Pharma’s Cutting Edge

I won’t be thoroughly reviewing all of the FDA briefing materials this evening. However, I don’t think it’s necessary to review every detail in order to draw some inferences about Exubera.

These are FDA’s central issues (as quoted from David Orloff’s summary):
1. Pulmonary safety in patients without and with existing pulmonary disease
2. Utility as an alternative short-acting insulin, perhaps particularly in regimens directed at “intensive” glycemic control
3. Safety regarding hypoglycemia, particularly in patients engaged in “intensive” insulin therapeutic regimens.
4. Use in populations with underlying acute or chronic pulmonary conditions (e.g., infectious, smoking) impacting the kinetics of insulin absorption from the lung
5. Use in young children with DM1.

As the FDA’s clinical efficacy document appears to have been damaged, I’ll restrict my comments to pulmonary safety, which was the one issue of major importance to Exubera’s success that has not been discussed publicly by Pfizer to any great extent until now. The quotes below are from FDA’s pulmonary division medical reviewer for Exubera.

1. “…limited pulmonary safety data in subjects with underlying lung disease is not adequate to assess the pulmonary safety of inhaled insulin in subjects with underlying lung disease.” [If approved, Exubera could be contraindicated for use in patients with pre-exisiting lung disease, at least until Phase3b studies specifically in this patient group have been submitted for review. This is a large group that probably comprises close to half of all insulin-treated diabetic patients.]

2. “Respiratory related adverse events were more common in the inhaled insulin group than in the comparator groups.” [Although pulmonary serious AEs and study discontinuations due to pulmonary AEs were higher for the Exubera groups, most pulmonary AEs were non-serious. The most common drug-related AE was cough and associated symptoms (sputum increased and dyspnea). Cough occurred nearly 4 times more frequently with Exubera than comparator. Labeling will reflect the increased risk of pulmonary AEs, particularly cough, but will also indicate the apparent mild, dosing-related nature of this side effect. More worrisome for FDA (and Pfizer) is the decline in pulmonary function as assessed by spirometry. Although the decline in pulmonary function appears to be reversible and not progressive after the first few months of therapy, it is clinically significant and is almost certainly to be reflected in label warnings.]

One has to wonder how Pfizer plans to manage the liability risk of Exubera. They’ve appropriately proposed a raft of post-marketing studies designed to better quantify the clinical risks of the drug in a variety of patients, but at the same time they have suggested that Exubera is safe to use in patients with mild to moderate asthma or COPD, in contrast to the internal FDA pulmonary consultant’s review, which indicated that current data were insufficient to draw such a conclusion. This leads me to believe that Pfizer is planning to fight to avoid a contraindication to use in such patients, clearly an anti-conservative position.

A cynic might say that Pfizer’s benefit-risk analysis weighed the risk of lawsuits for what appears to be a common but reversible, non-mortal side effect against the benefit of selling to a much larger target population from the get-go–and chose to go with the money. But then those cynics are always spouting off about something…those cooky, crazy, adorable cynics.