Saturday, 20 December 2014

OffLabel: leflunomide

Leflunomide is my 7th off-label DMT for treating MS in resource poor environments. #MSBlog #MSResearch #OffLabel

"The seventh in my series of posts to try and help neurologists who treat MS in healthcare environments where they cannot access high-cost innovator DMTs. For the history of this post please read my posts on my visits to South Africa and India. My positions on off-label prescribing has also been reinforced by recent trips to South America and Lebanon and an earlier visit to Egypt. These are all regions where personal access to DMTs is largely determined by how wealthy you are. The other six off-label DMTs that I have covered to date are methotrexate, azathioprine, mitoxantrone, cladribine, cyclophosphamide and rituximab."

"I wasn't going to include leflunomide on the list as it not been directly tried in multiple sclerosis. Leflunomide is a prodrug and is converted to teriflunomide in the body. As you are probably aware teriflunomide (Aubagio) has been licensed across the world as a treatment for relapsing-remitting multiple sclerosis. Therefore leflunomide that is licensed for rheumatoid arthritis and is now off-patent is a cheap way of giving teriflunomide. As only 70-80% of leflunomide is absorbed orally 20mg of leflunomide is therefore equivalent to the 14mg of teriflunomide, the licensed dose for treating relapsing multiple sclerosis. Interestingly, when I pushed Indian neurologists about leflunomide they were more likely to prescribe it off-license for MS than azathioprine, as teriflunomide is supported by class 1 evidence (see studies below)."

"I have personally not used leflunomide for treating MS, but am aware of some neurologists in the US who are using it. Please note that in the UK and Europe we are not allowed to prescribe an off-label products were licensed products exist for a particular indication. Interestingly, the EMA initially did not want to accept teriflunomide as a new chemical entity; they were claiming that there is little difference between it and teriflunomide. However, Genzyme-Sanofi managed to convince the regulators that teriflunomide is different to leflunomide and have therefore managed to protect their investment."

"How much would you save by using leflunomide compared to teriflunomide to treat RRMS? This will depend on local pricing. Using the list price in the BNF (British National Formulary) the cost savings in the UK works out to £13322.88 per annum. A 28-day pack of teriflunomide 14mg tablets costs £1037.84 (£37.07 per tablet or £13528.99 per annum) compared to a 30-day non-proprietary pack of leflunomide 20mg tablets, which costs £16.94 (£0.565 per tablet or £206.10 per annum). In summary, teriflunomide costs 65x as much as the equivalent dose of leflunomide. This is a very good demonstration of how much innovation costs society and the political deal we in Europe, and other parts of the world, have with the Pharma industry. If we allow them to make money from innovation, in this case repurposing of an active metabolite of a pro-drug, they have a period of market exclusivity to recoup their investment, make a profit and hopefully reinvest their profits in future cycles of innovation. In addition the Pharma companies employ many Europeans, pay tax on their profits and pay dividends to their shareholders. Many institutional shareholders are pension funds hence the Pharma industry supports many European pensioners. From a macroeconomic perspective having a healthy and profitable Pharma industry is important for Europe. Why then do we bash the Pharma industry so much? I suspect it because they tend to chance their arm and charge as much as they can for their products, pay some of their staff exorbitant bonuses and have excessive and dodgy marketing practices. This is why the Pharma industry is so heavily regulated. Unfortunately regulation comes with a downside; typically more money spent on compliance and hence higher drug prices. At the end of the day we need Pharma as we have no alternative with regard to drug development. What we also need is Pharma to appreciate that neurologists in resource poor countries need some flexibility to treat their patients with MS; MS is a bad disease and they need
affordable options. This series of blog posts on off-label prescribing has not been designed to undermine the Pharma industry, but simply to address an unmet need in resource-poor countries."


O'Connor et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011 Oct 6;365(14):1293-303.

BACKGROUND: Teriflunomide is a new oral disease-modifying therapy for relapsing forms of multiple sclerosis.

METHODS: We concluded a randomized trial involving 1088 patients with multiple sclerosis, 18 to 55 years of age, with a score of 0 to 5.5 on the Expanded Disability Status Scale and at least one relapse in the previous year or at least two relapses in the previous 2 years. Patients were randomly assigned (in a 1:1:1 ratio) to placebo, 7 mg of teriflunomide, or 14 mg of teriflunomide once daily for 108 weeks. The primary end point was the annualized relapse rate, and the key secondary end point was confirmed progression of disability for at least 12 weeks.

RESULTS: Teriflunomide reduced the annualized relapse rate (0.54 for placebo vs. 0.37 for teriflunomide at either 7 or 14 mg), with relative risk reductions of 31.2% and 31.5%, respectively (P<0.001 for both comparisons with placebo). The proportion of patients with confirmed disability progression was 27.3% with placebo, 21.7% with teriflunomide at 7 mg (P=0.08), and 20.2% with teriflunomide at 14 mg (P=0.03). Both teriflunomide doses were superior to placebo on a range of end points measured by magnetic resonance imaging (MRI). Diarrhea, nausea, and hair thinning were more common with teriflunomide than with placebo. The incidence of elevated alanine aminotransferase levels (≥1 times the upper limit of the normal range) was higher with teriflunomide at 7 mg and 14 mg (54.0% and 57.3%, respectively) than with placebo (35.9%); the incidence of levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and the placebo group (6.3%, 6.7%, and 6.7%, respectively). Serious infections were reported in 1.6%, 2.5%, and 2.2% of patients in the three groups, respectively. No deaths occurred.

CONCLUSIONS: Teriflunomide significantly reduced relapse rates, disability progression (at the higher dose), and MRI evidence of disease activity, as compared with placebo. (Funded by Sanofi-Aventis; TEMSO ClinicalTrials.gov number,NCT00134563.).

Confavreux et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Mar;13(3):247-56.

BACKGROUND: Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing-remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis.

METHODS: This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18-55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5.5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo,teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881.

FINDINGS: Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0.50 [95% CI 0.43-0.58]) than in those assigned to teriflunomide 14 mg (0.32 [0.27-0.38]; p=0.0001) or teriflunomide 7 mg (0.39 [0.33-0.46]; p=0.0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0.68 [95% CI 0.47-1.00]; log-rank p=0.0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0.95 [0.68-1.35]; log-rank p=0.7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group).

INTERPRETATION: Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis.

CoI: multiple

Advent Calendar-20

So we are looking at our drug development pathway and we can take bog standard drug powder dissolve it in water and administer to animals but that isn't good enough for human work.

So in animals we have to do things to conform with Good Laboratory Practice (GLP) but to deliver drugs to humans the standards are even higher and things have to be done to GMP standards.

Good manufacturing practices (GMP) are the practices required in order to conform to guidelines recommended by agencies that control authorization and licensing for manufacture and sale of food, drug products, and active pharmaceutical products. These guidelines provide minimum requirements that a pharmaceutical or a food product manufacturer must meet to assure that the products are of high quality and do not pose any risk to the consumer or public.

Good manufacturing practices, along with good laboratory practices and good clinical practices, are overseen by regulatory agencies in the United States, Canada, Europe, China, and other countries.


All guidelines follow a few basic principles:
  • Hygiene: Pharmaceutical manufacturing facility must maintain a clean and hygienic manufacturing area.
  • Controlled environmental conditions in order to prevent cross contamination of drug product from other drug or extraneous particulate matter which may render the drug product unsafe for human consumption.
  • Manufacturing processes are clearly defined and controlled. All critical processes are validated to ensure consistency and compliance with specifications.
  • Manufacturing processes are controlled, and any changes to the process are evaluated. Changes that have an impact on the quality of the drug are validated as necessary.
  • Instructions and procedures are written in clear and unambiguous language. (Good Documentation Practices)
  • Operators are trained to carry out and document procedures.
  • Records are made, manually or by instruments, during manufacture that demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the drug was as expected. Deviations are investigated and documented.
  • Records of manufacture (including distribution) that enable the complete history of a batch to be traced are retained in a comprehensible and accessible form.
  • The distribution of the drugs minimizes any risk to their quality.
  • A system is available for recalling any batch of drug from sale or supply.
  • Complaints about marketed drugs are examined, the causes of quality defects are investigated, and appropriate measures are taken with respect to the defective drugs and to prevent recurrence.

 So we have to get chemists involved again to formulate your drug into the pill or capsule or as an solution for injection. If you have a water soluble (dissolves in water) drug, like ours then this is easy to formulate but some are like brick dust and difficult to dissolve in anything.

Once you have drugs in pill form and the ethics in place we are ready to go. Phase I here we come!