Elsiglutide A GLP-2 agonist in development for the ... · Nimesulide Chemicals Others . 6 –Cancer Supportive Care –Niche Oncology Indications –Orphan Drugs –Pain / Inflammation

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Elsiglutide – A GLP-2 agonist in development for

the prevention of chemotherapy induced diarrhea:

Status and outlook

Alex Monteith, MBA

Business Development, Helsinn Therapeutics

New York City, November 29th, 2012

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Helsinn

Company Overview

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Overview and Mission

● Privately owned, third generation, Swiss-based Group founded in 1976, with 35 years of commercial success in 87 countries.

● Helsinn in-licenses, finances, develops, manufactures, registers, distributes and supports the commercialization of innovative, value added pharmaceutical products and medical devices to improve patients’ health and quality of life, with more than 70% commercialization success rate.

● Strategic areas:

− Cancer Supportive Care

− Pain and Inflammation

− Gastroenterology.

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Financial and

development

risk bearing

a ready-to-sell product

FDA and Centralized EMA Registrations directly managed

Worldwide Development

directly managed

In House Chemical and Drug Product Development, Manufacturing,

logistics and supply

Acquiring product rights

for development

Post-marketing surveillance Global branding & marketing strategy

Post approval studies

Helsinn’s Business Approach

Commercial

Licensing out

pre/post launch support

regulatory affairs

product development &

CMC

pre & clinical development

Licensing in

Compound originator 4

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● 455 employees (277 in CH + 178 abroad) of which 22.2% in R&D

● Profitable, cash flow generative and well capitalized

● Turnover invested in R&D in the last 5 years approx. 21% (approx. 299 million CHF)

* Compound Annual Growth Rate

Helsinn’s 2011 Financial Highlights

Revenues Breakdown

By Region

Revenues CHF 300.2 million

5.92% CAGR* in last 5 years

Revenues EURO 243.9 million

14.14 % CAGR* in last 5 years

53%

23%

19%

5%

US

EU

Japan

RoW

73%

8%

8%

8% 3 % Palonosetron

Netupitant

Nimesulide

Chemicals

Others

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– Cancer Supportive Care

– Niche Oncology Indications

– Orphan Drugs

– Pain / Inflammation

– Gastrointestinal

Corporate Business Development Framework

& Licensing-in Strategy

CHEMOTHERAPY INDUCED DIARRHOEA

CACHEXIA, SARCOPENIA

ORAL MUCOSITIS

OPIOID INDUCED BOWEL DYSFUNCTION

HAND AND FOOT SYNDROME

BRAIN EDEMA

CANCER INDUCED PAIN

NUTRACEUTICALS

MEDICAL DEVICES / WOUND HEALING

PRE-COLONOSCOPY TREATMENT

OPIOID-INDUCED BOWEL DYSFUNCTION

NUTRACEUTICALS

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ALOXI® ONICIT® PALOXI®

Chemotherapy-Induced Nausea and Vomiting (CINV)

Post-Operative Nausea and Vomiting (PONV)

GELCLAIR®

Oral mucositis

KLEAN-PREP®

Bowel preparation prior to Colonoscopy and Surgery

NIMESULIDE

(eg. Aulin® Mesulid® Nimed® Nexen®)

Pain and Inflammation

OXAPROZIN

(Duraprox® Walix®)

Pain and Inflammation

DAXIBEQOL

Dietary Supplement Product

Helsinn’s Nutritional Supplements

Helsinn’s Commercialized Products

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10 167 264 273 269

400 458 542 606

0

500

1,000

1,500

2,000

2,500

3,000

2003 2004 2005 2006 2007 2008 2009 2010 2011

Mill

ion

s C

HF

Yearly Sales CHF Cumulative Sales CHF

( (CINV/PONV/ORAL)

WW Sales Data in CHF from September '03 to December '11

2,990 M

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Helsinn’s Main Partners Worldwide

Selected partners

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Helsinn R&D

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NETUPITANT-PALONOSETRON FDC* CINV**

ANAMORELIN NSCLC

cachexia/anorexia***

PALONOSETRON Paediatrics CINV**

ELSIGLUTIDE (ZP1846) Chemotherapy/Induced

Diarrhea

GHRELIN RECEPTOR AGONISTS Cancer Cachexia/Anorexia

IPAMORELIN Post-operative bowel

dysmotility

GHRELIN RECEPTOR ANTAGONISTS Obesity

GHRELIN RECEPTOR AGONISTS Multiple

NEW TARGET Multiple

Helsinn’s pipeline of products Development Pipeline

*NETUPITANT-PALONOSETRON Fixed Dose Combination

** Chemotherapy-Induceded Nausea and Vomiting

*** NSCLC cachexia/anorexia: Non-Small Cell Lung Cancer associated cachexia/anorexia

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EPIDEMIOLOGICAL STUDIES

Helsinn’s Product Development

Product development is vital to Helsinn. Research & Development projects 2010 – 2011

PAEDIATRIC STUDIES

PHASE IV CLINICAL TRIALS

PHASE III CLINICAL TRIALS

PHASE II CLINICAL TRIALS

PHASE I CLINICAL TRIALS

2,772 patients tested

931 clinical centers

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7

6

1

2

2

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Elsiglutide in

Chemotherapy-Induced

Diarrhea (CID)

A disease overview

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ELSIGLUTIDE – In Partnership With Zealand Pharma

Helsinn Healthcare

●Exclusive global rights to develop and commercialize elsiglutide as

a new treatment in the field of cancer supportive care

Zealand Pharma

●Up to EUR 140 (DKK 1,040) million in milestones (EUR 14 (DKK

104) million received) plus royalties on Helsinn’s global sales of

elsiglutide

●Option to obtain commercial rights for the Nordic countries

ZEALAND PHARMA/HELSINN HEALTHCARE LICENCE AGREEMENT

Pathophysiology of CID

No cells available to move up the villus

Villus atrophy (mucositis)

Disruption between absorption and secretion

Diarrhea

Stem cells

Proliferating daughter cells

Migrating daughter cells

Migrating cells move up the villus

Chemotherapeutics target and destroy

rapidly proliferating cells in the crypts

Pathophysiology of CID

Osmotic Secretory

Dysmotility Exudative

CID

NCI criteria for CID severity grading (CTCAE version 4,02)

Grade Criteria

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2

3

4

5

Increase of <4 stools daily over baseline

Mild increase in ostomy output as compared with baseline

Increase of 4-6 stools daily over baseline

Intravenous fluids indicated <24 hours

Moderate increase in ostomy output compared with baseline

Not interfering with activities of daily living

Increase of > 7 stools daily over baseline

Incontinence; intravenous fluids >24 hours

Hospitalization

Severe increase in ostomy output compared with baseline

Interfering with activities of daily living

Life-threatening consequences (e.g, hemodynamic collapse)

Death

Dranitsaris G. et al. Can J Gastroenterol 2005

Impact of CID on Subsequent Chemotherapy CRC patients receiving chemotherapy (adjuvant setting or metastatic disease)

N=63

Dose reduction only 9.5%

Treatment delay only 3.2%

Both dose reduction and delay 23.8%

Change in chemotherapy regimen 15.9%

Discontinuation of chemotherapy 34.2%

Median dose reduction, % (range) (n=21) 25 (10 to 80)

Median duration of delays, days (range) (n=17) 14 (7 to 35)

Grade of Diarrhea and Chemotherapy Regimen Changes

Arbuckle et al. The Oncologist 2000 5:250-259 (modified)

No change Dosing

delay Dosing

decrease Discontinue

therapy 2 or more

changes

N n % n % n % n % n %

Grade 1 24 21 87.5% 1 4.2% 0 0.0% 2 8.3% 0 0.0%

Grade 2 24 16 66.7% 4 16.7% 2 8.3% 2 8.3% 0 0.0%

Grade 3 22 3 13.6% 3 13.6% 11 50.0% 2 9.1% 3 13.6%

Grade 4 30 4 13.3% 0 0.0% 9 30.0% 9 30.0% 8 26.7%

CID: Hospitalization and Supportive Care CRC patients receiving chemotherapy (adjuvant setting or metastatic disease)

Dranitsaris G. et al. Can J Gastroenterol 2005

N=63

Hospital admission 100%

Median Length of Stay, days (range) 8 (1 to 49)

Parenteral support 87.3%

Median days IV fluids, (range) 3 (1 to 24)

Antibiotics adimistered 79%

Frequency of CID with first-line Chemotherapy in

patients with metastatic CRC

Regimen Reference N All Grades Grades 3-4

FOLFOX-4 Cassidy J, et al. J Clin Oncol 2008; 26:2006-2012 649 62% 12%

FOLFOX-4 Colucci G, et al. J Clin Oncol 2005; 23:4866-4875. 182 46% 5%

FOLFOX-6 Ducreux M, et al. Int J Cancer 2011; 128:682-690 149 57% 7%

FOLFOX-6 World J Gastroenterol 2010; 16(25): 3133-3143 77 44% 14%

FOLFOX-7 Taieb J, et al. J Clin Oncol 2005; 23:502-509 47 77% 11%

XELOX o CapOx Cassidy J, et al. J Clin Oncol 2008; 26:2006-2012 655 65% 20%

XELOX o CapOx Ducreux M, et al. Int J Cancer 2011; 128:682-690 155 61% 14%

FOLFIRI World J Gastroenterol 2010; 16(25): 3133-3143 74 58% 12%

FOLFIRI Taieb J, et al. J Clin Oncol 2005; 23:502-509 44 68% 5%

FOLFIRI Fuchs CS, et al. J Clin Oncol 2007; 25:4779-4786. 137 n.a. 14%

FOLFIRI Van Cutsem E, et al. J Clin Oncol 2011; 29:2011-2019 602 n.a. 10.5%

FOLFIRI + cetuximab Van Cutsem E, et al. J Clin Oncol 2011; 29:2011-2019 600 n.a. 16%

FOLFIRI Colucci G, et al. J Clin Oncol 2005; 23:4866-4875 178 63% 10%

FOLFIRI Falcone A, et al. J Clin Oncol 2007; 25: 1670-1676 122 59% 12%

FOLFOXIRI Falcone A, et al. J Clin Oncol 2007; 25: 1670-1676 122 78% 20%

Marketed Monoclonal Antibodies and CID frequency

GENERIC NAME MARKETER DIARRHEA

N ALL GRADES (%) GRADE 3-4 (%) Indication

Bevacizumab Genentech 337 n.a. 21 Renal Cell Carcinoma (+ IFN)

392 n.a. 34 mCRC (+IFN)

287 n.a. 18 mCRC (+FOLFOX4)

84 21 1 Glioblastoma multiforme (alone)

Brentuximab Vedotin Seattle Genetics 102 36 1 HL

58 29 3 Anaplastic Large Cell Lymphoma

Cetuximab Imclone, BMS 317 66 16 mCRC (+FOLFIRI)

118 42 2 mCRC (alone)

219 26 5 Squamous Cell Carc. H&N + 5FU

208 19 2 Squamous Cell Carc. H&N + RT

Gemtuzumab Wyeth 277 32 n.a. CD33+ AML

Ibritumomab Biogen IDEC 206 11 0 NHL

Ipilimumab BMS 511 36 4 Metastatic Melanoma

Ofatumumab GSK 154 18 0 CML

Panitumumab Amgen 229 21 2 mCRC

Pertuzumab Genentech 407 67 8 MetastaticHER2+Breast cancer (+ trastuzumab)

Trastuzumab Genentech 1678 n.a. 7 MetastaticHER2+Breast cancer

91 45 n.a. MetastaticHER2+Breast cancer

352 25 n.a. MetastaticHER2+Breast cancer

143 45 n.a. MetastaticHER2+Breast cancer

294 37 9 MetastaticHER2+Gastric cancer

Marketed Kinase Inhibitors and CID Frequency GENERIC NAME MARKETER

DIARRHEA

N ALL GRADES (%) GRADES 3-4 (%) INDICATION

Axitinib Pfizer 359 55 11 Renal Cell Carcinoma

Crizotinib Pfizer 255 49 1 ALK+ NSCLC

Dasatinib BMS 258 18 1 1st line CML

165 27 2 2nd line CML

Erlotinib Genentech, OSI 433 20 2 NSCLC maintenance

485 54 7 NSCLC 2nd/3rd

259 48 6 Pancreatic cancer

Gefitinib AstraZeneca 102 48 n.a. NSCLC 250 mg

114 67 n.a. NSCLC 500 mg

Imatinib Novartis 551 30 1 CML new

1027 45 3 CML other

73 56 1 GIST 400 mg

74 60 4 GIST 600 mg

Lapatinib GSK 198 65 14 Breast cancer (+ Capecitabine)

654 64 10 Breast cancer (+ Letrozole)

Nilotinib Novartis 279 14 1 CML Chronic 1st Line

321 28 3 CML Chronic 2nd Line

137 24 2 CML Accelerated 2nd Line

Pazopanib GSK 290 52 4 Renal Cell Carcinoma

240 59 5 SOFT Tissue Sarcoma

Sorafenib Bayer, Onyx 297 55 10 Hepatocellular Carcinoma

451 43 2 Renal Cell Carcinoma

Sunitinib Pfizer 202 40 4 GIST

375 66 10 Renal Cell Carcinoma

83 59 5 pNET

Vandetanib Astra Zeneca 231 57 11 Thyroide medullary cancer

Vemurafenib Roche 336 28 1 1st Line BRAF+ melanoma

132 29 1 2nd Line BRAF+ melanoma

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Elsiglutide (ZP1846)

development

License Agreement with Zealand Pharma was

signed by HHC in November 2008

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Method of Action

GLP-2 receptor agonist

Indication(s) Chemotherapy induced diarrhea

Competitive Edge

First-in-class, once-daily subcutaneous treatment

Stimulates small-intestinal growth and repair, enhancing bowel function

Development Status

Safe and tolerable in Phase Ia (conducted by Zealand in the US) and Phase Ib (conducted by Helsinn)

Phase IIa: Multi-centre European study in colon cancer patients (conducted by Helsinn) – Expected to complete in H1 2013

IP Patent expiration in 2026 (+ up to 5 years extension)

Partnership Helsinn Healthcare has global rights to cancer supportive care indications

ELSIGLUTIDE : A Novel Approach In Cancer Supportive Care

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Co-Rx and Pre+Co-Rx with Elsiglutide inhibited

5-FU-induced small intestinal mucositis

Saline 5-FU Pre C o Pre + C o

Re

lati

ve

sm

all i

nte

sti

na

l m

as

s

(m

g/g

BW

)

0 ,0

1,8

2,0

2,2

2,4

2,6

2,8

3,0

ZP1846 (80 nm ol/kg, s.c.,once daily)

* P < 0.05, vs 5-FU

Elsiglutide

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Diarrhea score with Irinotecan 150 mg/kg

Elsiglutide (0.9 and 1.8 mg/kg) in Fischer rats

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Clinical Phase Ib study – TIDE-09-04 Phase I, double blind, placebo controlled, dose-escalation safety study on a

GLP-2 analogue (ZP1846), administered subcutaneously (4-day regimen) in

patients with colon cancer treated with 5-FU based chemotherapy.

● Ongoing: 28 patients randomized

● Dose Limiting Toxicity (DLT): related NCI-CTC Grade ≥ 3 AE

● Maximum Dose Tolerated (MTD): 33% probability of DLT

● Initial daily dose: 0.75 mg s.c. with escalation steps of 20%

● No DLT observed (DSMB evaluation)

● Last dose tested > 70 mg/day

● Excellent safety profile

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Clinical Phase IIa study – TIDE-11-10 Phase II, Double-blind, Randomized, Two-stage, Placebo-controlled Proof of Concept

Study in Colorectal Cancer Patients Receiving 5-FU-based Chemotherapy to Assess the

Efficacy of Elsiglutide (ZP1846) Administered s.c. in the Prevention of Chemotherapy

Induced Diarrhea (CID)

● Sample: 138 patients with colorectal cancer, chemotherapy naïve,

scheduled to receive the first cycle of either FOLFOX-4 or FOLFIRI

● Two-stage (58+80 pts.) trial with an interim futility analysis

● 4-day regimen of 24mg/day s.c. administered starting from the first

day of chemotherapy administration

● First stage completed, top-line final results expected in H1, 2013

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TIDE-11-10 – Efficacy Endpoints

Primary Endpoint

● Number of patients experiencing no diarrhea (any grade)

Secondary endpoints

● Proportion of patients experiencing grades 2 diarrhea

● Worst grade of diarrhea

● Time to occurrence of diarrhea

● Number of days with diarrhea any grade

● Number of days with diarrhea grade ≥ 2

● Number of days with presence of >1 bowel movement accompanied by

urgency

● Number of days with presence of >1 episode of fecal incontinence

● Proportion of patients who required i.v. fluids due to CID

● Proportion of patients who required changes to the primary therapy

(chemotherapy dose reduction, delay or change to regimen) due to CID

● Proportion of patients who use rescue medication

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Phase 2b/3: Future Considerations

●Target Population(s)

– Colorectal cancer pts. vs. other cancers

– Standard Chemotherapies vs. Targeted Therapies

● ‘Hard’ Endpoints

– Impact on chemotherapy intensity (dose, frequency) and

discontinuation rate

– Hospitalization rate and duration

– Need of parenteral support