Shire Tacks Away from Industry Norms with Head-To-Head Study

March 09, 2012 Shire tacks away from industry norms with head- to-head study

Joanne Fagg

Head-to-head trials have not always been kind to pharma companies wishing to show their drugs are superior to a marketed competitor – AstraZeneca and Amylin can attest to this. Yet with a major competitor in Johnson & Johnson’s Concerta already off patent, Shire is keen to attempt to show that its ADHD drug Vyvanse is better and, more importantly, prove to payers it is worth the higher brand-name price.

It is a risk that Jeffrey Jonas, senior vice president of research and development at Shire’s specialty pharmaceuticals business, says the UK group is willing to take as companies are increasingly required by payers to show the value of their products. The pressure to do so will be especially pronounced in such categories as cardiovascular and CNS drugs, where cohorts of very effective drugs are losing market exclusivity (see table).

Risk

Aside from pressure from payers, pharma groups with established products really have little incentive to pit their products head-to-head. Based on pivotal trial results against placebo, in many cases, companies are able to position their products within a competitive category based on factors such as efficacy, dosing, convenience or duration. Thus only a tiny fraction of marketed products will ever be directly compared to a competitor in a controlled clinical trial.

The recent history of such trials does not provide motivation, either. Roche’s recent win in rheumatoid arthritis with Actemra over Abbott’s Humira, soon to be the biggest-selling drug in the world, is a bit of an exception (Roche scores important win for Actemra, March 2, 2012);. The companies that have tried to challenge Novo Nordisk’s hold on the GLP-1 sector in diabetes, for example, have come a cropper (Amylin scores own goal in Bydureon vs Victoza head-to-head study, March 3, 2011).

Thus Shire’s announcement earlier this week of its coming phase IV trial probably has some of its investors swallowing hard. Pitting your best-selling drug against a genericised competitor – particularly starting nearly a year after Watson launched a generic competitor - could be a marketing disaster in waiting.

AstraZeneca knows well these risks - the Saturn study pitting Crestor against Lipitor did not fail, but it was not a runaway success either and at the end of the day is unlikely to have helped its biggest product much (Astra will reap few benefits from high risk Crestor study, September 2, 2011).

Highly calculated

Dr Jonas says Shire believes Vyvanse will win the head-to-head based on the results of a phase III trial that used both Concerta and the Shire stimulant as active comparators against placebo. That trial showed a statistically significant improvement for patients taking either of the stimulants when compared to placebo, and a greater numerical improvement for patients taking Vyvanse, although a statistical analysis of the two active drugs against each other was not part of the trial protocol.

“This is a highly de-risked and highly calculated trial,” Dr Jonas says. “I understand there’s intrinsic risk, but I believe this is more than a calculated risk. This is a scientific assessment of actual data that you have in a comparative trial with Concerta already and based on a long and frankly very successful history in developing Vyvanse.”

Shire’s trial, the cost of which it will not disclose, will enrol 1,000 patients at about 100 sites, with placebo arms as well as the Vyvanse and Concerta arms, and differing dose titration strategies. It will be powered to show superiority, if Shire’s theory is borne out, and is expected to report in the second half of 2013. Selected head-to-head trials

Drugs Sponsor Competitor Indication Results Trial ID

Completion of two Dolutegravir NCT01231516 ViiV Healthcare Merck & Co HIV studies in March vs Isentress NCT01227824 and July 2012

Dolutegravir Completion in July ViiV Healthcare Gilead Sciences HIV NCT01263015 vs Atripla 2012

Crestor vs AstraZeneca Pfizer Atherosclerosis Neutral to miss NCT00620542 Lipitor

Schering- Schering- Vytorin vs Plough/Merck Plough/Merck Atherosclerosis Miss NCT00552097 Zocor & Co & Co

Tyverb/Tykerb Due to GlaxoSmithKline Roche Breast cancer NCT00490139 vs Herceptin report in 2013

albiglutide vs Diabetes, type II GlaxoSmithKline Novo Nordisk Miss NCT01128894 Victoza (maturity onset)

Bydureon vs Eli Lilly/Amylin Diabetes, type II Novo Nordisk Miss NCT01029886 Victoza Pharmaceuticals (maturity onset)

Actemra vs Abbott Rheumatoid Roche Win NCT01119859 Humira Laboratories Arthritis

Cimzia vs Abbott Rheumatoid Results expected UCB NCT01500278 Humira Laboratories Arthritis 2016

Results are Vyvanse vs Johnson expected by Shire ADHD TBC Concerta & Johnson second half of 2013

Venous TB-402 vs Completion in July ThromboGenics Bayer Thromboembolic NCT01344954 Xarelto 2012 Events

Mircera vs Chronic kidney darbepoetin Roche Amgen disease Win NCT00394953 alfa (dialysis)

Tivozanib vs AVEO Bayer/Onyx Advanced Renal Win NCT01030783 Nexavar Pharmaceuticals Pharmaceuticals Cell Carcinoma

Brivanib vs Bristol Myers Bayer/Onyx Hepato Cellular Results expected NCT00858871 Nexavar Squibb Pharmaceuticals Carcinoma December 2012

Heavily exposed

Whilst Shire has become known for developing orphan drugs, it remains heavily exposed to the CNS space with three of its top selling drugs in 2011 ADHD products. Thus, it is likely to be rather keen to defend that franchise, and Dr Jonas noted that the Vyvanse trial is not the last, as comparative data will be useful for its customers and for its own development needs.

“The days of people holding up two labels and saying ‘if this were a head-to-head’ are over,” Dr Jonas said. “It’s incumbent on us to develop true evidence based decisions and value propositions. The irony is that people are clamouring for this and then when you do it they say, ‘Woah, why are you doing this?’

“This is not a one-off effort,” he added. “We will be looking to differentiate our products early on. If you think of it as a business model it actually allows you to make cleaner go-no-go decisions earlier on in development.”

Such statements are repeated endlessly at industry meetings, and government and private payers increasingly want to see better comparative data – even the usually hesitant US government has dipped its toe in the comparative effectiveness waters, although it is avoiding politically sensitive issues of cost effectiveness. Comparing experimental agents to market incumbents is becoming more common, in an attempt to pull the plug early on products that simply will not compete in the market place - Thrombogenics for example in the table above, pitting its blood thinner TB-402 against Xarelto. Yet the relative dearth of true head-to-head studies of already-marketed agents shows that pharma companies have not been quick to embrace this philosophy. It may ultimately take greater payer pressure for more to emerge, but it seems unlikely that studies like Vyvanse vs Concerta will become a common sight.