Effient failure illustrates the perils of head-to-head trials

Eli Lilly finds Effient is not flattered by comparison in Trilogy ASC trial.

Trial Results

Lawyers, it is said, never ask a question to which they do not already know the answer. Lilly and Daiichi Sankyo asked just such a question when they ran a head-to-head trial of Effient versus Plavix, with the result that the jury found against them. The phase III Trilogy ACS study showed that the proportion of acute coronary syndromes patients who suffered heart attack, stroke or cardiovascular death was not significantly lower with Effient than with Plavix.

Head-to-head trials are notoriously risky, but with generic versions of Plavix eating up much of the oral anticoagulant market Lilly had to take the gamble in the hope of gaining proof of superiority to justify Effient’s higher price. The failure will not cause a fall in sales: Effient is approved only as a therapy for patients undergoing percutaneous coronary intervention, and Trilogy ACS assessed its use in medically managed patients. The downside is that Lilly will now find it very difficult to expand Effient’s approval from patients undergoing PCI to all those with ACS.

The Trilogy ACS results might disappoint Lilly and its investors, but are unlikely to surprise them. Few analysts had expected the trial to succeed, a fact that was reflected in Lilly's share price. UBS described the results as “a modest disappointment", adding that it would have been a nice addition for Effient, the bank is currently forecasting worldwide sales of Effient in the range of $500m in 2012 to $700m in 2014.

The trial’s failure leaves AstraZeneca's Brilinta as the only drug to have shown an edge over Plavix in ACS patients in a head-to-head trial. Brilinta’s US label allows it to be used for the treatment of all ACS patients thanks to its head-to-head Plato trial, a feat Effient was almost certain to trying to replicate with the Trilogy ACS.

Brilinta is in line for sales of around $1.6bn in 2016, according to EvaluatePharma’s consensus data, compared with $1.3bn for Effient. Brilinta’s sales are forecast to hit nearly $2bn in 2018, benefiting from the expiry of Effient’s patent protection in 2017.

Mano a mano

The trial’s failure points to the inherent dangers of going one-on-one, with chances of a head-to-head trial providing the “right” answer appearing little better than fifty-fifty (see table). Amylin Pharmaceuticals’ disastrous attempt to prove that its diabetes drug Bydureon was as good as Novo Nordisk’s Victoza at lowering blood sugar levels led to the US biotech’s share price falling by 25%, and handed a huge sales advantage to the enemy (Amylin scores own goal in Bydureon vs Victoza head-to-head study, March 3, 2011).

Intorsect, a phase III trial aiming to show the superiority of Pfizer’s Torisel over Bayer’s Nexavar in patients with advanced renal cell carcinoma showed no difference in progression free survival with the two drugs, and overall survival actually favoured Nexavar. And the Saturn trial was at best neutral for AstraZeneca, showing Crestor to be as good as, but no better than, Lipitor generics (Astra will reap few benefits from high risk Crestor study, September 2, 2011).

One of the more notable failures was that of ThromboGenics’ phase IIb trial comparing TB-402, a long-acting anticoagulant, against Bayer’s Xarelto. Here the problem was not efficacy but safety: incidence of venous thromboembolism was similar with both drugs, but patients receiving TB-402 had a significantly higher incidence of bleeding events. Development of TB-402 was stopped immediately.

Selected head-to-head trials  
Sponsor Drugs Competitor Indication Results Trial ID Name
Eli Lilly/Daiichi Sankyo Effient vs Plavix Generic ACS Miss NCT00699998 Trilogy ACS
AstraZeneca Brilinta vs Plavix Generic ACS Win NCT00391872 Plato
Eli Lilly/Amylin Pharmaceuticals Bydureon vs Victoza Novo Nordisk  Diabetes, type II (maturity onset) Miss NCT01029886 Duration-6
AstraZeneca Crestor vs Lipitor Generic Atherosclerosis Neutral to miss  NCT00620542 Saturn
Pfizer Torisel vs Nexavar Bayer/Onyx Pharmaceuticals Advanced renal cell carcinoma Miss NCT00474786  Intorsect
Abbott Paricalcitol vs Cinacalcet Amgen Secondary hyperparathyroidism  Win NCT00977080 Impact SHPT
Bristol Myers Squibb Orencia vs Humira Abbott Laboratories Rheumatoid arthritis Win NCT00929864 Ample
Galenica PA21 vs Renvela Sanofi Hyperphosphataemia Win NCT01324128 -
Thrombogenics TB-402  vs Xarelto Bayer Venous Thromboembolism Miss NCT01344954 -
Shire Vyvanse vs Concerta Johnson & Johnson ADHD Primary completion date April 2013 NCT01552902 
AstraZeneca Brilinta vs Plavix Generic ACS Primary completion June 2013 NCT01642238 -
Medivir/Tibotec TMC435 vs Incivo Johnson & Johnson Hepatitis C Primary completion date March 2014 NCT01485991 Attain
Onyx Pharmaceuticals Carfilzomib vs Velcade  Johnson & Johnson Multiple myeloma Primary completion date January 2015 NCT01568866 -
Ariad Ponatinib vs Gleevec Novartis Chronic myeloid leukaemia Primary completion date June 2021 NCT01650805 Epic

Head-to-head drug trials run by pharma companies are becoming rarer, with few being initiated since March (Shire tacks away from industry norms with head-to-head study, March 9, 2012). With the stakes so high and the rewards uncertain, use of these trials to gouge out a niche at the expense of marketed drugs is a strategy for gamblers only.

To contact the writer of this story email Elizabeth Cairns in London at elizabethc@epvantage.com

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