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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
17
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
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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
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Pathophysiology of CID
Osmotic Secretory
Dysmotility Exudative
CID
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NCI criteria for CID severity grading (CTCAE version 4,02)
Grade Criteria
1
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
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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)
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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%
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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%
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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%
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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
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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