Memorandum

Elcelyx reports positive phase 2b topline data for Metformin Delayed Release (MDR) – November 18, 2016

Executive Highlights

  • Elcelyx Therapeutics reported positive topline data from the phase 2b dose-ranging study for its Metformin Delayed Release (DR). The drug met its primary endpoint of clinically and statistically significant reduction in A1c at 16 weeks.
  • Metformin DR could provide a promising treatment option for patients with renal impairment and those who cannot tolerate metformin due to GI side effects – a significant number of people.

Elcelyx Therapeutics recently reported positive topline data from the phase 2b dose-ranging study for its Metformin Delayed Release (DR), in which the drug met its primary endpoint of clinically and statistically significant reduction in A1c at 16 weeks (no further details). Initiated last year thanks to $40 million in Series E financing, the trial has enrolled 571 patients with type 2 diabetes who were randomized to daily treatment with one of four doses of Metformin DR (600 mg, 900 mg, 1200 mg, or 1500 mg) or placebo (double-blinded) or to twice-daily treatment with 1000 mg of immediate-release metformin (single-blinded). Unfortunately, the announcement did not share the magnitude of A1c reduction in the study or any other details, beyond noting that the A1c efficacy was dose-dependent; we are not sure what other measures beyond A1c will be provided. We look forward to learning the full results of Elcelyx’s phase 2b study in the months ahead, presumably when those results are published. Previous studies, two of which were published in Diabetes Care over a year ago, have demonstrated lower metformin exposure in the blood and comparable glucose-lowering efficacy with Metformin DR (which is targeted for absorption in the bowel) vs. existing metformin formulations. We’re  eager to better understand how Metformin DR is easier to prescribe and take, how much more tolerable it is, to what extent greater tolerability will lead to better adherence, etc. Metformin DR could provide a promising treatment option for patients with renal impairment and those who cannot tolerate metformin due to GI side effects – up to 20% of people with diabetes – as long as payers understand the value and are willing to cover it. We certainly hope to see this shift as market entry requires, now, safety, efficacy, and also economic value. Notably, Elcelyx now plans to conduct two phase 3 trials of Metformin DR. 

  • Enrollment criteria for the phase 2b study were as follows: Individuals with type 2 diabetes (A1c 7-10.5%) at least 25 years of age with an estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m2 who were not taking metformin for at least 2 months prior to screening. Subjects could wash out of prior metformin therapy after initiation of screening procedures if appropriate. Stable regimens of TZDs, sulfonylureas, DPP-4 inhibitors, and alpha-glucosidase inhibitors were allowed at screening (we aren’t sure how stability was defined).
  • Despite mounting pricing pressure, Elcelyx believes, based on payer interviews, that Metformin DR can expect pricing at parity to the DPP-4 inhibitors. The company says that Metformin DR boasts a strong value proposition as it fills the currently unmet need of patients who cannot tolerate metformin, the foundational type 2 diabetes therapy. Elcelyx is working to provide a better therapeutic option for the following groups of patients: (i) renally-impaired stage 4 chronic kidney disease (CKD) patients, stage 3b CKD patients, and new starts; (ii) those who can only be on sub-optimal doses of metformin (stage 3b CKD patients who are already on metformin when their renal function declines to this point are guided not to exceed 500mg twice-daily); and (iii) patients who cannot tolerate metformin due to GI intolerance.
    • Payers will have to be convinced that there is a major difference in adherence in order to pay for an expensive option to the generic metformin; we are very positive about paying more for therapy that patients adhere to and we think the evolution toward value-based healthcare could help Elcelyx considerably. Market entry requirements now rest not only on safety and efficacy, but also on economic value, and we believe much better outcomes are in store for patients that take more durable and patient-friendly therapies. If successful, this drug could also help doctors and nurses be more successful – no mean feat – with less work and better outcomes. We’re staying tuned for some of the actual data that can show this. Typically, we’re looking for outcomes beyond A1c – in this case, we’re also looking forward to seeing A1c data. Kudos to this company for trying to improve life for patients with particularly big needs who are also at major risk for avoidable costs to the system.  
  • A safety and pharmacokinetics analysis of Metformin DR was just presented as a poster at the 2016 Kidney Week conference in Chicago. Led by Dr. George Bakris (University of Chicago, Chicago, IL), the analysis involves a pharmacokinetic model that predicts metformin exposure from simulations of different doses of metformin (1000 and 2000 mg) and Metformin DR (600, 900, and 1200 mg) in patients with stage 3a, 3b, or 4 chronic kidney disease (CKD). Across all CKD stages, metformin DR elicited lower systemic exposure than the typical 2000 mg daily metformin dose. In particular, optimal dosing of Metformin DR in patients with CKD Stage 3b/4 is predicted to result in lower exposure than that observed with optimal dosing of current metformin in CKD Stage 3A.

-- by Abigail Dove, Helen Gao, and Kelly Close