debio 1143 - debiopharm · debio 1143 addition • mucosal inflammation and dysphagia occurred more...

Debio 1143Front-line breakthrough for Head and Neck cancer

Debio 1143: Front-line breakthrough for Head and Neck cancer patients

• First-in-class IAP antagonist• Compelling Phase 2 data generated in a robust trial design:

• LRC-rate improved by 21% over SOC at 18 months after CRT• Highly significant and clinically compelling PFS improvement after 2 years follow-

up• Predictable and manageable safety profile, no substantial added toxicity to CRT• Highly significant improvement of Duration of response (HR 0.22, p=0.003)

• Positioning in “high risk” LA-SCCHN patients (OPC/HPVneg and heavy smokers)• Phase III-ready asset with attractive market opportunity in Head & Neck• H&N Market exclusivity until 2040• Flexible oral dosing regimen adaptable to various drug combinations• Broad potential beyond H&N:

• Extensive clinical exploration of combinations with immune checkpoint inhibitors (ICI)

• Other CRT settings

Executivesummary

Mechanism of action & Pharmacology

Human Inhibitor of Apoptosis Proteins (IAPs)

Target

8 member protein family defined by BIR* domain, mediating diverse functions

• Caspase regulation• E3 Ubiquitin ligase activity• Protein-protein interactions

* BIR Baculovirus IAP Repeat

Debio 1143-binding domain

BIR1 BIR2 BIR3

IAP inhibitors can tackle two hallmarks of cancer

Mechanism of action

Lowering the thresholdfor tumor cell death

Enhancing anti-tumorimmunity

Hanahan D, Weinberg RA. Cell. 2011;144(5):646-74.

Debio 1143 is acting on both tumor and immune cells

Mechanism of action

Our Product

Physico-chemical propertiesDebio 1143

Property Results

CAS n° 1071992-99-8Chemical Name (5S,8S,10aR)-N-benzhydryl-5-((S)-2-

(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

MW 561.71 g/molAppearance white to off-white powderSolid state form Crystalline

Melting range 196-200°CSolubility in water unbuffered

0.2 mg/mL (water, 25 °C)

pKa 7.65Hygroscopicity Slightly hygroscopicStability Stable under long-term ICH storage conditions up to 5 years. No

Debio 1143-related degradation impurities have been observed for solid-state storage.

Inhibition of tumor growth and induction of apoptosis as single agent

Debio 1143

Debio 1143 binding affinities to BIR3 domains of IAPs (Ki nM)

XIAP cIAP1 cIAP2 ML-IAP

Debio 1143 66.4 ± 9.7 1.9 ± 0.2 5.1 ± 0.4 73 ± 3

Effect as a single agent on tumor celllines growth

Debio 1143 has minimal effect on normal cell lines

Debio 1143 Debio 1143 (144 +15)SM -428 (>3000, inactive control)

Debio 1143

Dowstream effect of Debio 1143 on biomakers of apoptosis

PreclinicalefficacyRationale for development in Head & Neck cancer

Debio 1143 enhances radiation-induced cell death in SCCHN models

Pharmacology

At molecular level, Debio 1143 combined with radiotherapy:

• enhances caspase-3 activity• increases Annexin V-positive cells

* BIR Baculovirus IAP Repeat

CI=0.50SER=1.84

CI=0.65SER=1.75

CI=0.67SER=2.24

CI=0.56SER=1.68

CI=0.55SER=5.89

CI=0.87SER=2.54

CI: Combination IndicesSER: Sensitizing enhancement ratio

Matzinger et al., Radiother Oncol. 2015 Sep;116(3):495-503

Debio 1143 synergizes with radiotherapy leading to sustained tumor regression in H&N models

In vivo pharmacology

Debio 1143 + RT in FaDu s.c. xenografts

Surv

ival

Fra

ctio

n

Matzinger et al., Radiother Oncol. 2015 Sep;116(3):495-503

RT: radiotherapy

On track with the pharmacologic audit trail

TranslationalMedicine

Population identification Tumor and blood markers at baselinefor PGX

Molecular target IAPs

Are sufficient drugconcentration achieved

Tumor MALDI, blood PK

Activity on the target cIAP1 in tumor and PBMCs

Modulation of the downstream pathway

Apoptosis, cytokines/chemokines in blood

Production of the desired biological effect Immunomodulation in the tumor

Clinical effect Imaging, pathological analysis

Clinical resultsin LA-SCCHNRationale for development in Head & Neck cancer

Debio 1143 is safe and well toleratedFIH MonotherapyPh

ase

First in Human, single agent

Indi

catio

n

Advanced solid tumors or lymphoma

Stat

us

Completed (N=51)

Key

Out

com

es D1-5 q3w: 900mg/Daily (1 DLT: ALT increase G3 [180mg])

D1-14D q3w: 400mg/Daily (1 DLT: ALT increase G3 [200mg])

MTD not reached

Target engagement: Rapid and sustained degradation of cIAP-1 at doses ≥ 100 mg

Liver is the target organ for toxicity (class effect): reversible asymptomatic increase of liver and pancreatic enzymes

Most commonly reported AEs are mild: fatigue, nausea, decreased appetite, constipation and vomiting, (grade 3/4 < 4%)

No drug-related cardiac, neurological or hematologicaltoxicities. No cytokine-release syndrome observed as monotherapy

Demonstrated target engagement in tumors

Tumor penetration

• Tumor concentration >>> IC50 cIAPs and XIAP

• Tumor/Plasma ratio > 20

Debio 1143

Gomez-Roca et al. AACR 2019Treatment schedule: Monotherapy, 200mg daily for 15 d

• Tissue distribution • cIAP1 levels markedly decreased in most subjects treated with Debio 1143

Squamous Cell Carcinoma of the Head and Neck (SCCHN) is the 6th most common malignancies diagnosed worldwide

Disease overview

6MM Incidence (Globocan 2018):

Lip, Oral cavity: 53’790 (44.5%)Larynx: 30’650 (25.3%)Oropharynx: 26’000 (21.5%)Hypopharynx: 10’550 (8.72%)Total: 120’950

Source: ESMO Essentials, Head & Neck cancers

• SCCHN is a diverse set of malignancies originating from the epithelial lining of the oral cavity, larynx, oropharynx and hypopharynx

• SCCHN develops mostly via one of the two primary carcinogenic routes• high-risk human papillomavirus (HPV) induced carcinogenesis• Exposure to tobacco and alcohol abuse

Risk of SCCHN is related to the frequency, intensity and duration of tobacco consumption

• Each year over 120’000 new cases are diagnosed in the 6MM, with over 36’000 estimated deaths

• ~50%- 60% of patients present with locally or regionally advanced disease (LA-SCCHN) at diagnosis, 65,000 in 2018 in 6MM

Packyears

Treatment treeTreatment tree

Locally advanced SCCHNFrontline therapy

50% of SCCHN

Erbitux +RT for patients with co-morbities

Low risk Stage III

Surgery+/-RT

High risk Stage III and Stage IV

~65’000 treatable pts 6MM**

85%15%

CRT: Cisplatin+RT

Up to 20% 65%

DCF* followed by CRT

DCF followed by surgery

15%

* Docetaxel, cisplatin, 5-FU

** Source Datamonitor H&N 2017 (forecasted epidemiology)

• LA-SCCHN current treatment algorithm

Focus on high-risk patientsUnmet need

• ~50% of oropharyngeal carcinoma (OPC) are HPV-• OPC/HPV- : poor prognostic with 5 year survival of ~50% vs ~ 80% for HPV+• No therapy approved specifically for HPV- patients to date

Ang et al. , JCO, 2014Target Segment• Higher unmet medical need• Competitive differentiation• Shorter endpoints

OPC HPV -

OPC HPV +

50 % Oral CavityHyphopharynxLarynx

• LA-SCCHN Stage III, IVA and IVB

Phase I/II study in combination with CRT in patients with LA-SCCHN

Study design

Phase I (14 patients)Dose escalation of Debio 1143 in patients with previously untreated locally advanced head and neck cancer (LA-SCCHN)

Q3w x up to 3 cyclesDebio 1143 oral

Cisplatin 100mg/m2 I.V.

Radiotherapy 70 Gy in 35 fractions (2Gy/Fraction, 5 fractions per week)

Phase II (94 patients)Double blind randomized19 clinical centers in EU, 3 years follow-up periodPrimary endpoint: Loco Regional Control rate (LRC) at 18 months after CRT Secondary endpoints: PFS, OS…

Clinical signs of efficacy Phase I outcome

100 mg (N=5)

200 mg (N=5) 300 mg (N=3)

Total (N=13)

CR 2 (40.0%) 4 (80.0%) 3 (100.0%) 9 (69.2%)

PR 2 (40.0%) -- -- 2 (15.4%)

PD 1 (20.0%) 1 (20.0%) -- 2 (15.4%)

ORR 4 (80.0%) 4 (80.0%) 3 (100.0%) 11 (84.6%)

• Efficacy: 84.6% ORR (69,2 CR / 15.4% PR)

24 3

92

2

1 1

2

0

2

4

6

8

10

12

14

100 mg 200 mg 300 mg All

Num

ber o

f Pat

ient

s

Confirmed Best overall response

Complete response Partial response Progressive disease

Sustained duration of response observed across subtypes of LA-SCCHN patients at RP2D or higher

Phase I outcome

PD = Progressive DiseaseC =Censored + = Responded up to 24 months last follow-up assessment

Safety: selected TEAEs by CohortPhase I outcome

Preferred Term Toxicity 100 mgN=5

200 mgN=6

300 mgN=3

Gastrointestinal disordersDysphagia Grade 1-2 3 (60.00%) 1 (16.67%) 1 (33.33%)

Grade 3-4 1 (20.00%) 2 (33.33%) 2 (66.67%)

Constipation Grade 1-2 3 (60.00%) 2 (33.33%) 3 (100.00%)

Nausea Grade 1-2 1 (20.00%) 6 (100.00%) 1 (33.33%)

Dry mouth Grade 1-2 1 (20.00%) 3 (50.00%) 1 (33.33%)

Diarrhoea Grade 1-2 1 (20.00%) 1 (16.67%) 2 (66.67%)

Odynophagia Grade 1-2 2 (40.00%) 0 (0.00%) 0 (0.00%)

Grade 3-4 1 (20.00%) 1 (16.67%) 0 (0.00%)

Aptyalism Grade 1-2 2 (40.00%) 1 (16.67%) 0 (0.00%)

Asthenia Grade 1-2 2 (40.00%) 5 (83.33%) 2 (66.67%)

Grade 3-4 2 (40.00%) 0 (0.00%) 1 (33.33%)

Mucosal inflammation Grade 1-2 2 (40.00%) 3 (50.00%) 1 (33.33%)

Grade 3-4 1 (20.00%) 1 (16.67%) 2 (66.67%)

• No Grades 5• No Grades 4

thrombocytopenia or neutropenia

• 1 G4 Febrile neutropenia only

• 1 G3 acute tubular necrosis and renal failure

• 200 mg daily PO D1-14 q3w is the RP2D of Debio 1143 in combination with CRT

• Treatment was tolerable and safety was predictable and manageable

• Treatment compliance was good and CRT delivery was not compromised by Debio 1143 addition

• Mucosal inflammation and dysphagia occurred more frequently, more severe and potentially earlier at higher Debio 1143 doses (Radiosensitizer effect).

• Other than anemia, no other potentially serious haematological toxicities were increased

• CDDP-related toxicity does not appears to have been increased

• CRs are promising in this high risk population

• CRs were long lasting, while PRs and failures occurred mainly in the 100 mg/d cohort

ConclusionsPhase I outcome

Study designRandomized phase II

Primary endpoint• Proportion of patients with

Locoregional control (LRC Rate) at 18 months after CRT (Δ>20% between arms with 0.8 power at two sided 0.2 significance level)

Key secondary endpoints• PFS• Duration of LRC • Overall survival • OR and CR at 3 and 6 months

after CRT completion• Duration of response

1:1

Debio 1143 + CRT n=48

Placebo + CRT n=47

R

Stratified by• N0-N1 vs N2-N3 • Primary tumor site (OPC vs non-OPC)

• If, OPC by HPV/p16 status

N=96 (ITT)• Debio 1143 at RP2D/Placebo

D1- D14 every 21 days

• CDDP100mg/m2 every 21days, up to 3 cycles

• Radiation2Gy 5d/week for up to 70Gy/50Gy to

GTV/elective lymph nodes

Main eligibility criteriaRandomizedphase II

• Main inclusion criteria• Previously untreated, unresectable stage III, IVA & IVB• LA-SCCHN

• Oral cavity• Hypopharynx• Larynx• Oropharynx-HPV/p16 both negative or positive

• Smoking history (>10 pack-years) • Negative HIV/HBV/HCV • ECOG 0 or 1

• Main exclusion criteria• Not compensated liver cirrhosis (Child-Pugh class C)• >75 years• Non CDDP eligible

Demographics: High-risk patientsRandomized phase II

1. Lill C et al. Wien Klin Wochenschr. 2017;129(11-12):398–403.2. Sturgis EM et al. JNCCN. 2011;9(6):665-673.3. Perri F et al. Futur Sci OA. 2018;5(1). 4. Vigneswaran N et al. Oral Maxillofac Surg Clin North Am. 2014;26(2):123.141.5. Ang KK et al. N Engl J Med 2010;363:24-35.

Debio 1143 + CRT (N=48)

Placebo + CRT(N=48)

Age: median (range) 57 (39-70) 59 (46-74)Sex: % male / % female 77.1 / 22.9 85.4 / 14.6ECOG (at baseline) % for grade 0 / 1 56.3 / 41.7 56.3 / 43.8 Primary tumor localization

Hypopharynx 7 (14.6%) 10 (20.8%)Larynx 8 (16.7%) 2 (4.2%)Oral cavity 2 (4.2%) 3 (6.3%)Oropharynx (OPC) 31 (64.6%) 33 (68.7%)

HPV/p-16 negative (% of OPC) 28 (90.3%) 28 (84.8%)HPV/p-16 positive (% of OPC) 3 (9.7%) 5 (15.2%)

TNM stagingStage III 7 (14.6%) 8 (16.7%)Stage IVA 35 (72.9%) 32 (66.7%)Stage IVB 6 (12.5%) 8 (16.7%)

Smoking historyTotal pack-years: median (range) 40 (15-104) 40 (11-90)

Alcohol historyCurrent drinker 26 (54.2%) 31 (64.6%)Average drinks/week: median (range) 21 (1-50) 21 (3-140)

• Baseline characteristics well balanced

• Over 80% of OPC HPV/p-16 negative1,2,5

• All Heavy smokers2,4,5

• Over 80% Stage IV3,5

• High alcohol consumption4

Good safety profile not compromising CRT administration

Randomized phase II

• Overall treatment exposure - comparable

• Identical CDDP dose intensity

• Comparable RT doses

Debio 1143 + CRT(N=48)

Placebo + CRT(N=47)

Number of administrations (Planned = 42) 39 (1;42) 41 (1;42)

Exposure to Debio 1143 or placebo mg• total cumulative dose • relative dose intensity ≥ 70%

7425 (200;8400)35 (72.9%)

8200 (200;8400)38 (80.9%)

Treatment delay days 2 (1;7) 2 (1;8)

CDDP• cumulative dose in mg/m2

• relative dose intensity (% of total planned dose)

288 (99;300)96.9%

288 (100;300)96.9%

RT• patients receiving ≥70% of planned

dose• patients receiving less than 66 Gy

44 (91.7%)

5 (10.4%)

41 (87.2%)

6 (12.8%)

Clinically compelling PFS improvementRandomized phase II

PFSHazard Ratio 0.37p-value 0.007

• mPFS of 16.9 months for control arm

• mPFS not reached for Debio 1143-treated arm

84% of patients treated with Debio + CRT respond for more than 18 months

• 84% of patients in Debioarm vs. 50% of patients in Placebo arm had a duration of response of at least 18months

DOR

Hazard Ratio 0.22

p-value 0.002

Randomized phase II

LRC-rate at 18 months after CRT is improved by >20%

Randomized phase II

Debio 1143 + CRTN=48

Placebo + CRTN=48

Debio 1143 + CRTvs. Placebo + CRT

Locoregional Control Rate (%) (95% CI)

54 %(39; 69)

33 %(20; 48)

Δ:21(1; 40)

Odds Ratio (95% CI) (Debio 1143 vs. Placebo)

2.69(1.13 ; 6.42)

p-value 0.026

• LRC-rate was selected as primary endpoint of this phase II Study • It’s relevant to assess local effects due to radiosensitization of Debio 1143• To reach a meaningful POC with a smaller sample size within a feasible

timeline to allow for confirmatory pivotal studies to be conducted.

• However, LRC-rate will not be Phase III endpoint • Not recognized as a surrogate for OS • Is not a time-bound endpoint for a pivotal study • High rate of censoring leading underpowered studies

Assessment of Phase II data supports the choice of EFS as primary endpoint for Phase III

Randomized phase II

EFS-like Hazard Ratio 0.50p-value 0.029

• EFS- Like is composed of

• PFS events

• LRC events due to Treatment failure

• PFS late events (reported more than 182 days after last non-PD assessment)

• LRC late events (reported more than 182 days after treatment end without previous non-locoregional failure assessment)

• Event Free Survival was shown to be good surrogate for OS in this setting andis supported by current FDA guidelines in Oncology trials as primary endpoint for the upcoming pivotal Ph III study

Positive trends towards improved OSRandomized phase II

OSHazard Ratio 0.65p-value 0.243

• Median duration of OS follow was 24.6 months overall

• Median OS not yet reached in either arm

• OS follow up ongoing however study not powered for OS

Consistent trend towards improved complete responses at 6 months post CRT

Randomized phase II

• Delayed effect at 6 months after CRT + Debio1143

• ΔOR=18.8% (p=0.06)

• Mechanistically consistent with Debio1143 mode of action and chemo-radiosensitizingeffect

Overall Response 62.5% 66.7%

3 Months

Debio1143

Placebo

66.7% 47.9%

6 Months

Debio1143

Placebo

Time after CRT end

SafetyRandomized phase II

Selected TEAEs regardless of relationship (CTCAE v4.03) (worst grade per patient)

Debio 1143 + CRT (N=48) Placebo + CRT (N=47)

All Grade 3 Grade 4 All Grade 3 Grade 4 *

Any TEAEs 48 (100%) 32 (66.7%) 9 (18.8%) 47 (100%) 29 (61.7%) 12 (25.6%)*

Mucositis. 36 (75%) 15 (31.3%) - 32 (68.1%) 10 (21.3%) -

Dysphagia 34 (70.8%) 24 (50.0%) - 29 (61.7%) 10 (21.3%) -

Weight decrease 27 (56.3%) - - 22 (46.8%) - -

Radiation skin injury 25 (52.1%) 1 (2.1%) - 20 (42.6%) 3 (6.4%) -

Nausea 21 (43.8%) 2 (4.2%) - 17 (36.2%) 1 (2.1%) -

Dry mouth 20 (41.7%) 1 (2.1%) - 18 (38.3%) 0 (0.0%) -

Asthenia 17 (35.4%) 2 (4.2%) - 17 (36.2%) 4 (8.5%) -

Constipation 15 (31.3%) 0 (0.0%) - 16 (34.0%) 1 (2.1%) -

Vomiting 15 (31.3%) 2 (4.2%) - 12 (25.5%) 3 (6.4%) -

Selected Maximum Lab Toxicity as TEAE

Anaemia 29 (60.4%) 17 (35.4%) - 26 (55.3%) 11 (23.4%) -

Neutropenia** 15 (31.3%) - 4 (8.3%) 17 (36.2%) - 2 (4.3%)

ALT increase 13 (27.1%) 6 (12.5%) - 8 (17.0%) 2 (4.3%) -

Creatinine increase 10 (20.8%) 2 (4.2%) - 7 (14.9%) 4 (8.5%) -

• Similar safety except for Grade 3 dysphagia, mucositis, anaemia: all consistent with RS effect

• Grade 4 were limited and similar

• Grade 5: none in Debio1143 arm

• Late toxicities (onset >60 days after CRT end) were very similar and not increased in Debio 1143 arm

* Includes 2 patients with Grade 5 AEs (considered as unrelated by investigator) ** Febrile neutropenia: Debio 1143 arm: 3 patients (6.3%), Placebo arm: 2 patients (4.3%)

ConclusionRandomizedphase II

• The study is positive, primary endpoint has been met: statistically significant improvement of 21% in LRC rate at 18 months after CRT (OR 2.69; p=0.026)

• Highly significant and clinically compelling PFS improvement (HR 0.37; p=0.007)

• Highly significant improvement of Duration of response (HR 0.22, p=0.003)

• Consistent positive trend towards improved OS (HR 0.65; p=0.243).Extended follow-up is ongoing

• Debio 1143 addition resulted in a good safety profile not compromising CRT administration

• These results warrants further investigation in a Phase III study

Beyond Head & NeckRationale for development in Head & Neck cancer

Debio 1143 enhances immunomodulatory effect of radiotherapy in tumor microenvironment


Tao et al., Clin Cancer Res. 2019 Feb 1;25(3):1113-1124.

0Days after LLC-OVA Injection

10 20 30

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500

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Syngenic Lewis Lung Cancer s.c. model (FACS: Day 19)

(Ablative Radiation Therapy)

***

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33% of regression rate in mice treated with combo

CD8+ T cells are required for an effective Debio 1143/radiotherapy combination


• Radiosensitizing effect dependent on TNF-α and IFN-γ-dependent• Immunologic memory is induced by the treatment with Debio 1143

Tao et al., Clin Cancer Res. 2019 Feb 1;25(3):1113-1124.Days after LLC Injection3020100

500

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2000

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2500

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Debio 1143 synergizes with anti-PD-1/ PD-L1 agents in vivo


• Combination potent and well tolerated

• Similar observation in multiple syngenicmodels

*: p<0.01, **: p<0.001; vs. vehicle by two-sided t-test with equal variance

MBT-2 syngeneic s.c. mouse bladder cancer model

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Vehiclesanti-PD-L1 5mg/kg ip d1, 4, 8, 11Debio 1143 100mg/kg po QDx5Debio 1143 100mg/kg + anti-PD-L1 5mg/kg

**

*

Attinger et al., AACR 2028.

Extensive clinical investigations with approved Immune Checkpoint Inhibitors (ICIs)

Overview of I/O clinical development

• NSCLC 2nd line

Combo With AvelumabIn ICI naive patients

Patients for whom ICIs provide clinical benefits

Combo With NivolumabIn Relapsed patients

Patients who have been benefiting or not, from ICIs but need further therapy

• SCCHN• SCLC• MSI-H/MMR-d tumors

• GI• Gyneco

• MSS Colorectal cancer (CRC)

• Pancreatic ductal adenocarcinoma (PDAC)

Combo with PembrolizumabIn Primary Refractory patients

Patients with tumors for which ICIs therapy have shown no activity

Q2 2020 Q4 2020Q2 2021

Phase Ib study in NSCLC patientsCombination with avelumab

Q2 2020

Part B (35 patients)Expansion in NSCLC patients exclusively10 clinical centers in Canada and Eastern EuropePrimary endpoint: Objective Response Rate (ORR) RECIST v1.1

Supply agreement with:

Part A (16 patients treated)Dose escalation of Debio 1143 in patients with any solid tumor4 clinical centers in Canada

q4w cycleDebio 1143 oral

Avelumab 10 mg/kg I.V.

D1 D10 D15

Early signs of efficacy in NSCLCCombination with avelumab

*

*** Confirmed PR** CNS progression

• 1 confirmed PR (NSCLC) and 5 SD

• Tumor shrinkage in 3 out of 5 NSCLC patients

Juergens et al., ASCO 2019 .

Recommended Phase 2 dose: 200mgCombination with avelumab

Debio 1143+ Avelumab (10 mg/kg i.v. q2w) 100 150 200 250 Overall

N=3 N=2 N=7 N=4 N=16

Dose Limiting toxicities 0 0 0 1G3 ALT/AST increase

1G3 ALT/AST increase

Treatment ongoing patients # 1 1 2 1 5

Any Treatment Delay due to TEAEs 1 1 1 1 4

Dose reductions due to TEAEs 0 0 0 0 0

Treatment Stopped due to TEAEs 0 0 0 1 1

• Majority of TEAEs were mild and the treatment was well tolerated• No treatment-related AEs ≥ grade 4 occurred

Basket trial in ICI resistant/refractory patients

Combination with avelumab

Part A Dose Optimization (up to 12 patients)Dose optimization of Debio 1143/safety run-in~9 clinical centers in Western Europe

Part B (32 - 60 patients)4 exploratory arms. Adaptive design based on continuous futility assessment:• 4 arms

• SCLC• H&N• MSI-H/MMRD/HRD GI• MSI-H/MMRD/HRD gynecologic

Primary endpoint: ORR

q4w cycleDebio 1143 oral

Nivolumab 240mg

D1 D10 D15

Q4 2020Q2 2019

Investigator Sponsored Trial: Phase I/II Study in primary refractory patients

Combination with pembrolizumab

Part A Dose Optimization (up to 18 patients)Dose escalation part

Part B (28 patients)

• non-MSI-high advanced/metastatic PDAC

• non-MSI-high advanced/metastatic CRC

Primary endpoint: ORRq3w cycleDebio 1143 oral

Pembrozulimab 200mg

D1 D14

Q2 2021Q3 2019

q3w cycle

D21

Our Value proposition

• Advisory Board fully supportive for Phase III • Bourhis Jean MD, PhD• Burtness Barbara, MD • Licitra Lisa, MD • Schoenfeld Jonathan, MD MPH• Ezra Cohen, MD

• CMC activities launched for Phase III API production

• Scheduled Regulatory consultations (US/EU) and HTA meetings in EU

• BTD submission planned

• Protocol writing in progress

• CRO selection and sites identification initiated

Preparatory activities to enable first patient in Q3 2020

Phase III readyasset

Pivotal Study designProposed Adaptive Design

Primary endpoint: EFS by investigator

1:1

Debio 1143 (200mg/day D1-D14) + HD CDDP up to 3 cycles (q3w) +Std RxT (70 Gy to GTV (2Gy/day)Matched Placebo (D1-D14) + HD CDDP up to 3 cycles (q3w) +Std RxT (70 Gy to GTV (2Gy/day)

R

Stratified by• N0-N1 vs N2-N3 • Primary tumor site (OPC vs non-OPC)• Region (US/EU vs RoW)• Others? ECOG=0, etc…

N=600 (ITT)Debio 1143(200mg/day D1-D14 q3w) up to 3 additional cycles

Matched Placebo(200mg/day D1-D14 q3w) up to 3 additional cycles

End of CRT

• Active Substance

• Industrial supply chain in place

• 3 Registration stability batches underway for Ph III supply

• Linear 13 steps synthesis

• Indication specific formulations developed

• Oral solution form for SCCHN

• Oral solid dosage form for I/O

CMCPhase III readyasset

• Formulation for LA-SCCHN

• Oral solution for per os and gastric tubing administration for LA-SCCHN

• 200 mg strength, type 3 amber glass vials, monodose

• Innovative formulation under evaluation

• Tech transfer for Ph III at proposed industrial partner on-going (Farmea, France)

• Formulation for ICI combinations

• Conventional solid dosage form for oral administration, 200 mg strength

• Capsules used to date, tablets foreseen for Ph III

• Innovative formulation under evaluation

• Tech transfer for Ph III at proposed industrial partner to be initiated Q1.2020

CMCPhase III readyasset

Positioning in high risks patients for faster market entry

Phase III ready asset

• Pending SAB and Health Authorities interactions:• Phase III: multicenter, randomised, double-blind, placebo-controlled, parallel group

study. Approximately 650 patients.• Patients population : stage III, IVA and IVB LA-SCCHN, heavy smokers, oral cavity,

hypopharynx, larynx, if OPC HPV-• FPI expected in September 2020• Potential registration

• 2024: First comparative analysis (IA), triggered when 225 EFS (Best Case)• 2025: Primary analysis, triggered when 346 EFS – expected 42 months from FPI

Chemoradiotherapy: LA-SCCHN

96 patients

Topline results

Debio 1143 is the front runner IAP antagonist

Competitors in class

Iap antagonists Stage Route of administration

Target indications Combo partners

LCL161,Novartis Ph2 Ph1/2Ph 1

oral PMF, Post PVMF, Post-ETMF* (IIT: MD Anderson)SCLC, Ovarian cancerNSCLC, CRC, TNBC treated ICI, r/r Multiple Myeloma

-TopotecanPDR001 (anti-PD1)

Birinapant, Medivir Ph1/2Ph1

IV Solid tumors: CRC, EOC, cervical, SSCHN, GEJ, SCLCLocally recurrent SCCHN, HPV+/- (IIT: NCI)

PembrolizumabIMRT (intensity modulatedRT9

ASTX-660, Otsuka Ph1/2 oral r/m SCCHN, r/rDLBCL, r PTCL, r CTCL, R cervical cancer, agnostic in tumors with alteration confering sensibility to ASTX-660

-

Ascentage Ph1/2 IV Solid tumors & lymphomas Combo Pembrolizumab, paclitaxel/carboplatin

BI 891065,Boehringer Ingelheim

Ph1 oral Advanced Solid tumors BI-754091 (antiPD-1)

• Debio1143 has an unique positioning in LA-SCCHN in combination with chemo-radiotherapy

• Competition focused on ICI combination rather than CRT

*Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocytosis Myelofibrosis

Competitive edge over ICI in development in frontline LA-SCCHN

Competitors in the indication

• Favorable competitive positioning for Debio 1143• Target high unmet medical need – only late-stage product combo CRT to

focus exclusively on high risk pts (OPC HPV- and non OPC)• Convenient, outpatient oral administration • No maintenance treatment• Irrespective of PD1/PDL1 status• Opportunity keep ICI for recurrent and metastatic patients

Product Design and patient pop. Primary endpoint

Target completiondate

Comments

Nivolumab LA unresectable and resectable with organ spraing, oral cavity, oropharynx, hypopharynx, larynx

Incidence of AEs

Q4 2019 Turned into safetystudy

Avelumab Stage III, IVa, Ivb, oral cavity, oropharynx, hypopharynx, larynx, HPV+OPX, T4 or N2C or N3

PFS Q2 2021

Pembrolizumab LA unresectable, oral cavity, oropharynx, hypopharynx, larynx

EFS Q2 2021 Approved for recurrent and metastatic SCCHN

LA-SCCHN frontline forecasted at 2 B$ in 7MM by analysts

Attractive marketopportunity

Source: Decision Resources Group – H&N report 2018Note: ‘Major Markets’ include US, 5EU and Japan (7MM)

Projected sales for new entrants in frontline H&N

Chemo/radio sensitizer effect observed in H&N can be leveraged in other indications

Potential for expansion

Source: Globocan 2018

CRT/RT as SOC

Rectal cancer

Glioblastoma

Brain metastasis

LA-Pancreatic Cancer

Inflammatory Breast Cancer

GEJ adenocarcinoma

…

• Today 50% of cancer patients are treated with Radiation-based therapy alone or in combination wit Chemotherapy

Strong IP portfolio, market exclusivity until 2040 in H&N

IP

Patent Family Short title / Keyword Owner Debiopharm rights Expected Expiry Date SPC - up to max 5y extension*

# Patent Offices granted

(US/JP/EP/CN)

WO 2007/130626 Chemical intermediates University of Michigan WW Exclusive licence May 2027 55/57US,JP, EP, CN

WO 2008/128171 DEBIO 1143, Basic Invention University of Michigan WW Exclusive licence Apr 2028 Apr 2033 54/56US,JP, EP, CN

WO 2017/143449 IAP inhibitors (D1143) + ICIs CHEO RI** WW Exclusive licence Feb 2037 Feb 2042 0/27

WO 2019/077132 D1143 + anti-PDL-1 antibodyStudy NSCLC-105

Debiopharm/Merck/Pfizer Non-Exclusive rights Oct 2038 Oct 2043

WO 2019/122337 Induction therapy D1143 + ICImethod of treatment

Debiopharm - Dec 2038 Dec 2043

EP 19 152 384.4 D1143 + NivolumabStudy SMARTPLUS-106

Debiopharm - Jan 2040 Jan 2045

EP 19020411 D1143 Lipidic Formulation Debiopharm - July 2040 July 2045

Filed Sep 19 D1143 Head & Neck method of treatment

Debiopharm - Sept 2040 Sept 2045

Debio 1143: Front-line breakthrough for Head and Neck cancer patients

• First-in-class IAP antagonist• Compelling Phase 2 data generated in a robust trial design:

• LRC-rate improved by 21% over SOC at 18 months after CRT• Highly significant and clinically compelling PFS improvement after 2 years follow-

up• Predictable and manageable safety profile, no substantial added toxicity to CRT• Highly significant improvement of Duration of response (HR 0.22, p=0.003)

• Positioning in “high risk” LA-SCCHN patients (OPC/HPVneg and heavy smokers)• Phase III-ready asset with attractive market opportunity in Head & Neck• H&N Market exclusivity until 2040• Flexible oral dosing regimen adaptable to various drug combinations• Broad potential beyond H&N:

• Extensive clinical exploration of combinations with immune checkpoint inhibitors (ICI)

• Other CRT settings

Executivesummary

© Design : www.superhuit.com© Photos : J.Straesslé (lake)Copyright Debiopharm Group

page 59

Contact information

Debiopharm Group™ Headquarters

Lausanne, Switzerlandwww.debiopharm.com

59

Serge SagodiraHead of Transactions

Debiopharm [email protected]

mailto:[email protected]

debio 1143 - debiopharm · debio 1143 addition • mucosal inflammation and dysphagia occurred more...

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