Bydureon dual-chambered pen approved by the FDA – March 3, 2014

Yesterday, AstraZeneca announced the FDA approval of its dual-chambered pen for the GLP-1 agonist Bydureon (exenatide once weekly). Additionally, we got a peek at the device and the administration procedure through the FDA’s updated medication guide (see the first bullet below). The single-use injection device eliminates the need for patient-end reconstitution, which was a detracting factor for the current version of the product as it added “hassle factor” for patients and made training more time-consuming.

The approval arrived a bit earlier than had been most recently expected, as AZ management guided during its most recent quarterly earnings call for a US regulatory decision in 2Q14, although patients and HCPs have been waiting for the pen for some time. Older estimates had it being approved as early as 2012 (travel back in time to our Amylin 4Q10 Report for an example); that didn’t happen since the FDA required additional testing. We imagine that the multiple handoffs in Bydureon’s ownership (from Amylin, to Lilly, then to BMS/AZ, and now to AZ alone) had an adverse impact on the development process – as well as, of course, the commercialization evolution for Bydureon “first gen”. The press release states that AZ plans to make the device available in the US “later this year,” which (depending on the interpretation of that phrase) could leave a few months or more between now and a launch. It is possible that AZ, planning for a 2Q14 decision from the FDA, is still working on building manufacturing capacity for the new device or training sales reps on the new device though we would assume the latter should be pretty easy, particularly with one organization and sales force now. The company has not disclosed the date of its US filing. The dual-chambered pen is under regulatory review in the EU, where it was submitted at the end of 2013, and management has guided for a 4Q14 decision there. AZ is also developing a suspension formulation and an auto-injector device for Bydureon, with filings planned for 2015.  

• An illustrated guide for the newly approved Bydureon dual-chambered pen was recently posted in Bydureon’s updated FDA drug label (see page 62). See the images below for a picture of the device. Notably, we learned that the procedure for readying the pen and administering the injection is a bit more involved than we had been expecting. First, the pen must be refrigerated for storage, and be allowed to rest at room temperature for at least fifteen minutes before administration. That limits to some degree where and how patients can take it, although we suspect most patients will want to take it at home anyway, so it’s by no means a deal breaker. Second, the patient twists the base of the pen to combine the Bydureon microspheres and the solvent in a mixing chamber; at this point, the patient taps the pen firmly against the palm of their hand to mix the components, pausing to rotate the pen every ten taps (see the images below). The guide states that patients may need to tap the pen “80 times or more,” a process that (by our estimate) would take upwards of 30 seconds, and perhaps more for elderly or impaired patients. This is not a problem, per se, though there could be a bit of fatigue related to this. If the solution is still cloudy upon inspection through the pen’s mixing window, further tapping (to encourage more mixing) is required. The good news is that it should be easy for patients to see when the pen is ready. Although the pen is certainly a very meaningful improvement over the old Bydureon administration protocol by virtually any definition, it does not yet approach the convenience of most insulin pens and Victoza’s pen, which are dial-and-inject. We anticipate that AZ’s Bydureon suspension formula and auto-injector (filing planned for 2015) will bring an even larger leap forward in terms of convenience.

Image 1: Bydureon dual-chambered pen 

Image 2: Mixing procedure for Bydureon dual-chambered pen 

* Both images are from the updated drug label on the FDA website

• The dual-chambered pen should help the Bydureon franchise (the only once-weekly GLP-1 agonist current available) continue building momentum in the short-term. AZ featured Bydureon’s relatively strong recent performance in its 4Q13 Report, highlighting that the drug’s total prescription share (TRx) was climbing through 17.5% as of mid-December, with further growth in January likely due to the Express Scripts contract won from Novo Nordisk.
  
  • The approval of the dual-chambered pen is especially important for AZ in the face of more competition arriving on the long-acting once-weekly GLP-1 agonist front: GSK’s once-weekly GLP-1 agonist Eperzan (albiglutide) could be approved by the FDA in April and Lilly’s once-weekly dulaglutide could be approved later this year (potentially in October given a standard 12-month review cycle; please see table below for late-stage GLP-1 agonist competitive landscape). The convenience factor of the devices for each drug could be a major differentiating factor. At the moment, it seems that Lilly’s dulaglutide may have a leg up on the competition with its one-step automatic injector device (patients never have to see the needle or worry about mixing ingredients together), at least until AZ’s auto-injector arrives. From the wording of GSK’s press releases, it appears that the device for Eperzan will be a pre-filled pen requiring mixing of ingredients that are contained within the pen, which would give it roughly the same patient convenience factor as the Bydureon dual-chambered pen, although it is of course difficult to speculate on such comparisons without knowing more details. For more details on Eperzan, see our GSK 4Q13 Report; for more on dulaglutide, see our Lilly 4Q13 Report and our more recent report on dulaglutide showing noninferiority to Victoza. Intarcia is also working on a once or twice-yearly implantable exenatide osmotic mini-pump (ITCA-650), which has the potential to be disruptive from a user experience perspective (both patients as well as HCPs). The company presented striking data on the candidate (mean 3.2% A1c reduction from a high baseline of 10.9%) at Day #1 of this year’s JP Morgan Healthcare Conference.
• For much more on Bydureon, including it’s recent financial performance, line extensions, and the once-weekly GLP-1 agonist competitive landscape, read our AZ 4Q13 Report.

Our questions about the new Bydureon pen include:

• How will the competitive landscape for the once-weekly GLP-1 agonist field be defined by injection devices vs the drugs’ clinical properties?
• How will payers consider device characteristics in decisions over coverage and formulary positioning for this class of products?
• How will the Bydureon pen be priced?
• How do manufacturing costs change with the Bydureon pen?
• The press release notes the current Bydureon formulation will still be available. Why is this?
• How should patients and HCPs interpret “later this year” for the pen’s launch?
• What were the nature of the tests that delayed approval from 2012?
• When was the Bydureon pen submitted to FDA and what does likely regulatory timing look like globally? In what other countries has this been submitted? Might the EU regulatory process also be completed ahead of schedule?

Table: Late-stage GLP-1 agonist competitive landscape

-- by Manu Venkat, Jessica Dong, and Kelly Close