Memorandum

FDA approves Lilly/BI’s first-in-class Glyxambi (empagliflozin/linagliptin) fixed-dose combination – February 3, 2015

Executive Highlights

  • Lilly/BI announced yesterday that the FDA has approved its empagliflozin/ linagliptin fixed-dose combination (FDC), which will be marketed under the trade name Glyxambi.
  • Glyxambi is the first product in the much-anticipated SGLT-2 inhibitor/DPP-4 inhibitor FDC class to receive regulatory approval.

Lilly/BI announced yesterday that the FDA has approved its empagliflozin/linagliptin fixed-dose combination (FDC), which will be marketed under the trade name Glyxambi (“ambi” being a Latin root meaning “both”). Glyxambi is the first SGLT-2 inhibitor/DPP-4 inhibitor FDC to receive regulatory approval, and we are thrilled to see this much-anticipated class of combinations finally on the verge of reaching patients. Glyxambi will be available in two doses (10 mg empagliflozin/5 mg linagliptin and 25 mg empagliflozin/5 mg linagliptin) and is indicated for all patients with type 2 diabetes for whom treatment with both components is appropriate. The timing of the announcement is consistent with a standard review cycle of ~10 months between NDA acceptance and approval; we await more details from Lilly/BI on the expected launch timing and any post-approval requirements. Lilly confirmed during its 4Q14 update that the combination should be filed in the EU in 2015; the main competitor in this class will be AZ’s saxagliptin/dapagliflozin FDC, which was recently submitted in the US (EU submission is slated for 2Q15). There is also a possibility for an ertugliflozin/sitagliptin combination from Merck and Pfizer, which would be a potentially promising contender given management’s comments that ertugliflozin has potential best-in-class properties and sitagliptin’s (Januvia) market-leading status within the DPP-4 inhibitor class – whether or not it will be differentiated, the two marketing giants certainly will be interesting to watch market this fixed dose combination.

There has been a great deal of excitement over the past few years surrounding SGLT-2 inhibitor/DPP-4 inhibitor FDCs, which combine two classes with highly attractive and complementary profiles. The products have demonstrated impressive efficacy for an oral medication in phase 3 trials (A1c reductions >1%), though the effects fell short of the additive/synergistic efficacy that some had predicted. We believe this efficacy, along with the potential for weight loss and blood pressure reductions, the mild side effect profile, and the convenience of a single, once-daily pill (with one co-pay, very importantly), should make this class an appealing option for a wide range of patients with type 2 diabetes. We are curious to see whether the class primarily attracts patients who are already on multiple oral medications or whether it could emerge as a common second-line treatment option for patients more poorly controlled on metformin alone. Pricing and reimbursement also remain key unanswered questions; in particular, we wonder whether Lilly/BI will attempt to price Glyxambi according to the sum of its parts (we doubt it could do this entirely) and whether the product will have a copay assistance program comparable to those for Jardiance (empagliflozin) and other SGLT-2 inhibitors. We are also interested in learning more about implications for gross margins, etc though we assume that is very confidential information.   

  • Glyxambi’s phase 3 program involved two trials, one testing the combination in patients on background metformin and another testing it in drug-naïve patients:
    • In the trial enrolling patients already on metformin, full 52-week phase 3 data presented at EASD demonstrated superior efficacy with Glyxambi vs. either component alone. The results were consistent with 24-week data presented at ADA: both doses of Glyxambi achieved A1c reductions >1% (baseline = 8.0%) that were superior to the reductions with either empagliflozin (~0.7%) or linagliptin (~0.5%) alone. The A1c reductions were remarkably durable with the combination and with empagliflozin; the linagliptin group saw a slight upward creep in A1c during the second half of the study. A subgroup analysis found that Glyxambi’s efficacy was close to additive in patients with a lower baseline A1c (<8.5%), whereas the efficacy was largely driven by the empagliflozin component in those with a higher baseline A1c. Patients treated with the combination saw improvements in systolic blood pressure (~3 mm Hg) and body weight (~3 lbs) comparable to those achieved with empagliflozin. There was a slight increase in genital mycotic infections with Glyxambi (as with empagliflozin), though the incidence remained below 10% for all study groups; there were no unexpected or worrying imbalances in adverse events.
    • The results in the drug-naïve study (see our ADA poster coverage) were also generally positive, though with one caveat (at least at 24 weeks). While the efficacy seen with the high-dose (empagliflozin 25 mg/linagliptin 5mg) was certainly strong, it did not achieve a statistically significantly greater A1c reduction than empagliflozin monotherapy. Empa/lina 25 mg/5 mg yielded a mean A1c reduction of 1.08% after 24 weeks, compared to 0.67% with linagliptin 5mg (p<0.001) and -0.95% with empagliflozin 25 mg (p = 0.179), from a baseline of ~8%. From what we could tell, the results may have been dampened by a weaker-than-expected performance from the high-dose FDC group, as the lower-dose FDC (empa 10 mg/lina 5 mg) had a greater mean A1c reduction (-1.24%) and achieved statistically significantly better efficacy than its component monotherapy doses.
  • Triple-therapy SGLT-2 inhibitor/DPP-4 inhibitor/metformin FDCs could potentially be the next frontier in oral combination therapy for type 2 diabetes. AZ recently completed a phase 3 trial (ClinicalTrials.gov Identifier: NCT01619059) of triple therapy (taken as separate tablets in this study) with saxagliptin, dapagliflozin, and metformin and has another ongoing trial expected to complete this month (ClinicalTrials.gov Identifier: NCT01646320). We hope to hear more about these studies and the company’s plans for a potential triple-therapy FDC during AZ’s 4Q14 update on February 5; management has indicated in the past that a regulatory submission would not occur until 2017 at the earliest. We wonder whether Lilly/BI have any plans to pursue such a combination; Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX) concluded his EASD presentation on Glyxambi by suggesting that the two compounds could eventually be combined in one tablet with metformin, but we have not heard anything concrete from the companies on this.
  • Several companies are also exploring the possibility of GLP-1 agonist/SGLT-2 inhibitor combination therapy. AZ has initiated a phase 3 trial of exenatide/dapagliflozin combination therapy (ClinicalTrials.gov Identifier: NCT02229396; primary completion expected June 2016), and Dr. Ralph DeFronzo is conducting a trial with Janssen evaluating combination therapy with J&J’s Invokana (canagliflozin) and Novo Nordisk’s Victoza (liraglutide). These combinations could potentially produce even more impressive efficacy than SGLT-2 inhibitor/DPP-4 inhibitor combinations given the greater potency of GLP-1 agonists, though they would lack the convenience of a single-pill, single-copay FDC.

Close Concerns Questions

  • What is the expected launch timeline? To what extent will the launch target endocrinologists vs. PCPs?
  • How impressive will the “real-world” efficacy of the combination be compared to SGLT-2 inhibitors alone?
  • Will Glyxambi be prescribed primarily to patients already on multiple oral medications or will it become a common second-line treatment option?
  • Will Glyxambi be priced according to the sum of its parts? Will Lilly/BI offer a copay assistance program? How well will Glyxambi be reimbursed?
  • How much of an advantage will Glyxambi’s first-in-class status give the product over future competitors?
  • How will providers and patients view Glyxambi’s clinical profile vs. the benefits offered by GLP-1 agonist/basal insulin combinations?
  • Does Lilly/BI have plans to investigate a triple-therapy FDC (Glyxambi + metformin) or GLP-1 agonist/SGLT-2 inhibitor combination therapy?

-- by Emily Regier, Manu Venkat, and Kelly Close