Transcript New Drugs from Old

“New drugs from old”
Drug & Therapeutics Bulletin
Vol 44 No. 10 Oct 2006
Scott Pegler,
Pharmacist, National Health Service, UK
Presented at The Medical Journal Club,
Morriston Hospital, Swansea NHS Trust
Swansea SA6 6NL
20th November 2006
Patent protection
• Patent protection – usually 20 years
• Typical for pharmaceutical products to be
covered by 20 - 40 different patents, including
the manufacturing process, formulation, salts &
isomers etc.
• Earlier the drug can be brought to market, the
quicker it can start to recoup R&D (research and
development) costs and return a profit
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Bringing new drugs to market
(licensing)
• 10–12 years to bring a new medicine to market
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Assessment via molecular models
In vitro & animal tissues
Healthy volunteer studies (Phase I)
Phase II & Phase III studies
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Market authorisation
• (European Union (EU) legislation states when
considering applications, drugs only be
assessed for:
– quality
– efficacy
– safety
• No requirement for medicines to be compared
with current standard treatments
• Hence, many products licensed offer no
significant advantages over established
treatments
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Background
• Loss of patent protection represents a
potentially large loss of income to PI
• PI uses ‘lifecycle management’ to minimise loss
& maximise returns from such products,
including:
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Prioritising products for development
Strategic alliances to share resources
Using legal processes to protect patents
Intensive marketing of new formulations or
derivatives of existing medicines nearing the end of
their patent life
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Changing formulation
• Changing formulation can be beneficial if it
demonstrably improves safety, efficacy &
adherence to treatment
• However, often there is no good evidence of
clinical advantage associated with formulation
change & the timing usually suggests that
launch is aimed at defending market share
rather than improving patient care
– Tritace/Altace (ramipril) tablets followed Tritace
capsules
– Flomaxtra XL (tamsulosin m/r tablets) followed
Flomax MR capsules
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Modified-release products
• Modifying the release properties of an oral
formulation can extend the effect of a drug
– Prolong the action of a short-acting drug (nifedipine)
– Reduce frequency of administration (morphine)
– Reduce fluctuations in drug plasma concentrations
(lithium)
• Can also be used to minimise impact of patent
expiry without offering significant clinical
benefits to patients
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Doxazosin
• In the UK, in 2001, Pfizer announced
discontinuation of doxazosin 4mg (Cardura) and
the introduction of the modified-release product
(Cardura XL) – both once daily dosing
• In the absence of a generic formulation, which
arrived some months later, doctors had little
choice to change patients to the m/r product
• When generic introduced, most patients were
already established on the (more expensive) m/r
product
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Cardura XL
• In the UK, licensed for hypertension & BPH
• Claimed advantages are reduced risk of
hypotension due to lower peak blood levels
• Combined results of two double-blind RCTs (705
patients) suggest immediate release doxazosin
is as effective with no significant difference in
adverse effects
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Combination products
• Lifecycle management sometimes combines a
drug nearing the end of its patent life with one
or more other drugs to provide a new patented
product
• Companies often claim that this reduction in
number of tablets improves adherence to
treatment
• Many claims are not supported by good
evidence of clinical benefit
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Combination products
• Fosavance [Fosamax Plus D] (alendronate
+ vitamin D)
– Marketed following expiry of patent for
alendronate (Fosamax)
• Costs more than treatment with generic
alendronate plus calcium & vitamin D
• Does not remove the need for patients to take
additional calcium
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Second-generation products
• Many commonly used drugs are 50:50
mixtures of two isomers of the drug
molecule (a racemic mixture or racemate)
• The two isomers (enantiomers) are
identical in chemical composition, but are
mirror images of each other
– ‘Left-handed’ (‘levo’ or ‘s-’) form
– ‘right-handed (‘dextro’ or ‘r-’) form
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Second-generation products
• Chirality can have significance on drug action
e.g. interaction with receptors
• Analogy is like placing a hand in a glove – the
‘left handed’ drug will only fit the ‘left-handed’
receptor
• So, within a racemic
mixture, only a half of the drug
molecules are responsible for
its therapeutic effect
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Second-generation products
• Some drugs were introduced to the
market as single isomers e.g. paroxetine,
sertraline
• Replacement of an already approved
racemate by a single enantiomer is also
used to create ‘new’ products
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Second-generation products
• Potential advantages (claimed) may be:
– Increased potency & selectivity and fewer unwanted
effects
– Improved onset & duration of effect
– Decreased risk for drug interactions
• Theoretical advantages do not always translate
in practice
– e.g. dilevalol (isomer of labetalol) was more
hepatotoxic than the racemate & never marketed
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Esomeprazole (Nexium)
• s-isomer of omeprazole (Losec [Prilosec])
• Launched in 2000, two years before expiry of
omeprazole patent
• Omeprazole & esomeprazole are equally well
absorbed
• S-omeprazole is less susceptible to small
intestinal & hepatic metabolism
• After administration of equal doses, serum
concentrations are 70-90% higher with
esomeprazole
– Therefore the same (c)degree
of acid suppression
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obtained with lower doses of esomeprazole
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Esomeprazole (Nexium)
• Both s- and r-omeprazole are pro-drugs, which
are converted in parietal cells to the active PPI
• Unlike pro-drug, the active PPI does not have a
distinct chiral isomer, so structural differences
have no bearing
• Increasing the dose of omeprazole has an
identical clinical effect to using esomeprazole
without any evidence of different adverse
effects
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Esomeprazole (Nexium)
• No trials have demonstrated a therapeutic
advantage of esomeprazole over other
PPIs when used at equivalent therapeutic
doses
– Omperazole 20mg daily (£98 for 1 year)
– Esomeprazole 20mg daily (£241 for 1 year)
(c) S.Pegler, NHS
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Escitalopram (Cipralex [Lexapro])
• In the UK, citalopram (Cipramil [Celexa])
accounted for 78% of the total turnover for
Lundbeck in 1999
• 2001-2002, faced with patent expiry,
escitalopram launched
• S-isomer responsible for almost all serotonin
reuptake inhibition
• Debatable if this translates into clinical benefits
with fewer adverse effects
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Escitalopram (Cipralex [Lexapro])
• In UK in 2003, Lundbeck was criticised for the
way data was presented in marketing material
– Portrayed escitalopram as more effective and
citalopram as having more adverse effects than
originally detailed in promotional material for
citalopram
• There is no compelling evidence to support
claims that escitalopram is more effective or
has a faster onset of action than citalopram &
unwanted effects are similar
– Escitalopram 10mg & 20mg qd (£194 & £329/year)
S.Pegler,qd
NHS(£39 & £55/year)
– Citalopram 20mg & (c)
40mg
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Metabolites and anologues
• Development of a ‘new’ drug molecule
from an active metabolite
– E.g. replacement of terfenadine with
fexofenadine (less cardiac side effects)
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Loratadine (Clarityn [Claritin]) to
desloratadine (Neoclarityn [Clarinex])
• Desloratidine is main metabolite of loratadine
• No studies have compared loratadine with
desloratidine
• In December 2001, Schering Plough withdrew
supplies of loratadine tablets to wholesalers in
UK & wrote to GPs recommending changing to
desloratadine while informing them of the
withdrawal
– Clarityn remained available as an expensive OTC
product
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Loratadine (Clarityn [Claritin]) to
desloratadine (Neoclarityn [Clarinex])
• In the UK, a year later, patent of loratadine
expired and generic loratadine produced
• Hiatus induced a large change in prescribing
practice in favour of new product
(desloratadine)
• No evidence of clinical benefit over loratadine
– Desloratadine 5mg qd (£21 for 3 months)
– Loratadine 10mg qd (£7 for 3 months)
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Pregabalin (Lyrica)
• Pregabalin is structurally and pharmacologically
related to gabapentin & both marketed by Pfizer
• Launch coincided with gabpentin’s iminent
availablity as a generic
• No direct evidence to suggest pregabalin has a
faster onset of action than amitriptyline & no
published trials to compare with gabapentin or
carbamazepine
• Despite paucity of data, it is heavily promoted
and use has grown substantially since UK
launch in July 2004
– No evidence to use (c)
pregabalin
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generic gabapentin
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Conclusions
• Use of generics allows NHS (National
Health Service) to fund effective
treatments with limited resources
• This may be undermined by strategies
used by manufacturers of branded
products to extend profitability as they
approach patent expiry
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Conclusions
• Lifestyle management of drugs can include:
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Changes of formulation
Drug combinations
Use of metabolites/isomeric forms
 Heavy promotion as ‘new products’ with premium
pricing
• Reality: typically no demonstrable clinical
advantage & no comparative data
– At best  waste of money
– At worst  force unnecessary change on patients,
encourage widespread use of medicines with limited
safety data
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Bottom line
• Be aware of industry strategies to
manipulate prescribing
• Question the value of new products
– Using ‘STEPS’ can help…
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‘STEPS’
S = Safety (major/important adverse effects)
T = Tolerability -- look for pooled drop-out rates
rather than comparative data on individual
adverse effects
E = Effectiveness -- studies showing that the new
drug is better than ‘standard therapy’ using
patient-oriented evidence in a populations
similar to that seen in your practice
P = Price (consider all costs)
S = Simplicity of use (e.g. frequency of dosing,
availability as a liquid etc.)
Preskorn SH. Advances in antidepressant
therapy:
(c) S.Pegler,
NHS the pharmacologic basis. San
Antonio: Dannemiller Memorial Educational Foundation, 1994
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