7/28/2019 Orphan Drugs - Kalydeco(1) (1)
1/24
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
2/24
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
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
3/24
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)
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
4/24
Incentives for orphan drug development
Kiran et al. (2012) Drug Discovery Today, 17, 660 - 664
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
5/24
Why Pharma loves them.
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
6/24
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
7/24
Source: www.terrapin.com/orphandrugs
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
8/24
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
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
9/24
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
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
10/24
Inheritance of CF
Carrier screening test
Blood or saliva test=> Checks to see if
parents are
heterozygotes
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
11/24
CFTR
CFTR 1480 amino acids longand has a MW of 168 kDa
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
12/24
Basis of salty CF sweat
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
13/24
The airway ion transport defect
Cuthbert, AW, BJP, 2011
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
14/24
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:
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
15/24
Treatments
AIRWAY
CLEARANCE
TECHNIQUES
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
16/24
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
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
17/24
CFTR mutation classes
No
synthesis
G542X
(2.4%)
Defective
processing
F508
(66%)
Dysregulated
function
G551D
(2.2%)
Reduced Cl
Conductance
R117H
(T
1600 mutations
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
18/24
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
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
19/24
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
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
20/24
Changes from baseline through week 48 in sweat chloride.
Phase III. Ramsey et al 2011
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
21/24
Changes from Baseline in Percent of Predicted FEV1, Phase III
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
22/24
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
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
23/24
Help for main group? Correctors needed
II
Defective
processing
F508
(66%)
Riordan, J.Ann Rev. Biochem. 2008
7/28/2019 Orphan Drugs - Kalydeco(1) (1)
24/24
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
Top Related