DNDI-0690: a new promising drug candidate for the treatment

of visceral leishmaniasisStéphanie Braillard, Béatrice Bonnet, Eric Chatelain

Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland

WorldLeish 6

16 – 20 May 2017

Poster number C1568

Leishmania donovani / infantum transmitted by sand flies is the causative pathogenresponsible for visceral leishmaniasis (VL), a fatal disease present in eastern Africa, Indiaand Latin America. There are between 150,000 and 300,000 cases a year, 50% of whichare children. Few treatment options are available and all drugs suffer from significantdrawbacks, limiting their use in endemic countries. There is a clear need for novel drugsfor VL that are efficacious, affordable, better tolerated and safer than current treatments.We present here DNDI-0690, a 7-substituted nitroimidazooxazine compound, issued froma DNDi collaborative lead optimization effort which is currently undergoing formal pre-clinical development before moving to first in human trials in Q1 2018.

INTRODUCTION

PHYSICO-CHEMICAL PROPERTIESChirality

One stereogenic centre(R enantiomer)

Melting point (DSC) Peak temp ~205°C

pKa (measured) 3.95

Salt formationHCl selected among 4 identified (HCl, H2SO4, H3PO4

and MeSO3H)

ELogD pH 7.4 2.45 (racemate)

Thermodynamic Solubility (Free base) µg/ml

pH 1.2: 128

pH 7.4: 2

Water: 114

Solubility in organicsolvents at 20°C

DMSO (64.4 mg/mL)

AcOH, Acetone, 2-butanone,

THF: 3.8-9.2 mg/mL

Solubility FaSSIF/FeSSIF(µg/ml) at 4h

FaSSIF: 1.35

FeSSIF: 5.18

Polymorphic form Only one polymorphic form

Permeability MDCK/MDR1Papp (nm/s) A to B / B to A

29.15 / 26.17 (no efflux)

XRPD Crystalline material

Polarized Light Microscopy

Irregular small crystalline particles

UV absorption 255 nm (λmax)

Hygroscopicity non hygroscopic

PROCESS ROUTE5 convergent steps (Overall yield~16%).Validated up to 4kg scaleHigh HPLC and chiral purity material (>99%)

ADME PROFILE

CONCLUSION AND PERSPECTIVES

PHARMACODYNAMIC PROFILE

Contact

sbraillard@dndi.org

N

N

Cl

O2N

O

2-chloro-4-nitro-1-[2-(oxiran-2-yl)ethyl]-1H-imidazole

C7H8ClN3O3

MW 217.61

rac-9N

N

Cl

O2N

O

2-chloro-4-nitro-1-{2-[(2R)-oxiran-2-yl]ethyl}imidazole

C7H8ClN3O3

MW 217.61

(R,R)Co(III)(OAc)Salen chiral-9

(R,R)Co(II)SalenO

Br

rac 2-(2-bromoethyl)oxirane

C4H7BrO

MW 151.00

NH

N

Cl

O2N

2-chloro-4-nitro-1H-imidazole

C3H2ClN3O2

MW 147.52

N Br

OH

C5H4BrNO

MW: 173.995

6-bromopyridin-3-ol

F

BOH

OH

N

OH

F

C11H8FNO

MW:189.186

6-(4-fluorophenyl)pyridin-3-ol

MW 139.92

C6H6BFO2

4-F-benzeneboronic acid

Int 14

N

N

O

O

N

F

O2NC18H15FN4O4

MW 370.335

DNDi-0690

step 1

step 4

step 2

step 3step 5

crude

DNDi-0690

step 6

(slurry)

step 7

(clarification)

2-(4-fluorophenyl)-5-{[(7R)-2-nitro-2H,3H,5H,6H,7H-imidazo[2,1-b][1,3]oxazin-7-yl]methoxy}pyridine

GMP Starting material

GMP Starting material

step 2

step 4

step 5

step 3

GMP Starting material

DNDI-0690

No cytotoxicity. Genotoxicity: negative in both mini-AMES and in vitro Micronucleus test. hERG: IC50 =10.29 and IC20 =0.8 µM (whole cell patch clamp, HEK 293 cells at physiological

temperature, GLP). Off-target activity: no significant activity (>50%) at 10 µM against a wide panel of receptors,

channels, transporters and enzymes. GLP 14-day toxicity study in rat: NOAEL identified at the highest dose of 250 mg/kg in both male

and female, corresponding to an AUC0-24h at steady-state of 698 and 619 h*µg/mL, respectively.

Exposure increase less than dose proportional and limited by solubility Absorption limit in rat at AUC ~80000 h*ng/mL No exposure in dog, but suitable exposure in monkey Low risk for drug-drug interaction: No CYP inhibition of 1A2, 2C19,2C9, 2D6 and 3A4, no CYP induction of 1A2 and 2B6, but equivocal data on 3A4

1

10

100

1000

10000

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108114120126Co

nce

ntr

atio

n (

ng

/mL)

Time (h)

PO 6.75 mg/kg

PO 13.8 mg/kg

PO 12.5 mg/kg (5 days, bid)

Hamster (G. Syrian) plasma exposure

1

10

100

1000

10000

100000

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96102108114120126132138144

Co

nce

ntr

atio

n (

ng

/mL)

Time (h)

PO 6.63 mg/kg

PO 13.4 mg/kg

PO 26.3 mg/kg

PO 51.5 mg/kg

PO 6.25 mg/kg (5 days, qd)

1

10

100

1000

10000

0 10 20 30 40 50

Co

nce

ntr

atio

n (

ng

/mL)

Time (h)

1 mg/kg IV

5 mg/kgPO

1

10

100

1000

10000

100000

0 6 12 18 24 30 36 42 48 54 60 66 72 78

Co

nce

ntr

atio

n (

ng

/mL)

Time (h)

IV 1.03 mg/kgPO 4.73 mg/kgPO 44.5 mg/kgPO 255 mg/kgPO 870 mg/kg

Rat (SD) plasma exposure Dog (Beagle) plasma exposure

CLint

(mL/min/kg)microsomes

CLint

(mL/min/kg)hepatocytes

Fraction bound (%)

CLint

(mL/min/kg)microsomes

CLint

(mL/min/kg)hepatocytes

Fraction bound (%)

Monkey (Cynomolgus) plasma exposure

< 8.6 26.7 96.6

Mouse (Balb/C) plasma exposure

1

10

100

1000

0 10 20 30 40 50 60 70

Co

nce

ntr

atio

n (

ng

/mL)

Time (h)

1 mg/kg IV

5 mg/kg PO

20 mg/kgPO

13-27 < 4.0 96.583.3 nd 98.8

69.3 nd 96.3 18,6 4.9 97.5

13.1 20.9 89.8

Human plasma exposure

1

10

100

1000

10000

0

Co

nce

ntr

atio

n (

ng

/mL)

Time (h)

?

SAFETY PROFILE

Potency of DNDI-0690 was assessed against various strains/isolates in intra-macrophageassays.Efficacy was determined in vivo in an acute mouse model where Balb/c were infectedwith L. donovani HU3 or L. infantum ITMAP263, while hamsters were infected withITMAP263 strain in a chronic model. In both models, treatment duration was 5 days,unless specified.

0

10

20

30

40

50

60

70

80

90

100

12.5mg/kg

qd

6.25mg/kg

qd

3.125mg/kg

qd

50mg/kg

qd

25mg/kg

qd

12.5mg/kg

qd

6.25mg/kg

qd

3.125mg/kg

qd

1.56mg/kg

qd

12.5mg/kgqd - 1day

6.25mg/kgqd - 1day

6.25mg/kgqd - 3days

2.08mg/kgqd - 4days

L. infantum L. donovani

Par

asit

e lo

ad r

edu

ctio

n in

live

r (%

)

0

10

20

30

40

50

60

70

80

90

100

Live

r

Sple

en

Bo

ne-

mar

row

Live

r

Sple

en

Bo

ne-

mar

row

Live

r

Sple

en

Bo

ne-

mar

row

Live

r

Sple

en

Bo

ne-

mar

row

Live

r

Sple

en

Bo

ne-

mar

row

Live

r

Sple

en

Bo

ne-

mar

row

12.5 mg/kg bid 12.5 mg/kg qd 6.25 mg/kg bid 6.25 mg/kg bid -10 days

25 mg/kg bid 12.5 mg/kg bid

L. infantum L. donovani

Par

asit

e lo

ad r

edu

ctio

n (

%)

VL reference strains IC50 µM

L. donovani DD8 <0.37

L. donovani HU3 0.03 ±0.00

L. infantum

MHOM/MA/67/ITMAP263

0.10 ±0.07

Clinical isolates

L. donovani BHU1 0.26

L. donovani SUKA001 0.46

L. donovani GR265 < 0.37

CL strains

L. major MHOM/IR/-/173 0.32

L. major

MHOM/SA/85/JISH118

4.56

L. guyanensis

MHOM/GF/1999/LG

0.68

L. mexicana

MNYC/BZ/62/M379

<1.11

L. tropica Anwari 2.7

L. tropica

MHOM/IQ/2007/LT

1.6

L. amazonensis DS Red 2 <1.11

POTENCY AGAINSTLEISHMANIA STRAINS

CHRONIC HAMSTER MODEL

ACUTE MOUSE MODEL

5 days

12.5 mg/kg bid

AUC24 (h*µg/mL)

8.14

(0.10)

Cmax (µg/mL)

0.98

(0.01)

Cave (µg/mL)

0.34

(0.004)

Hamster – infantumand donovani

5 days

12.5 mg/kg qd

AUC24 (h*µg/mL)

75.6

(2.69)

Cmax (µg/mL)

6.9

(0.26)

Cave (µg/mL)

3.02

(0.11)

Mouse- infantum

PK/PD

Due to a short half-life, DNDI-0690 will need a twice a day administration. Predicted range: 2x19 to 2x54 mg/day for a 50 kg human being , based on efficacious free

exposure from hamster and mouse studies respectively and predicted human pharmacokinetics based on data from rat and monkey, and human in vitro as well.

Taken together, these results, emphasized by an encouraging safety margin, lead to the conclusionthat DNDI-0690 has the properties of an oral drug candidate for VL.Interestingly, this nitroimidazole compound showed excellent results in two different in vivocutaneous leishmanial models (see poster C1601).Finally, Mode of Action resolution is under completion.

Following the development of a nanosuspension formulation suitable for rodent and non-rodentspecies, DNDI-0690 is currently going through a regulatory pre-IND package.First In Human (FIH) study in scheduled for Q1 2018.

Supported byAcknowledgments

Dr. Andrew Thompson

3 days

6.25 mg/kg qd

AUC24 (h*µg/mL)

52.1

(1.9)

Cmax (µg/mL)

6.21

(0.23)

Cave (µg/mL)

2.17

(0.08)

Mouse - donovani

Cmin (µg/mL)

0.084

(0.001)

Cmin (µg/mL)

0.1

(0.004)

Cmin (µg/mL)

0.05

(0.002)

(): values corrected with free fraction (protein binding)

Efficacious minimal concentration:84 to 100 ng/mL total = 3 to 10.2 nM free

HUMAN DOSE PREDICTION