Orphan Drugs Kalydeco case study

What are orphan drugs and why has pharma and biotech become so interested? What are the main differences in developing an orphan drug to market versus normal molecules Be able to understand the R & D behind Kalydeco based on understanding of cystic fibrosis gene defects

Orphan Drugs
Medicines to diagnose, prevent or treat rare disease Disease is life-threatening or chronically debilitating No current decent treatment or new one is of decent benefit Therapies unlikely to be developed in normal market Prevalence: < 5/10,000 (EU) or <200,000 cases (USA)* Financial and scientific assistance from FDA / EMA Market exclusivity for 7-10 years for product 326 approvals in 25 years since Orphan Drug Act rare cancers, metabolic and endocrine disorders dominate

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 to degenerative and proliferative causes 80% of rare diseases have identified genetic origins (3% -4% of births) <1,000 orphan diseases associated with minimum scientific knowledge-hence big focus of FP7 grant funding
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500069805.pdf

Incentives for orphan drug development

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

Why Pharma loves them.

Source: www.terrapin.com/orphandrugs

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

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 and sinuses, fat maldigestion due to pancreatic exocrine insufficiency, infertility in males due to obstructive azoospermia, and elevated concentrations of chloride in sweat Besides the F508 mutation, accounting for >50% of CF cases, >850 mutant alleles Colon Pancreas

Lung

Inheritance of CF

Carrier screening test Blood or saliva test => Checks to see if parents are heterozygotes

CFTR

CFTR 1480 amino acids long and has a MW of 168 kDa

Basis of salty CF sweat

The airway ion transport defect

Cuthbert, AW, BJP, 2011

Evidence of CFTR Abnormality:

Nasal Potential Difference (NPD)

CF patients have: Higher basal NPD Greater decline in NPD after amiloride perfusion
NPD (mV) NPD (mV)

NORMAL
60 50 40 30 20 10 0 1 Amiloride 0 Cl Amiloride

Iso 0 Cl Amiloride

Time (minutes)

CYSTIC FIBROSIS
70 60 50 40 30 20 10 0 1 Amiloride 0 Amiloride Cl Iso 0 Cl Amiloride

Lack of response to Cl free perfusion and isoproterenol

Time (minutes)

Treatments

AIRWAY CLEARANCE TECHNIQUES

Ultra-Orphan (Kalydeco, Ivacaftor)

No disease modifying CF medicines Treat infection aggressively and avoid p.aeruginosa Gene therapy for CF history of failure since 1991 due to delivery, efficacy and toxicity issues no current pharma investment Increase in knowledge of mutant allele-associated phenotypes linked to science of intracellular trafficking of CFTR Need HTS for molecules to get chloride out of cells

CFTR mutation classes

1600 mutations

No synthesis G542X (2.4%)

Defective processing F508 (66%)

Dysregulated Reduced Cl function Conductance G551D (2.2%) R117H (<1%)

Reduced CFTR level 3849 + 10kb C>T

A new mode of action with G551D mutation

VX-770
Normal levels of surface Gating defect CFTR low chloride flow Potentiators increase CFTR Gating Increased Ion Flow

G551D

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

Changes from baseline through week 48 in sweat chloride. Phase III. Ramsey et al 2011

Changes from Baseline in Percent of Predicted FEV1, Phase III

A new personalised medicine by design

Kalydeco is an excellent example of the promise of a personalized medicinetargeted drug that treat patients with a specific genetic makeup, FDA Commissioner, Margaret Hamburg

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

Help for main group? Correctors needed

II

Defective processing F508 (66%)

Riordan, J. Ann Rev. Biochem. 2008

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

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

n = 20

Duration of 21 days
VX-809 (200 mg) + KALYDECO (250 mg)

62 people

n = 21

VX-809 placebo + KALYDECO placebo

n = 21

Primary end: effect on CFTR function as measured by sweat chloride during the combination-dosing portion of the study (day 14 to day 21)