Forest Laboratories and Almirall’s attempts to make a firm and lasting impression on the respiratory space look set to come up short again, despite positive results in the first phase III study of their COPD combination of aclidinium and formoterol.
The partners’ development of the LAMA/LABA combo makes perfect sense and mirrors competitors' efforts, and until now has gone largely under the radar. But in a hugely competitive COPD market their product will struggle to make greater waves than standalone aclidinium – itself an underwhelming COPD drug – given its efficacy and twice-daily dosing. Its key differentiation is a fast onset of action.
In the 24-week, 1,729-patient trial both doses of the combo showed statistically significant improvements in FEV1 against placebo before morning dosing – the standard trough FEV1 measurement – as well as one hour post-dose. Comparisons were also made against its components, and statistical significance was hit against standalone formoterol in trough FEV1, and versus aclidinium in the one-hour post-dose endpoint.
So far so good. However, as Leerink Swann analysts point out, the numerical FEV1 benefit versus placebo of the two doses – 111ml and 143ml – is less than the 167ml and 238ml seen with GlaxoSmithKline/Theravance’s rival LAMA/LABA combo, Anoro. Another key competitor in this class, Novartis’s QVA149, demonstrated a benefit of some 200ml.
Admittedly, comparing data between different studies with different designs is not particularly robust, but it does raise obvious questions as to how Forest/Almirall’s project might fare in the market in terms of giving a symptomatic benefit versus drugs that seem to have a longer-lasting effect.
After all, competition from Anoro and QVA149 – both are awaiting approval – will be fierce. Blockbuster revenues are at stake, and there will be everything to play for when the leading LAMA monotherapy, Boehringer Ingelheim/Pfizer’s Spiriva, loses patent protection in 2018.
Moreover, competition will also come from Boehringer itself, which recently secured US advisory panel backing for a novel LABA, olodaterol, and is widely expected to combine this with Spiriva (Boehringer breathes more easily after Striverdi adcom vote, January 30, 2013).
Another crucial point is that the market is very much set on the convenience of once-daily dosing; this is what Spiriva boasts, and what Anoro and QVA149 are shooting for too. Olodaterol having been endorsed in a once-daily format, Boehringer’s combo will likely follow suit.
Against this Forest and Almirall’s twice-daily dosing looks like a retrograde step, and aclidinium monotherapy – a twice-daily drug launched last year in the US as Tudorza Pressair and in some EU countries as Eklira/Bretaris Genuair – sets a poor example.
Aclidinium had suffered clinical trial setbacks and regulatory delays; its sales were $58m last year, and are forecast to reach $703m by 2013. Consensus forecasts for sales of the combo are currently at only $131m by 2018, according to EvaluatePharma, versus around $800m each for Anoro and QVA149.
Ace up the sleeve
Still, in Forest and Almirall’s combo’s effect on the one-hour post-dose FEV1 the companies do have one possible ace up their sleeve. This unusual endpoint demonstrates a compellingly rapid onset, and might be critical in persuading doctors of a differentiated profile in the absence of a once-daily benefit.
Forest and Almirall say that if a second phase III trial, due to read out within weeks, also yields positive data, the combo will be filed for US and EU approval. This second trial has a similar design in a similar number of patients, and as such must have a high chance of success; clinicaltrials.gov reveals two additional ongoing studies.
However all these issues play out, it will be vital for Forest and Almirall to make the most of the fast onset of action to try and capture a key niche of the market. For the time being, despite the positive result and filing plans, they are destined to remain also-rans to Glaxo, Novartis and Boehringer.
|Phase III studies of aclidinium + formoterol|
|Study detail||Completion||Trial ID|
|1,729 patients, efficacy vs monotherapies & placebo||Jan 2013||NCT01462942|
|1,692 patients, efficacy vs monotherapies & placebo||Mar 2013||NCT01437397|
|590 patients, safety & tolerability||Apr 2013||NCT01437540|
|1,240 patients, safety & efficacy vs monotherapies & placebo||Jun 2013||NCT01572792|