Orphan Drugs (Kalydeco)

INTRO
1. orphan drugs
  1. pharmaceutical agents developed specifically to diagnose, prevent, or treat a rare medical condition (an orphan disease)
2. orphan disease
  1. highly debilitating or life threatening disease
  2. generally no adequate treatment available
  3. rare diseases
    1. disease that affects ~5/10,000 in the EU or <200,000 people in USA
    2. 5000-8000
      1. e.g. CF, infantile spinal muscular atrophy, lysosomal storage disorders, patent ductus arteriosus and familial adenomatous polyposis
    3. 1/2 acquired in adulthood
      1. e.g. glioma and renal cell carcinoma
3. not profitable, counteracted by a number of financial and R&D related incentives
  1. outlined by Kiran et al in 2012
    1. extended exclusivity period of 7-10 years
    2. research grands for orphan drug development
    3. lowered marketing costs
    4. tax credits
    5. waived FDA fees
    6. shorter development timelines/quicker approval
legislation
1. orphan drugs follow the same regulatory pathway as other pharmaceutical products
  1. testing focuses on pharmacokinetics and pharmacodynamics, dosing, stability, safety and efficacy
  2. some statistical burdens are lessened in an effort to maintain development momentum
    1. e.g. orphan drug regulations acknowledge the fact that it may not be possible to test 1000 patients in a phase III clinical trial, as very few people may have the disease
2. many governments introduced legislation to push orphan drug research forward and to encourage pharmaceutical companies to develop drugs that have a small market
  1. based on ethical principle that those with rare diseases have an equal right to treatment as those with common diseases
3. The Orphan Drug Act
  1. passed in USA in 1983
  2. states that any drug developed to treat an orphan disease can have 7 years on the market without competition
  3. In 1999 EU adopted similar legislation allowing market exclusivity for up to 10 years for orphan drugs
  4. before this legislation 8 Orphan drugs in EU and 10 in USA approved
    1. since legislation adoption, 70 and 403 orphan drugs approved in EU and USA respectively
  5. Franco, 2013, Drug discovery today
"The Economic Power of Orphan Drugs", Drug Discovery Today
1. highlighted that orphan drugs have the potential to outperform non-orphan drugs
  1. premium costs
  2. rapid growth rate of approved orphan drugs
2. the orphan drug market provides a good opportunity for growth and success
  1. in light of recent legislation and the pharma industry's requirement to research these drugs
3. over 7000 rare disease and only a small number of these have approved treatments
4. Matthew Turner, at the World Drug Congress, 2012, gave 10 reasons why pharma companies are starting to research in this area
  1. 1. global market worth of rare disease drug development is approaching 75 billion euro
  2. 2. of the 700 catalogued rare diseases, fewer than 5% have drug therapies available
  3. 3. There are almost 600 orphan drugs in development
  4. 4. biologic drugs presently account for over 65% of the orphan and rare disease market
  5. 5. Orphan drugs have better odds of approval with an 82% success rate as opposed to 35% for traditional drugs
  6. 6. 85% of orphan products are initially developed by small pharma/biotechs
  7. 7. Orphan drug approvals in Europe are becoming less evenly split between large pharma and small biotechs - big players are entering market and collaborations are being made with patient groups
  8. 8. licensing deals are still seen as the most common deal type fro Pharma to gain access to orphan drugs
  9. 9. There are 3 commercialisation strategies to maximise orphan drug sales
    1. A non-orphan drug secures an orphan indication
      1. Topamax, initially indicated for epilepsy, extended patent protection through the additional orphan indication for Lennox-Gastaut syndrome, a severe form of epilepsy
    2. A pureplay orphan drug
      1. Gleevec, currently licensed for two orphan cancers, is effective in at least four other rare diseases
    3. Indication expansion into non-orphan indications
      1. Remicade was initially launched for the orphan indication of Crohn's disease before receiving approval for the much larger Rheumatoid arthritis market
  10. 10. 10 years - the amount of market exclusivity awarded to an orphan drug after EU approval is granted
Cystic Fibrosis
1. classified as an orphan disease
  1. even though it is one of the most common autosomal recessive diseases in Caucasians (~1/2,500 births, 1/1,500 in Ireland) due to its heterogeneity.
2. caused by mutations in the CF transmembrane conductance regulator (CFTR) gene
  1. regulates fluid flow within cells and affects components of sweat, digestive fluids, and mucus.
  2. genetic defects underlying CF disrupt the functioning of several organs
    1. cause ducts or other organs to become clogged by thick, sticky mucus or other secretions
    2. clogging and infection of the bronchial passages impedes breathing.
      1. Infections progressively destroy the lungs
    3. Plugging of small bile ducts impedes digestion and disrupts liver function in 5% of patients
    4. occlusion of ducts prevents the pancreas from delivering critical enzymes to the bowel in 85% of patients
    5. Absence of the vas deferens renders 95% of males infertile
    6. females are occasionally made infertile by a dense plug of mucus that blocks sperm from entering the uterus
3. diagnostics
  1. Lack of a CFTR chloride channel in the sweat duct blocks salt reabsorption
    1. its elevated concentration in sweat is diagnostic of the disease
  2. CF patients have an elevated nasal potential difference (NPD) due to increased luminal sodium absorption
4. mutations
  1. over 850 known mutations in the CFTR gene that cause CF
  2. delF508 is the most common, >50% of cases
  3. no cure for CF
    1. however mean age of survival has increased with earlier diagnosis
    2. current treatments involve
      1. nutrient repletion by a change in diet and pancreatic enzyme supplements
      2. relief of airway obstruction by postural drainage
      3. treatment of airway infection through oral and intravenous antibiotics
      4. suppression of inflammation using steroids or high dose ibuprofen
    3. none of these treatments are disease modifying
      1. need for medicine to treat the infection aggressively and prevent p. aeruginosa - an opportunistic infection that causes severe pneumonia in CF patients
      2. needs to be an increase in knowledge of mutant allele-associated phenotypes linked to science of intracellular trafficking of CFTR
      3. needs to be HTS performed to identify small molecule correctors
  4. G551D mutation
    1. affects 4% of CF patients
    2. glycine replaced with aspartic acid
    3. characterised by a dysfunctional CFTR protein on the cell surface
      1. protein is trafficked to the correct area, the epithelial surface, but once there the protein cannot transport chloride through the channel
    4. targeted by new orphan drug
      1. Ivacaftor (Kalydeco, Vertex Pharmaceuticals - approved in 2012)
        a CFTR potentiator
        improves transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating whihc in turn increases the probability that the channel is open
        oral efficacy examined in a randomised, double-blind, placebo-controlled, international trial on 161 CF patients with at least one G551D allele (83 given Kalydeco, 78 given placebo)
        Ramsey et al, 2011, N Eng J Med
        v positive results
        FEV1 was improved by over 10 percentage points in active vs placebo
        subjects receiving Kalydeco were 55% less likely to have a pulmonary exacerbation that placebo
        patients taking Kalydeco had improved lung function after 2 weeks which lasted for 48 weeks
        they gained weight, and showed an improvement in patient reported respiratory symptoms and sweat chloride levels
        costs ~294,000 dollars for a years supply.
        Vertex have said that they would make the drug available free to patients in the US with no insurance and a household income of under 150,000 dollars
        also currently being evaluated for other CF mutations including delF508

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