Posted by Jeff Berk, BOLT International; On March 9, 2011 indacaterol 75 mcg received a positive review (13-4) from FDA’s Pulmonary-Allergy Advisory Committee for use as a once-daily long-term maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease, including chronic bronchitis and/or emphysema. They recommended against (5-12) approval of the 150 mcg dose, since this dose had similar efficacy as the 75. Indacaterol is marketed in over 50 countries for COPD at 150 mcg and 300 mcg qd under the brand name Onbrez® Breezhaler®. The US brand name is going to be Arcapta™ Neohaler™.
Recently we had a chance to discuss indacaterol with a group of predominantly European pulmonology thought leaders (a couple of US stragglers). They felt that Novartis was introducing indacaterol monotherapy for COPD in an effort to discourage the automatic linkage by physicians of LABAs and LAMAs. They don’t expect to see any uptake of a beta2-agonist monotherapy for asthma, indacaterol certainly won’t have a label for that use, and Novartis has wisely not pursued an asthma indication.
According to our Thought Leaders, the strength of indacaterol is that it is a true once-a-day beta2-agonist, with rapid onset and no evidence of tolerance dependence. For COPD monotherapy, once-daily indacaterol is going to be superior to twice-daily formoterol. Onbrez will compete with Spiriva (a LAMA) for 1st line COPD monotherapy. There is a head-to-head trial ongoing, but as of now there’s no perceived difference in efficacy between the two approaches.
The drawback to indacaterol is that it will not have the dose flexibility that is seen with formoterol. Key toxicities at higher doses of indacaterol are palpitations, tremor, QTc prolongation and (unexpectedly) transient cough in 25% of patients.
Here are some of the comments that BOLT’s Thought Leaders shared with us:
“So does that combination of indacaterol glycopyrrolate give Novartis better access to the asthma side then if they came through with indacaterol mometasone? I don’t think so. Anticholinergics are not very effective in asthma. Although there are some studies now in tiotropium in severe asthma showing that about a third of the patients showed good response. But as you know in asthma we are very concerned about LABAs being used without inhaled steroids. I think Novartis have very wisely not launched indacaterol for asthma”.
“That is one because of the bad rap of the LABAs, you might assume that is also going to fall along with them and come out of favor, but it may not. It could actually work the other way. That is why what if somebody had studied the long-acting because it has a little bit of a different mode of action in order to be ultra long-acting let’s say (once a day). Maybe it will escape the concerns that people have about the usual long-acting twice a day product let’s say with the salmeterol and formoterol group. So it can work either way. Indacaterol, if they luck out, might have a different profile. Chances are it won’t and it will just get the black box warning like everything else because it may take big numbers to know. But it could be a blockbuster because people like LABAs. They help people. And who is the patient in whom you are prescribing the monotherapy? You mean like a COPD patients with monotherapy with long-acting beta? Exactly. Is it limited to the COPD patient? It is the COPD patient now for monotherapy. So is there any application for indacaterol monotherapy beyond COPD? I think you would be in trouble if you did it for asthma unless we know that it has a different profile. I see FDA getting very conservative and since there are other options out there it would be really hard for me to imagine that they are going to cut Novartis any slack in terms of the labeling. Right. They have to get really lucky or they have to have a lot of data. Chances are it will be guilt by association”.
“There are two advantages. One is that it is more convenient and more important is that it is more effective as far as we can see. So I would say that it is as effective as tiotropium once a day, but it may be more effective, and it is more effective than twice a day B2 agonist. I think the choice is more between indacaterol and tiotropium. And I don’t know that there is that much difference between them but there are comparison trials going on apparently”.
“Indacaterol is clearly a once a day drug. It has a rapid onset of action and there is no evidence that tolerance develops. There are studies where it has been given over a year and is well tolerated. I think the once a day can convenience is very good and I think the data that exists to date suggests that once a day indacaterol is much better than twice a day formoterol. And this is strictly speaking as the monotherapy for COPD? Correct? Yes, this is as monotherapy for COPD”.
“It is dose limited – well limited is not the right word, but there are side effects if you go above the recommended dose. So it doesn’t have the sort of flexibility that you can see with formoterol where you can increase the dose quite a lot before you get side effects. What is the key toxicity? The expected toxicity is you get palpitations and tremor and you can show that the QT interval is reduced. They are the expected effects. But with indacaterol an unexpected effect is that it causes coughing in about 25 percent of people. But my understanding is that is not a big problem because the cough tends to wear off when the patient uses the drug over several days”.