“New drugs from old” Drug & Therapeutics Bulletin Vol 44 No. 10 Oct 2006

1. “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

2. 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 (c) S.Pegler, NHS

3. Bringing new drugs to market (licensing) • 10–12 years to bring a new medicine to market • Assessment via molecular models • In vitro & animal tissues • Healthy volunteer studies (Phase I) • Phase II & Phase III studies (c) S.Pegler, NHS

4. 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 (c) S.Pegler, NHS

5. 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: • 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 (c) S.Pegler, NHS

6. 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 (c) S.Pegler, NHS

7. 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 (c) S.Pegler, NHS

8. 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 (c) S.Pegler, NHS

9. 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 (c) S.Pegler, NHS

10. 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 (c) S.Pegler, NHS

11. 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 (c) S.Pegler, NHS

12. 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 (c) S.Pegler, NHS

13. 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 (c) S.Pegler, NHS

14. 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 (c) S.Pegler, NHS

15. 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 (c) S.Pegler, NHS

16. 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 degree of acid suppression obtained with lower doses of esomeprazole (c) S.Pegler, NHS

17. 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 (c) S.Pegler, NHS

18. 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

19. 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 (c) S.Pegler, NHS

20. 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) • Citalopram 20mg & 40mg qd (£39 & £55/year) (c) S.Pegler, NHS

21. Metabolites and anologues • Development of a ‘new’ drug molecule from an active metabolite • E.g. replacement of terfenadine with fexofenadine (less cardiac side effects) (c) S.Pegler, NHS

22. 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 (c) S.Pegler, NHS

23. 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) (c) S.Pegler, NHS

24. 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 pregabalin in place of cheaper generic gabapentin (c) S.Pegler, NHS

25. 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 (c) S.Pegler, NHS

26. Conclusions • Lifestyle management of drugs can include: • 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 (c) S.Pegler, NHS

27. Bottom line • Be aware of industry strategies to manipulate prescribing • Question the value of new products • Using ‘STEPS’ can help… (c) S.Pegler, NHS

28. ‘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: the pharmacologic basis. San Antonio: Dannemiller Memorial Educational Foundation, 1994 (c) S.Pegler, NHS