cancer (CRC)

Resminostat Solid Tumours *

Resminostat Non-small-cell lung cancer (NSCLC) *

4SC-202 Haematological Tumours

4SC-205 Solid Tumours

AUTOIMMUNE AND INFLAMMATION Vidofludimus Inflammatory Bowel

Disease (IBD)

1st line HCC programme in preparation

Complete Phase I studies, for later partnering / Phase II

Seek external part-ner for Phase IIb

Key Focus

*) Study performed by Yakult Honsha in Japan

EARLY-STAGE DRUG DISCOVERY COLLABORATIONS & PARTNERSHIPS BY 4SC DISCOVERY INCLUDING

Study completed

AN ATTRACTIVE VALUE-FOCUSED CLINICAL PIPELINE

(7)

APRIL 2014

:: BY PEOPLE. WITH PEOPLE. FOR PEOPLE

7

RESMINOSTAT

(8)

RESMINOSTAT

RESMINOSTAT: YAKULT HONSHA DEAL FOR JAPAN

Yakult Honsha is a leader in gastro-intestinal oncology in Japan, spearheaded by

blockbusters irinotecan and oxaliplatin.

Japanese oncology market accounts for c. 10-12% of global oncology market

Upfront payment of €6m Up to €127m in milestone payments Double-digit royalties linked to product sales

(9)

APRIL 2014

5

th

most common cancer disease worldwide

3

rd

leading cause of cancer-related mortality (~700,000 deaths/year)

High unmet medical need

Only 1 approved 1

st

line therapy for advanced HCC: Sorafenib (Nexavar

®

)

No approved 2

nd

line therapy for advanced HCC

Blockbuster indication

ESTIMATED NEW LIVER CANCER CASES

(TOP 29 w/o Japan)

Source: Globocan

EXPECTED HCC MARKET DEVELOPMENT

(w/o China)

Source: Data Monitor

9

RESMINOSTAT –

LARGE OPPORTUNITY IN LIVER CANCER (HCC) MARKET

606 T 637 T 719 T

809 T 904 T

1000 T

2008 2010 2015 2020 2025 2030

4SC expects peak sales potential of > €1 billion for resminostat in 1

st

and 2

nd

line HCC

The combined value of hepatocellular cancer

(HCC) drugs in the US, Japan and five major EU markets will peak at $1.4bn in 2019.

2012 2013 2014 2015 2016 2017 2018 2019

(10)

THERAPEUTIC EFFECTS THROUGH COMBINATION WITH STANDARD CANCER THERAPIES4

KREBSMEDIKAMENTEN RESISTENT

MONOTHERAPEUTIC EFFECTS

RESMINOSTAT MODE OF ACTION:

MULTIPLE WAYS OF EPIGENETIC HCC TARGETING

Epigenetic (Re)Programming

Induction of growth arrest, apoptosis1

Inhibition of key tumour signalling pathways (e.g. NOTCH, WNT)

Inhibition of EMT, metastasis, tumour progression, stemness2,3

HCC cells

1 Mandl-Weber et al., Br.J.Haematol.2010;149:518-28; 2 van Zijl et al., 2009; 3 van Malenstein et al., 2012; 4 Sharma et al.,2010

SENSITIVE TOLERANT Epigenetic modifications (reversible) HDAC inhibition via resminostat Genetic alterations Irreversibel Resminostat Reversible Standard cancer drugs

Various Mutations

Resminostat targets HCC through inhibition of tumour progression & metastasis

1,2,3

as well

(11)

APRIL 2014

BSC

11

Sorafenib

4.7 months

Standard

Treatment:

Sorafenib

(1st line)

1

Resminostat

/

Sorafenib

Combination

(2nd line)

2

1 SHARP STUDY: Llovet et al., 2008; 2 SHELTER STUDY: Bitzer et al., ILCA 2012

BSC

8.1 months survival

after first progression2

+2.9 Months Resminostat 2nd line overall survival benefit

Placebo + Best Supportive Care (BSC)

Placebo

(1st line)

1

Sorafenib

Resminostat

+ Sorafenib

10.7 Months Overall Survival 7.9 Months Overall Survival

5.5 months until disease progression under 1st

line sorafenib 1

Cumulated 13.6 Months Overall Survival

RESMINOSTAT: SIGNIFICANT SURVIVAL BENEFIT OVER

STANDARD OF CARE IN 2

ND

LINE HCC INDICATED

+2.7 Months Sorafenib 1st line overall survival benefit

Resminostat stabilises the disease and prolongs overall survival of second-line HCC

patients by approximately 3 months compared to standard of care.

(12)

NICD

NOTCH

ZFP64 Nuclear membrane b-Catenin TCF/LEF

HEDGEHOG

GLI GLI

WNT

Cell membrane b-Catenin

Wnt

Resminostat 4SC-202 4SC-202 Resminostat 4SC-202 Resminostat 4SC-202

TARGETED REPROGRAMMING OF CANCER BY

EPIGE-NETIC DISRUPTION OF MAJOR CANCER NETWORKS

HH

TCF/LEF

Biomarker ZFP64

down regulated

by resminostat

Several pathways control cell proliferation & migration (EMT), angiogenesis, metastasis,

AND cancer stemness

(13)

APRIL 2014

Baseline ZFP64 gene expression split –

HIGH vs. LOW expression

PERSONALISED MEDICINE: BIOMARKER ZFP64 INDICATIVE

OF DOUBLING OVERALL SURVIVAL IN HCC & HL

13

PHASE II SHELTER STUDY IN HCC (n=31) PHASE II SAPHIRE STUDY IN HL (n=30)

 Split: 65% high / 35% low ZFP64 expression

 Split: 60% high / 40% low ZFP64 expression

relative ZFP64 expression low high p = 0.04 relative ZFP64 expression low high p = 0.04

High baseline ZFP64 expression in blood samples is indicative of doubling overall survival

with resminostat.

(14)

UPCOMING VALUE INFLECTION POINTS

FOCUS ON HCC 1

ST

LINE TREATMENT

Performing a stepwise HCC 1

st

line clinical development offers ideal starting point for risk

adjusted phase III with already validated biomarker ZFP64

2014 2015 2016 2017 2018 2019 2020

1st line HCC

Market Approval Phase II 1st line HCC,

placebo controlled, randomized

Phase III 1st line HCC

EU and US Full biomarker validation (ZFP64, DCP) IND, CMC Phase I/II , ~140 pts, TTP Japan, Korea, randomized

Phase III , OS Japan/Asia

Active, recruiting

(15)

APRIL 2014

HEMATOLOGY

UROLOGY

OTHER MAJOR

INDICATIONS

GASTRO-ENTEROLOGY

RESMINOSTAT: TARGETING CANCER BROADLY

Hepatocellular

(ZFP64 high)

Phase IIa completed1

Phase II/III in preparation1

Phase I/II (Yakult)1

Esophagus

Stomach

Colorectal

Phase I completed2

Hodgkin‘s Lymphoma

(ZFP64 high)

NHL

Phase IIa completed3

Prostate

Bladder

NSCLC

Breast

Phase I/II (Yakult)4

Scientific rationale and preclincal data support development of resminostat in combination

therapy with classical cancer drugs in a broad variety of potential cancer indications.

15 1 combination with sorafenib; 2 combination with FOLFIRI; 3 monotherapy; 4 combination with docetaxel

(16)

:: BY PEOPLE. WITH PEOPLE. FOR PEOPLE

NEXT GENERATION CLINICAL PROGRAMMES

4SC-202:

selective HDAC inhibitor targeting WNT & HH

4SC-205:

oral EG5 inhibitor

Vidofludimus:

(17)

APRIL 2014

Next generation epigenetic in clinical development

Selective inhibitor of LSD1 (KDM1A), HDAC1, 2 and 3 modulating WNT & Hedgehog (HH) pathways

Oral available small molecule inhibitor

Currently in clinical hematologic phase I TOPAS trial

Treatment of cancer stem cells offer opportunities for all kinds of

Combination therapies

Adjuvant and neo-adjuvant therapy

Attractive clinical potential in various haematological & solid tumours going forward

Targeting long-term survival and quality of life of cancer patients

17

4SC-202 – NOVEL EPIGENETIC APPROACH

TARGETING CANCER STEM CELLS

Conventional

Chemotherapy / Radiation

Long-term clinical

benefit and

improved OS

4SC-202 treatment

(18)

EPIGENETIC CANCER CANDIDATE 4SC-202: COMPLETE

RESPONSE SEEN IN CURRENT PHASE I STUDY

PATIENT, AT ENTRY PATIENT, AFTER 6 WEEKS OF TREATMENT

 Promising clinical efficacy signals seen in preliminary Phase I data (complete response in AITL patient)

 Good PK properties, biomarker response seen already at low doses, safe and well tolerated

 Data of current Phase I study in haematological tumours expected in H1 2014

P ati en t : m al e, born 1943 , angi oi m m unob last ic T -cel l ly m phom a

(19)

APRIL 2014 19

4SC-205 – A NOVEL ORAL ANTI-MITOTIC DRUG IN

PHASE I PROGRAMME IN SOLID TUMOURS

Valentine, Fordyce and Block, Cell Division 1:31 (2006)

Monoaster formation upon Eg5 inhibition

Overview

4SC-205: small molecule Eg5 inhibitor and the only orally

administered Eg5 inhibitor in clinical development

Potentially a break-through for antimitotic cancer treatments

About EG5 – a promising cancer target

Kinesin Eg5 motor protein is essential for separation of

spindle poles during mitosis

It is exclusively expressed during mitosis in dividing cells

Side efects (e.g. peripheral neuropathies) as seen with other

spindle targeting drugs (taxols) not expected for Eg5 inhibition

Current clinical development status

Phase I “AEGIS“ study (data expected in mid 2014)

Safe and well tolerated to date with excellent PK properties

Amended for testing of a new innovative treatment schedule

(20)

Oral, once daily tablet

Mode of action

Targeted therapy

– strong IL-17 (IL-17A & F)

and IFN-gamma cytokine suppression

Validated

– inhibition of DHODH

Strong preclinical data in MS, lupus,

psoriasis, transplant rejection etc.

Strong clinical Phase IIa data in lead indication

IBD (Crohn’s disease, ulcerative colitis)

• Clean safety & tolerability

• Encouraging activity: 88.5% response rate

IBD: high market potential & medical need:

• Market forecast to grow: $ 5.7 bn. by 2019

• Patient population forecasted 4 million by 2016

Currently seeking project & financing partner for further external development

• Planned next step: Start Phase IIb study in Crohn’s disease

DUAL MODE OF ACTION OF VIDOFLUDIMUS (4SC-101)

VIDOFLUDIMUS: TARGETED IMMUNE MODULATOR IN

(21)

APRIL 2014 21

4SC DISCOVERY GMBH

Commercialisation of early-stage research as a

financing contribution and for long-term value creation

: : BY PEOPLE. WITH PEOPLE. FOR PEOPLE.
(22)

COMMERCIALISE EARLY-STAGE R&D AS A FINANCING CONTRIBUTION TO 4SC GROUP AND FOR LONG-TERM VALUE CREATION

Pharmacology Biology Medicinal chemistry Computational chemistry X-ray crystallography In vitro screening In silico screening

ALL CRUCIAL DISCOVERY STEPS IN HOUSE

KEY FACTS

4SC DISCOVERY – AT A GLANCE

 Fully-owned subsidiary of 4SC AG

 Start of operations in 2012

 26 researchers

 strategic alliance with CRELUX GmbH, Munich

is aiming to be a leading partner of pharmaceutical industry for innovative drug discovery in the fields of epigenetics, cancer stem cells and inflammation.

 Early-stage partnering deals with biotech & pharma for co-development and commercialisation of own discovery assets

 Research collaborations with biotech & pharma

(23)

APRIL 2014

4SC DISCOVERY: STRONG TRACK RECORD

23

STRONG DISCOVERY AND

PARTNERING TRACK RECORD

APRIL 2012

Formed “i2c” - a strategic partnership for structure based drug discovery with CRELUX

Research collaboration with Henkel

NOVEMBER 2013

Research collaboration with AiCuris

DECEMBER 2012 / JANUARY 2013

Licencing deal with BioNTech in cancer immune therapy

(€2.5m upfront payment, further milestone potential plus royalties)

Broad research collaboration in oncology

SEPTEMBER 2013

Partnership with Panoptes for autoimmune uveitis incl. equity stake

FEBRUARY 2013

Exclusive licence option agreement with LEO Pharma for psoriasis

(€1m upfront payment, €95 m milestone potential plus royalties) JUNE 2013

(24)

4SC DISCOVERY: LEO PHARMA LICENSE (OPTION)

DEAL & RESEARCH COLLABORATION IN PSORIASIS

PSORIASIS

Upfront payment €1m Up to €95m in milestone payments Up to double-digit royalties based on product sales

Leo Pharma S/A (Denmark) is a leading specialty pharma player specialised in dermatology.

Both companies will co-develop 4SC discovery’s cytokine modulation programme as a

novel potential breakthrough therapy in psoriasis.

(25)

APRIL 2014 25

FINANCIAL OVERVIEW

(26)

IN M €

KEY FINANCIAL FIGURES AND CASH REACH

4.9 -10.5 -7.2 4.9 17.7 4.4 -13.2 -15.1 12.1 29.1

Revenue Profit/loss for the period

Operative Cashburn Funds Balance sheet total

2013 2012

2013

Revenue increased by 13% year-on-year

Costs decreased

Operating result considerably improved

Cash Burn significantly reduced

Funds: 4.9 m € (31 Dec. 2013)

Average cash burn 2013 reduced by 50%

to 0.6 m€ / month; expected to decrease

further in 2014 (not including new clinical

trials)

Cash reach through the next 12 months

secured (as of 26 March 2014)*

(27)

APRIL 2014

SHARE AND SHAREHOLDERS‘ STRUCTURE*

27

Ø NUMBER OF SHARES TRADED PER DAY

XETRA ALL ** 2010 10,050 14,449 2011 26,307 43,221 2012 30,434 56,713 2013 18,179 37,060 2014 (YTD 21 March 2014) 29,909 65,204

ANALYSTS DATE TARGET PRICE / RECOMMENDATION

Edison 14.11.2013 2.41 €

equinet 07.11.2013 3.60 € (BUY) Kempen 09.01.2014 1.60 € (HOLD)

* Based on management estimates ** All German exchanges plus Tradegate

 Prime Standard Listing (FSE:VSC)

 No. of shares outstanding: 50,408,654 (26 Mar. 2014)

 “Free Float“ acc. to Deutsche Börse: 30.3%

 Backing by family offices and experienced life science investors SHAREHOLDERS in % Others: 24.7 Founders & MGMT: 1.2 Santo Holding: 48.1 Roland Oetker: 4.2 Heidelberg Capital: 5.9 FCP: 9.6 DVCG / VCG: 6.1

12 Feb 2014: Convertible notes agreement with Yorkville for up to 15 m € nominally until 31 Dec. 2016

(28)

REACHED AND UPCOMING VALUE INFLECTING

MILESTONES

ATTRACTIVE GOALS AHEAD

 Execute further development of resminostat towards the market in 1st line HCC (discuss planned

development plan with authorities; ensure funding; initiate study)

 Yakult Phase I/II efficacy data with resminostat in 1st line HCC (Japan)

 Secure external financing for planned Phase IIb trial with vidofludimus in IBD

MILESTONES REACHED 2013

 Complete Phase II resminostat HCC

 Start Japanese resminostat Phase I/II in 1st line HCC (by Yakult)

 Start Japanese resminostat 2nd/3rd line NSCLC (by Yakult)

 Complete Phase I resminostat in CRC

 Detailed biomarker data resminostat HL & HCC

 4SC Discovery: service deals & early-stage partnering deals

UPCOMING MILESTONES 2014  Complete Phase I 4SC-202 in haematologic tumours  Complete Phase I 4SC-205 in solid tumours

 Complete Phase I resminostat in solid tumours (in Japan by Yakult)

 Further partnerships of 4SC Discovery

(29)

APRIL 2014

4SC INVESTMENT CASE - STRATEGY TO A MATURING

COMPANY CREATING LONG-TERM VALUE FOR INVESTORS

Strengthen

Partnering Base

Leverage

Early-Stage R&D

Biomarker-driven development of

resminostat towards market

approval in advanced HCC

Development of remaining 4SC

portfolio towards next major clinical

value inflection points

Establish partnerships for

co-development & commercialisation

of clinical assets

Augment deal track record with big

pharma/biotech partners

Commercialise 4SC Discovery

products through collaborative

business and licensing deals

Provide pharma partners and 4SC

AG with development candidates

Increase

Product Value

Becoming an

established

pharma partner

for innovative

drugs in

cancer and

immunology

1 2 3 29
(30)

THANK YOU VERY MUCH !

::

:: BY PEOPLE. WITH PEOPLE. FOR PEOPLE

CONTACT

Enno Spillner, CEO & CFO

enno.spillner@4sc.com

Jochen Orlowski, Head of CC & IR

jochen.orlowski@4sc.com

(31)

APRIL 2014

Attractive business model

 Discovery & development of novel small molecule drugs for unmet medical needs

 Growth through clinical stage partnering

 Attractive deal flow, revenue and value generation though early R&D and discovery collaborations

Corporate structure

 Integrated clinical development (4SC AG) and drug discovery (4SC Discovery GmbH) organisation

 56 FTEs (31 Dec. 2013)

 Headquartered in Munich/Germany

 Founded in 1997

Top technologies, products & markets

 A leader in epigenetic cancer therapies

 Attractive pipeline with four compounds in clinical Phases I & II

 Lead compound resminostat in preparation of late stage programme in liver cancer (peak sales potential > €1 bn.)

Finance & Shares

 Market cap ~ 69 m € (26 March 2014)

 Prime Standard Listing (FSE:VSC)

 50,408,654 shares outstanding (26 March 2014)

 Convertible note agreement with Yorkville as of 12 Feb. 2014 for up to 15 m € nominally

 Committed investor base

4SC AT A GLANCE – CORPORATE FACT SHEET

31

Novel targeted drugs for

cancer & autoimmune

diseases

(32)

4SC - FINANCIAL CALENDAR 2014

Event

Date

Annual Financial Report 2013

26 March 2014

3-Months Financial Report (Q1) 2014

8 May 2014

Annual General Meeting, Munich (Germany)

9 May 2014

Half-Year Financial Report (Q2) 2014

7 August 2014

9-Months Financial Report (Q3) 2014

6 November 2014

Analyst Conference, German Equity Forum,

Frankfurt/Main (Germany)

References

Related documents

For example, it was found that several adjacent WSR-88D sites near or along the Gulf coast between Louisiana and Florida exhibit a Precipitation Radar (PR) minus Ground Radar

The region of high mountains, including the symbol of Slovenia, Triglav, is almost entirely Alpine. A large part of this statistical region is protected as a national park. The

[r]

Student will clean the interior Instruct the students using the following procedures: of a refrigerator.. It is a good habit to clean a refrigerator thoroughly once a week, but

[r]

These findings highlight the presence of model minority stereotypes within a collegiate music school, a setting which little research concerning model minority stereotyping and

Zhang, “Magnetic Field Distribution Inside Metallic Grid-like Buildings Struck by Lightning Based on Finite Element Method,” international conference on lighnting

Comparative sequence analysis of the O139 O-antigen biosynthesis genes in the case 1 isolate showed that it was distinct from those within the O1 N16961 and O139 MO10 isolates,