François B.1,2, Collin G.3, Dequin P.F.4, Laterre P.F.5, Perez A6.

1 Medical-Surgical ICU, CHU Dupuytren, 87042, Limoges, France

2 Inserm CIC-1435, CHU Dupuytren, 87042, Limoges, France

3 Medical-Surgical ICU, District Hospital Center, La Roche-sur-Yon, France

4 Medical-Surgical ICU, University Hospital, Tours, France

5 ICU, Cliniques universitaires Saint-Luc, Université catholique de Louvain (UCL), Brussels,

Belgium

6 Combioxin SA, Geneva, Switzerland

CAL02: A LIPOSOMAL ADJUNCTIVE ANTI-TOXIN THERAPY IN INFECTIONS

A NEW THERAPEUTIC APPROACH FOR SEVERE COMMUNITY-ACQUIRED PNEUMONIA

• Over the past 2 years, steering committee and/or advisory board

member for Inotrem, Lascco pharma, Combioxin Therapeutics, GSK,

The MedCo, Arsanis, Ferring, Daiichi-Sankyo, Asahi-Kasai

• Coordinating principal investigator of an ongoing international phase 2

trial within COMBACTE, an IMI-funded program testing a mAb against

S. aureus to prevent VAP in ICU patients in collaboration with

MedImmune

• Coordinating principal investigator of a recently terminated international

phase 1b trial testing a mAb against S. aureus to treat VAP in ICU

patients in collaboration with Aridis

TRANSPARENCY DECLARATION

ECCMID 2017 3

MEDICAL NEED

More than 5 million people hospitalized with severe pneumonia each year (EU, US, JP)

Mortality rates reach 30% despite best treatments available

Need for combination antimicrobial therapy in high-risk and severely infected patients

Severe pneumonia-causing pathogens:

S. Pneumoniae (most common), followed by

S. aureus, Legionella, and GRAM- such as P. aeruginosa (increasingly frequent)

Potentially toxic effects of antibiotics and release of inflammatory components

Soaring emergence of resistance to treatments

Limited agents targeting virulence factors responsible for complications and septic shock

ECCMID 2017 4

AVAs

Anti-virulence agents

Target virulence factors responsible for colonization, tissue and cellular destruction, organ failure,

evasion of host immune mechanisms, and septic shock

Exert antimicrobial effects via mechanisms dissimilar but not inhibitory to those of antibiotics

May inhibit or halt pathogenesis without exerting the inevitable selective pressure for evolutionary

adaptation of resistance to one or more antibiotics

AVAs create a new era

for treatment of anti-bacterial infections

alone or in combination with standard of care antibiotics

Peptidomimetic

inhibitorsmAbs Liposomal decoys

ECCMID 2017 5

AVAs

mAbs Liposomal decoysPeptidomimetic

inhibitors

Specific target

Safe

Toxin- / Pathogen-agnostic

Equally efficacious against GRAM+ and GRAM-

Specific target

Challenges: Diagnostic considerations / Time to intervention

Optimum utilization of pathogen-specific AVAs may rely in part on the ability of clinicians to perform rapid

bedside diagnostics to quickly identify the specific pathogens causing disease in individual patients

ECCMID 2017 6

CAL02

Combination of empty, uni-lamellar, uncoated, neutral, small liposomes

Acts as a decoy by mimicking microdomains targeted by diverse bacterial toxins

Lipids devoid of any antigenic, pyrogenic and toxic properties (cholesterol and sphingomyelin)

Tightly packed & highly stable: they remain intact in the circulation

Toxins target cell

microdomains that are

unstable and small

CAL02 liposomes form

large and stable surfaces

acting as a decoy

ECCMID 2017 7

CAL02

First-in-class, clinical-stage AVA for the treatment of severe infections

Unique broad-spectrum AVA

Activity demonstrated against various virulence factors and biofilm formation

In vivo protective effects shown against Gram+ & Gram- (S. pneumoniae, S. aureus, P. aeruginosa)

Potentially active against 8 of the 12 “priority pathogens” posing the greatest threat (WHO, 27 Feb 2017)

Addresses the issue of resistance

Acts regardless of any existing antibiotic drug resistance

Does not prompt the emergence of new resistance

Minimal / No off-target potential

Does not impact commensal flora

Can be administered in combination with any antibiotics (no impact on MIC)

Low drug-drug interaction potential

Non-immunogenic & biologically neutral

ECCMID 2017 8

PRECLINICAL EFFICACY

• Henry et al. Nature Biotechnology 2015

• ECCMID 2015 – Oral PresCAL02 doses used correspond to the HED of 4-8 mg/kg (single dose)

In vivo efficacy against S. pneumoniae

n= 8 per group

*P < 0.05, **P < 0.01 0

50

100

0 1 2 3 4 5 6 7

Su

rviv

al (

%)

Time (Days)

* **

Pneumococcal pneumonia model

Amoxicillin +/- CAL02 at 4hpi

n= 10 per group

***P < 0.001, **P < 0.01, *P < 0.05

Pneumococcal bacteremia model

CAL02 alone (100mg/kg)

No treatment

Admin. at 16 hpi

Admin. at 6 hpi

Admin. at 10 hpi

No treatment

Antibiotics alone

Antibiotics + CAL02

CAL02 alone

ECCMID 2017 9

0

50

100

0 10 20 30 40

Su

rviv

al (%

)

Time (h)

CAL02 +/- Vancomycin

n= 10 per group

***P < 0.001

No treatment

Subtherapeutic Vancomycin

Vancomycin + CAL02

Subtherapeutic CAL02

In vivo efficacy against other pathogens (Gram+ / Gram-)

PRECLINICAL EFFICACY

Synergistic effect with antibioticsImpact on outcome when CAL02 is given as monotherapy

CAL02 alone

n= 10 per group

***P < 0.001, **P < 0.01, *P < 0.05

No treatment

CAL02 12.5 mg/kg

CAL02 50 mg/kg

CAL02 25 mg/kg

CAL02 100 mg/kg

P. aeruginosa pneumonia model

CAL02 alone

n= 5 per group

No treatment

CAL02 100 mg/kg

• Henry et al. Nature Biotechnology 2015

• ECCMID 2017 – ePoster #1664

Staphylococcal bacteremia model

ECCMID 2017 10

CAL02-001 TRIAL

Randomized, double-blind, placebo-controlled : Two cohorts (4 mg/kg and 16 mg/kg)

Primary endpoints: Safety and tolerability

Efficacy: Clinical cure at the TOC visit (Days 15-22)

Key secondary clinical efficacy endpoints

Clinical cure on Day 8 (pre-TOC) and on Day 29 (EOS)

28-day all-cause mortality

Changes in SOFA (and respiratory SOFA) during ICU stay

Evolution of PaO2/FiO2 during ICU stay

28-day ventilator free days

Abbreviated inclusion criteria

Severe CAPP

CURB-65 score ≥ 3 in patients aged ≥ 65 and CURB-65 ≥ 2 in patients aged < 65

At least 1 major criterion (mechanical ventilation / vasopressors) or 3 minor criteria

D -1 D 1 D 2 D 8 D 15-22 D 29

TREATMENT

First dose within

12h of diagnosis of severe CAPP

and 24h of i.v. antibiotics

Follow-up and Test-of-Cure Randomisation

early TOC TOC EOS

ECCMID 2017 11

Patients Characteristics n = 6

Age (Years) (Mean (range)) 55 (37-79)

Temperature (°C) (Mean (range)) 37.8 (35.6-39.6)

CURB65 (Mean (range)) 3.3 (3-4)

APACHE II (Mean (range)) 21.8 (14-30)

SOFA (Mean (range)) 8.8 (6-12)

PaO2/FiO2 ratio (Mean (range)) 102.5 (64-167)

S. pneumoniae identification: Urine / Resp. sample / Blood (n) 6 / 4 / 2

CAPP severity criteria: Major / Minor 4 / 2

Ventilation: Invasive / Non-invasive (n) 4 / 2

Septic shock at screening (n) 3

Acute renal failure at screening (n) 3

CRP (ng/mL) (Mean (range)) 333 (149-499)

BASELINE

First Cohort (CAL02 4 mg/kg (‘LOW DOSE’) versus Placebo (3:3):

ECCMID 2017 12

Tolerability

No local reactions at site of infusion (Itching / Pain / Swelling / Redness / Bruising)

No change in vital parameters (T, HR, BP, QT/QS (ECG-12))

Safety

No adverse event related to the IMP

Most frequent AEs: - Hypophosphoremia (n=3)

- Hypokalemia (n=3)

Other AEs: - Septic shock (n=2)

- Respiratory failure (n=2)

TOLERABILITY & SAFETY

SERIOUS ADVERSE EVENTS 2

NON-SERIOUS ADVERSE EVENTS 37

Mild 14

Moderate 19

Severe 4

TOTAL ADVERSE EVENTS 41

ECCMID 2017 13

First Cohort (CAL02 4 mg/kg (‘LOW DOSE’) versus Placebo (3:3):

EVOLUTION

Parameters

Mortality* 1 / 6 (17%)

Cure rate

Early TOC (day 8) 1 / 6 (17%)

TOC (day 15 – 22) 5 / 6 (83%)

Time to discharge (5 patients)

From ICU (Days) (Mean (Range)) 13.2 (8-21)

From Hospital (Days) (Mean (Range)) 25 (12-54)

Respiratory support 6 / 6 (100%)

Patients intubated at treatment start 4 / 6

Need for intubation after treatment start 1 / 2

* Cause of death: refractory septic shock (n=1)

ECCMID 2017 14

CONCLUSIONS

First-in-class, clinical-stage, broad-spectrum non-antibiotic agent for the

treatment of severe infections

First-in-man utilisation in CAPP

Promising safety profile at low dose

Many potential other indications in acute severe infectious diseases

(including hospital-acquired and MDR infections)

Next trial in severe CAP regardless the pathogen

THANK YOU !

Participating sites:• Orléans (FR)

• La-Roche-sur-Yon (FR)

• Saint-Brieuc (FR)

• Tours (FR)

• Limoges (FR)

• Besançon (FR)

• Versailles (FR)

• Ottignies (BE)

• Bruxelles 2 sites (BE)

Monitoring team:• C. Mabilat

• V. Simeon-Vieules

• I. Broussoles-Goudin

• J. Vignaud

• C. Berghe

• MF. Dujardin

Back-up slides

ECCMID 2017 17

AVAs

DRUG COMPANY MOA USE STAGE

CAL02 Combioxin Broad-spectrum toxin neutralizer (Gram+ and Gram-) Adjunct treatment for severe

pneumonia

Phase 1/2

ongoing

Aerucin Aridis Binds to alginate exopolysaccharide involved in cellular

adhesion

Adjunct treatment for pneumonia

caused by P. aeruginosa

Phase 2

planned

AR-301

(Salvecin)

Aridis Inhibits the assembly of α-hemolysin subunits into

pore-forming complex

Adjunct treatment for severe

pneumonia caused by S. aureus

Phase 1/2

completed

514G3 XBiotech Promotes opsonophagocytic activity and neutralizes

immune evasion mechanisms by binding to protein A

Adjunct treatment for bacteraemia

caused by S. aureus

Phase 1/2

completed

MEDI4893 MedImmune Blocks binding of α-hemolysin to cellular receptor and

prevents formation of the pore-forming complex

Prevention of VAP caused by

S. aureus

Phase 2

ongoing

MEDI3902 MedImmune Bispecific: binds PcrV in T3SS cytotoxic injectisome

and Psl exopolysaccharide involved in biofilm

Prevention of VAP caused by

P. aeruginosa

Phase 2

ongoing

ASN100 Arsanis Two mAbs that block α-hemolysin and leukocidins Prevention of VAP caused by

S. aureus

Phase 2

ongoing

AR-101

(Aerumab)

Aridis Opsonizes LPS serotype O11 Adjunct treatment for HAP caused

by P. aeruginosa serotype O11

Phase 2a

completed

Belzotoxumab Merck & Co Inhibits Toxin B Prevention of recurrence of

C. difficile infections

FDA-

approved

ECCMID 2017 18

DRUG PROFILE

Broad-spectrum agent

Acts regardless of any existing antibiotic drug resistance

Does not prompt the emergence of new resistance

Does not impact commensal flora

Can be administered in combination with any antibiotics (no impact on MIC)

FIRST-IN-MAN: ICU PATIENTS WITH SEVERE PNEUMOCOCCAL PNEUMONIA

Patients rapidly diagnosed

Well-defined infection characteristics, acute phase, and complications

Well-defined standard antibiotherapy

Homogeneity of toxin/toxic profile

Patients evolve into serious condition