Memorandum

Lilly’s once-weekly GLP-1 agonist Trulicity (dulaglutide) approved in the US – September 18, 2014

Executive Highlights

  • Lilly just announced the FDA’s approval of its GLP-1 agonist Trulicity (dulaglutide), the first ready-to-use once weekly GLP-1 agonist available; US launch expected later this year.
  • The FDA is requiring a pediatric clinical trial, a medullary thyroid carcinoma registry, a preclinical study on development, and the completion of the REWIND CVOT as well as a study in patients with renal impairment.
  • The Trulicity single-use-pen (auto-injector), which allows quick drug administration without patients needing to see a needle, stands to be a leap forward in terms of patient comfort and convenience with injectable therapy for diabetes.

The FDA and Lilly today announced the approval of the GLP-1 agonist Trulicity (dulaglutide), the first once-weekly GLP-1 agonist approved that is available as a ready-to-use formulation rather than as a powder that requires reconstitution. It’s always a big deal when FDA itself announces an approval – we can certainly understand why they appear to be quite excited about this new entry. At EASD, we were able to see Lilly’s stellar single-use pen (an auto-injector; see below for more details); the product could well be a significant step forward for patients. GSK and AZ both have once-weekly GLP-1 agonists already on the market in the US – Tanzeum (albiglutide) and Bydureon (exenatide), respectively – and both products require a reconstitution process that takes upwards of 15 minutes. The timing is about as expected; as a reminder, Lilly first announced that it had submitted US/EU applications for dulaglutide during its investor meeting on October 3, 2013, meaning that the FDA review process likely took around a year. We have not yet heard word of an opinion from the EMA’s CHMP, meaning that a European decision is likely a couple of months away, although it should not be much farther beyond that. As a sidenote, EU regulatory authorities have also been busy, as the EU approval of Novo Nordisk’s IDegLira was also announced today – some true milestones, indeed.

Lilly states that the company plans to launch the product later this year. Trulicity will be available in 0.75 and 1.5 mg doses. The FDA is requiring five post-marketing studies in total, including a clinical study in pediatric patients along with the completion of the REWIND cardiovascular outcomes trial (scheduled to complete in early 2019) and AWARD-7 (in patients with moderate or severe chronic kidney disease). The agency is also requiring a preclinical study to assess potential effects on sexual maturation, reproduction, and CNS development and a medullary thyroid carcinoma (MTC) case registry of at least 15 years. Although this was a greater number of studies than was asked of Tanzeum or Victoza (at least via their FDA approval press releases), we do not see the load as burdensome overall, particularly given that some of the studies are already ongoing. With so much excitement about GLP-1/insulin combinations, we will be eager to see how Trulicity plays a role; while this isn’t combination therapy per se, it is in a way, since the usual 14 shots of a daily GLP-1/basal insulin “separate” combo therapy is being reduced to eight shots. While IDegLira and Lixi/Lantus will have seven shots a week, arguably the ability to titrate and dose insulin more flexibly will be billed as a major advantage. We’re really excited to be entering the realm of branded combination therapy and we can’t wait to see how this does in the marketplace.  

  • Although we are used to seeing GLP-1 agonists characterized for efficacy at reducing postprandial glucose, the longer-acting GLP-1 agonists have shown more balanced effect on postprandial and fasting glucose. Lilly has emphasized the favorable comparison for Trulicity versus basal insulin (non-inferior or greater A1c reductions, less hypoglycemia and weight gain, less frequent administration) seen in AWARD-2 and AWARD-4, and hopes to change the conversation that patients and providers have when moving beyond oral therapies. Additionally, the results from AWARD-6 make Trulicity the only GLP-1 agonist to achieve non-inferiority vs. the market-leading Victoza, a valuable feather-in-the-cap (so to speak) as Lilly appeals to payers and providers. We do note that Victoza did demonstrate slightly better weight loss in the trial, a material consideration for many patients. Still – the convenience (and help for adherence) that comes with a once-weekly, plus the ease of use, will be quite powerful selling tools, we think (we can just picture PCPs saying “Oh yeah – just take it every Sunday!”).
  • More than a tool to gain share in the GLP-1 agonist market, Lilly sees Trulicity as a tool to expand the entire class. This is a goal that (given the product’s clinical profile) should be within reach, and one that is badly needed given the recent slowdown in the GLP-1 agonist class due to the introduction of SGLT-2 inhibitors and the pancreatitis controversy. At the “Solvable Problems in Diabetes” at The diaTribe Foundation Benefit last night in Vienna, in the “quick lightning” round, both Professors Philip Home and Jens Sandahl Christiansen said that GLP-1 agonists were more likely to be billed cardioprotective than SGLT-2 inhibitors – that could be a game changer in our view, though we do wonder whether trials testing this are long enough (we are also concerned that the design to prove cardiac safety won’t be optimal for showing cardioprotection).
  • Trulicity received the standard broad type 2 diabetes indication from the FDA, with a few minor but notable caveats. Both the agency and company press release note that Trulicity is not recommended in patients with severe gastrointestinal problems, because the drug was not studied in this patient population (this includes severe gastroparesis). Lilly’s press release very specifically recommends against the use of Trulicity in patients with a history of pancreatitis, although the pancreatitis warning on GLP-1 agonist labels means that it is doubtful that the drug would have been prescribed much in this patient population anyways. We don’t think either of these is a big deal.
  • We see Trulicity’s single-use pen as unique, in that it allows patients to administer the drug without ever having to see a needle. With a single push of a button, the device inserts a 29-gauge needle into the skin, administers the injection, and withdraws the needle, all in a matter of seconds. We had the chance to put our hands on a demonstration model of the pen, and it was quite intuitive and simple to use – particularly relative to other pens in the class. We are excited that all will continue to improve – Lilly has set a pretty high bar here. Indeed, we were quite impressed with the amount of thought that Lilly put into optimizing the patient experience for Trulicity – it of course did not hurt that Trulicity is a ready-to-use suspension, and we also have to hand it to GSK and AZ for turning what could have been a very complicated reconstitution process into a relatively straightforward protocol with their respective pens. That said, under the guidance of the most impressive Dr. Sherry Martin, Lilly’s project lead – we believe taking GLP-1 has come quite a long way.  
    • Notably, having a quick and streamlined injection procedure means that Trulicity will be easy for providers to train patients on – we expect this to be a valuable advantage given the meager and shrinking amount of time that many providers have with patients. This characteristic could also make Trulicity remarkably primary-care-friendly for a GLP-1 agonist, although it does come with the same relatively complex set of contraindications and counter-recommendations that are linked to the GLP-1 agonist class. Still, we hope to see more focus by PCPs on how to really improve life for their patients and the composite effects of this product should certainly help on this front.
  • At day #1 of this year’s EASD meeting (EASD is just now wrapping up), Lilly hosted a morning symposium on GLP-1 agonists. Speaker Dr. Anthony Barnett (University of Birmingham, Birmingham, UK) characterized Trulicity as an important addition to the armamentarium” of treatment options. While that’s a pretty generic statement (this could be said about literally any new therapy and we worry sometimes there is too much chatter like this), in particular, Dr. Barnett stressed that Trulicity would be the first once weekly GLP-1 agonist on the market that does not require reconstitution and the only one that has demonstrated equal A1c-lowering efficacy to Novo Nordisk’s Victoza (once daily liraglutide). He urged providers to “think about the value of the drug, not just the cost of the drug” when making prescribing decisions, as he believes benefits like weight loss and a reduced risk of hypoglycemia are crucial for patients but often not taken seriously enough by the medical community.
  • The absence of an FDA Advisory Committee meeting for Trulicity (no AdComm was required either for Tanzeum) certainly appears to signal that the FDA is growing increasingly comfortable with the GLP-1 agonist class. A recent EMDAC AdComm on Saxenda, a higher dose of liraglutide intended for the treatment of obesity, provided a window into the FDA thought process – pancreatitis remains an unanswered question, but all in all the agency appears positive about the fact that there are multiple ongoing outcomes trials for the drug class.

Close Concerns Questions:

  • How will Trulicity’s efficacy, safety, tolerability, and weight profile compare against Novo Nordisk’s semaglutide, which looks to be the next ready-to-use once-weekly GLP-1 agonist coming down the pipeline?
  • To what extent will the modest but statistically significant weight loss advantage seen with Victoza over Trulicity in AWARD-6 be a decision-making factor for payers and providers?
  • Will Trulicity be able to secure optimal reimbursement in the US, given GSK’s recent decision to price its once-weekly Tanzeum at a significant discount vs. currently marketed GLP-1 agonists?
  • Could a device like the Trulicity single-use pen be used for other injectable diabetes therapies?

 

-- by Manu Venkat and Kelly Close