Orphan Drugs - Kalydeco(1) (1)

7/28/2019 Orphan Drugs - Kalydeco(1) (1)

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Orphan Drugs

Medicines to diagnose, prevent or treat rare disease

Disease is life-threatening or chronically debilitating No current decent treatment ornew one is of decent benefit

Therapies unlikely to be developed in normal market

Prevalence: < 5/10,000 (EU) or


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Facts and Figures from EMA

246,000 persons in 27 Members. Most have diseases at rates < 1 in 100,000

5,000-8,000 rare diseases:

-infantile spinal muscular atrophy

- lysosomal storage disorders

- patent ductus arteriosus (PDA)

- familial adenomatous polyposis (FAP)

- cystic fibrosis (CF)

>50% of rare diseases appear during adulthood-renal cell carcinoma

-glioma

-acute myeloid leukaemia

Others result of infections (bacterial or viral) and allergies, or are due todegenerative and proliferative causes

80% of rare diseases have identified genetic origins (3% -4% of births)


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Incentives for orphan drug development

Kiran et al. (2012) Drug Discovery Today, 17, 660 - 664


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Why Pharma loves them.


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Source: www.terrapin.com/orphandrugs


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Tax Payer Problem.

-The line is what typical quality-adjusted life year (QALY) calculates for normal

drugs used by reimbursement agencies to estimate value for intervention.-QALY for orphan indications and childhood diseases have higher calculation


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Cystic Fibrosis (CF) CF is a heterogeneous recessive genetic disorder with features that reflect

mutations in the cystic fibrosis transmembrane conductance regulator

(CFTR

) gene CF is characterized by chronic bacterial infection of the airways andsinuses, fat maldigestion due to pancreatic exocrine insufficiency, infertilityin males due to obstructive azoospermia, and elevated concentrations ofchloride in sweat

Besides the F508 mutation, accounting for >50% of CF cases, >850

mutant allelesColon PancreasLung


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Inheritance of CF

Carrier screening test

Blood or saliva test=> Checks to see if

parents are

heterozygotes


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CFTR

CFTR 1480 amino acids longand has a MW of 168 kDa


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Basis of salty CF sweat


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The airway ion transport defect

Cuthbert, AW, BJP, 2011


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Evidence of CFTR Abnormality:

Nasal Potential Difference (NPD)

Higher basal NPDNPD(mV)

NORMAL

0

10

20

30

40

50

60

1 0 1 2 3 4 5 6 7 8

Time (minutes)

9

Amiloride

Amiloride

0 Cl

Amiloride

0 Cl

Amiloride

Iso0 Cl

Amiloride

Iso0 Cl

Amiloride

NPD(mV)

CYSTIC FIBROSIS

0

10

20

30

40

50

60

70

1 0 1 2 3 4 5 6 7 8

Time (minutes)

9

Greater decline inNPD after amilorideperfusion

Lack of response toCl free perfusionand isoproterenol

CF patients have:


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Treatments

AIRWAY

CLEARANCE

TECHNIQUES


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Ultra-Orphan (Kalydeco, Ivacaftor) No disease modifying CF medicines

Treat infection aggressively and avoidp.aeruginosa

Gene therapy for CF history of failure since 1991 due todelivery, efficacy and toxicity issues no current pharma

investment

Increase in knowledge of mutant allele-associatedphenotypes linked to science of intracellular trafficking

of CFTR

Need HTS for molecules to get chloride out of cells


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CFTR mutation classes

No

synthesis

G542X

(2.4%)

Defective

processing

F508

(66%)

Dysregulated

function

G551D

(2.2%)

Reduced Cl

Conductance

R117H

(T

1600 mutations


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Normal levels

of surface

CFTRGating defect

low chloride

flow

Increased

Ion Flow

Potentiators increase

CFTR Gating

VX-770

G551D

A new mode of action with G551D mutation


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A CFTR Potentiator-VX770

Allele population information known by CFF

150 mg x 2 tablets, taken with fatty food

Adverse even profile acceptable

Drug interactions with CypP450 substrates

Post-marketing safety studies for 5 years started


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Changes from baseline through week 48 in sweat chloride.

Phase III. Ramsey et al 2011


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Changes from Baseline in Percent of Predicted FEV1, Phase III


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A new personalised medicine by design

- Vertexs Kalydeco(ivacaftor) is targeted to correct CFTR with residual function

- G551D mutation is 4% of all CF (1200 people in US, 110 in Ireland)- 2 Phase III trials of 213 people: improved lung function

- Small molecule, oral twice a day

- 3 months in FDA, a record

- $294K p.a. / free to uninsured households earning < $150K in the US

Kalydeco is an excellent

example of the promise of a

personalized medicinetargeteddrug that treat patients with a

specific genetic makeup, FDA

Commissioner, Margaret

Hamburg


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Help for main group? Correctors needed

II

Defective

processing

F508

(66%)

Riordan, J.Ann Rev. Biochem. 2008


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VX-809 (200 mg) + KALYDECO (150 mg)

Study of Phase II Double-Blinded, Placebo-Controlled, Multiple-Dose Study

Duration of 21 days

VX-809 placebo + KALYDECO placebo

Primary end: effect on CFTR function as measured by sweat chloride

during the combination-dosing portion of the study (day 14 to day 21)

62 people

VX-809 (200 mg) + KALYDECO (250 mg)

n = 20

n = 21

n = 21

Orphan Drugs - Kalydeco(1) (1)

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