Development of Class D CpG ODN D35 as an Adjunct to Chemotherapy for CL & PKDL

Daniela Verthelyi, M.D. Ph.D.

CDER/FDA

May 8, 2014: WHO Meetings of Stakeholders for Selected Health R&D Demonstration Projects

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Map to this talk: • Part 1:

– Needs and opportunities

– Scientific basis and Agent selection

– Preliminary Evidence of Efficacy

Part 2:

– Intellectual property

– Technology transfer

– Delinking R&D

– Open knowledge

– Target expansion

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Cutaneous Leishmaniasis and PKDL Needs:

•1 million new cases/yr. (70%

children)

•Skin lesion, scars, emotional and

economic impact

•Current available treatment is

expensive, prolonged, toxicities

•No vaccine

•New treatments needed

– More effective

– Less toxic

– Cheaper

– Amenable to region

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Opportunities: Demonstration project

•Develop New Therapy

•Licensing available- WIPO

•Delink R&D cost from Rx cost

•Tech transfer

• Open knowledge base expansion

• Platform adaptable to other diseases

New mechanism for product development

D35 for CL and PKDL

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The Immune System as a Therapeutic Target

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Leishmania

Innate Immune System

Ag Memory

Adaptive

Immunity IFNγ IL-10

Lymph Lymph

Innate

Immunity NK DC Mo N

X

6

Leishmania

LESION

Immune system

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• TLR2 - Proteoglycans (bacteria)

• TLR3 - dsRNA (RNA viruses)

• TLR4 - Endotoxin (gram negative bacteria)

• TLR5 - Flagellin (bacteria)

• TLR6 - Proteoglycans (bacteria) with TLR2

• TLR7 – viral RNA

• TLR8 – viral RNA

TLR9 - CpG DNA (virus, bacteria, yeast)

Strategy: Activate the Immune system

Most TLR activators act

on multiple immune cell

types, and are toxic

systemically

CpG ODNs selected

CpG DNA is behind BCG activity as adjuvant

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- Pure (synthetic)

- Durable signal in vivo

-Cheap

-Stable

-Simple manufacture

CpG ODN D35

Many sequences were tested for

type of response

consistency

universality of activation

•D35 was chosen because it consistently induced

the right immune response in >95% of donors

tested

•D35 acts on 1 cell type

•Unlike other ODN, induces little inflammation

•Inactive in rodents. Model: primates 9

Model: Leishmania amazonensis

Challenged w/L. major or amazonensis (106 metacyclic promastigotes) ID .

Days Since Infection

0

10.0

20.0

30.0

40.0

50.0

60.0

0 10 20 30 40 50 60

Le

sio

n S

ize

(m

m2)

10

Adapted from Amaral et al.

Note: Lesion size of D ODN treated animals was significantly

reduced when compared to controls (p <.03, N=6/group).

CpG as an immunoprotective agent: D ODN reduces

the severity of a Leishmania amazonensis infection

J.Immunol.2003

Day after infectious challenge

0 7 14 22 28 35 42 49 63

Mean L

esio

n A

rea (

mm

2 )

0

20.0

40.0

60.0

80.0

100.0

SALINE

-3 3

D ODN

K ODN

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Local treatment with D ODN reduces

the severity of L. major lesions

Days post infection

0 3 10 18 24 31 38 46 53 60 67 74 82

Lesio

n a

rea

(m

ean

+ S

D m

m2)

0

10

20

30

40

50

60

70

80

90

100Untreated

D ODN in situ id

-3

D35

Saline

Examples of lesions in macaques challenged with L. major and left

untreated or treated with D35 or Pro-D35 (SC 0.5mg/kg)

Lesions ~3 weeks post challenge 13

Systemic treatment with D ODN reduces

the severity of L. major lesions

Days post infection

0 3 10 18 24 31 38 46 53 60 67 74 82

Lesio

n a

rea

(m

ean

+ S

D m

m2)

0

10

20

30

40

50

60

70

80

90

100Untreated

D ODN in situ id

-3

Days post infection

0 3 10 18 24 31 38 46 53 60 67 74 82

Lesio

n a

rea

(m

ean

+ S

D m

m2)

0

10

20

30

40

50

60

70

80

90

100Untreated

D ODN SC

D ODN IM

-3

Cutaneous lesions in macaques re-challenged with

L.major

Parasite load in reinfected macaques

NaiveUntreat.in situ sc im

Para

site load

0

20

40

60

80

100

D ODN

Re-infected

Days post reinfection0 7 14 21 28 35 42 49 6268 78

Le

sio

n a

rea

(g

eo

me

tric

me

an+

SD

)

0

20

40

60

80

100

120

140

p<0.01

Naive LM UntreatedLM D ODN in situ idLM D ODN scLM D ODN im

Macaques re-challenged

4 months after lesions cleared

3 x 106 L. major

N= 6/group

Does CpG ODN treatment open subject to reinfection?

15

a

Days after challenge

0 3 1018243138465360677482

Le

sion

are

a (

me

an +

SD

)

0

20

40

60

80

100

120

b

0 3 1018243138465360677482

0

20

40

60

80

100

120 Untreated

D ODN sc day +14

Untreated

D ODN id in situ day +10

Treatment of established lesions?

• 4-6 macaques per group challenged with 106 metacyclic promastigotes

• Treated 15 days after challenge with 500 ug CpG ODN ID or SC (0.5mg/kg). 16

Leishmania and HIV

WHO Report on Global Surveillance of

Epidemic-prone Infectious Diseases -

Leishmaniasis 1990-1998

Cases of the co-infection have been reported from 35 countries around the world

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UN

TR

EA

TE

D

D O

DN

Nu

mb

er

of

pa

rasites

1000

10000

100000

Days post challenge

0 7 14 21 28 35 42 49 56

Me

an

le

sio

n a

rea

(m

m2)

0

20

40

60

80

100

120

140

***

-3 3

D ODN

K ODN

Control

- 4 monkeys /group

- L.Major, 107 metacyclic promastigotes id in situ

- No increase in VL during study with D ODN

CpG ODN reduces the severity of the lesions by

L.Major in SIV infected macaques

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Type I IFN

TLR and IRF

Tcells

Tcell activation

Cytotoxicity

Interleukins

Adhesion

Tcell chemotaxis

pDC

APC

pDC

APC

Type I IFN

TLR & IRF

Tcells

T cell

activation

Tcell

chemotaxis

Cytotoxicity

Interleukins

Adhesion

<0.05

0.05-0.1

0.1-0.3

0.3- 3

3-5

5-10

10-50

50-100

100-500

500-1000

1000-5000

>5000

Accelerate and magnify the immune response to leishmania

Leishmania

gene d0 d1 d4 d10 d24 d66

CD209

CD80

CD83

CD86

IFNa2

IFNB1

IRF7

TLR7

TLR9

CD3e

CD4

CD8

CD28

CD40

CD69

CCL5

CXCL10

IFNG

GZMB

PRF1

IL1A

IL1B

IL2

IL2RA

IL6

IL8

IL10

IL-12A

IL12B

TNF-ALPHA

TGFb

FAS

FasL

FOXP3

NOS9A

SELE

SELP

SALINE D-ODN C-ODN

gene 0 6 24 48 0 6 24 48 72 0 6 24 48 72

CD209

CD80

CD83

CD86

IFNa2

IFNB1

IRF7

TLR7

TLR9

CD3e

CD4

CD8

CD28

CD40

CD69

CCL5

CXCL10

IFNG

GZMB

PRF1

IL1A

IL1B

IL2

IL2RA

IL6

IL8

IL10

IL-12A

IL12B

TNF-ALPHA

TGFb

FAS

Fas Ag CD95

FOXP3

NOS9A

SELE

SELP

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HOW? Changes the response to the parasite in the skin

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IFNg, IL2, IL-2RA, IL-15

CCL20 and CCR4

CD8T cells NK cells

Granzyme Perforin

IL-10, IL-4

Parasite clearance

Local inflammation

6 rhesus macaques/group

CpG ODN id (500ug/dose), TLR7 /8 topical (100ug/dose)

Untreated

0 20 40 60

0

20

40

60

80

100

D ODN

0 20 40 60

0

20

40

60

80

100 L

ES

ION

AR

EA

(m

ean +

SE

M) C ODN

0 20 40 60

0

20

40

60

80

100

TLR-7

0 20 40 60

0

20

40

60

80

100

TLR- 8

0 20 40 60

0

20

40

60

80

100

pre-infected

0 20 40 60

0

20

40

60

80

100

CpG ODN type D protect from cutaneous

leishmaniasis in macaques

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• SC administration of 0.5-1 mg/kg

(6 macaques + 6 controls) x 3 studies No changes in:

– Body weight

– Behavior

– Temperature

– CBC and differential

– Metabolic panel

– Renal panel

– Minimal localized lymphadenopathy

– No signs of skin irritation

– No increase in VL in SIV infected macaques

Pre-clinical safety:

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• Similar oligonucleotide based therapies have reached phase III clinical trials (>3000 patients).

• Doses ranging from 0.08-0.36mg/kg resulted in no SAE

• Most frequent AE: Injection site reactions.

• D35 is expected to induce higher levels of IFNa but little local inflammation or reactogenicity.

Single clinical study – melanoma- in VLP No AE.

Clinical Safety

Where are we?

Research Development Accessibility

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• Target selection

• Proof of concept

• Preclinical development

• Product development

• GMP Manufacture

• Formulation

• Clinical Trials

• Regulatory

• Product Manufacture & distribution

• Commercialization & Accessibility

• Technology transfer

Timeframe and milestones:

• Year 1 : GMP production and characterization. Stability. Formulation. Frame clinical studies.

• Year 2: Preclinical testing completed. IND.

• Year 3: Phase Ia in CL patients.

Phase Ib in PKDL patients

• Year 4: Phase II studies. Manufacture of Phase III clinical material. Initiation of commercial product design.

• Year 5-6: Phase III studies at multiple clinical sites in South America, Asia and Africa. Commercial product scale-up, validation and registration activities initiated.

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The estimated cost : • GMP quality D35 in contract facility: 250,000

• Comparability study: 50,000

• Preclinical studies: 250,000

• Formulation development: 200,000

• Stability studies: 100,000

• Assay development and validation : $380,000

• Phase Ia and Ib(based on 100 patients): $450,000

• Phase II clinical studies (based on 150 patients): $580,000

Total needed to take the project to phase III: $2,260,000 over 6 years

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The demonstration project will enable a collaborative approach governed by WHO: • Translation from a public institution for product that has

no economic interest

• Organize and coordinate stakeholders

• Channel funding from interested parties

– De-linking R&D from cost

• Partner with a managing group (e.g. DNDi)

• Facilitate registration, access and distribution in endemic countries

• Lend their experience in product and clinical development.

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Thank you

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Demonstration project as an opportunity to:

• develop a short, safe, affordable and field-friendly treatment that is efficacious for CL and PKDL

• demonstrate the effective use of delinking of R&D cost through equitable or humanitarian licensing to attain global access.

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