ADA 2019 – another gut punch for Lilly

Lilly is still trying to find a therapeutic window following gastrointestinal issues with its brightest pipeline hope, the GIP/GLP1 agonist tirzepatide.

Yesterday’s big news for Lilly was disappointing data from a cardiovascular outcomes trial of its marketed GLP1 agonist Trulicity. But there were also signs that the group’s follow-up type 2 diabetes project, the dual GIP and GLP1 agonist tirzepatide, might not be progressing as smoothly as hoped.

The candidate is the most valuable in Lilly’s pipeline, with $1.2bn in sales forecast for 2024, according to EvaluatePharma sellside consensus. However, it has been linked with gastrointestinal side effects and worrying drop-out rates. And data presented at the American Diabetes Association meeting over the weekend failed to answer the question of whether the company can find a therapeutic window.

Titration trial

A previous phase IIb trial of tirzepatide, also known as LY3298176, found impressive HbA1c reductions of up to 2.4%, and weight loss of as much as 11kg after 26 weeks' treatment (Lilly shows that innovation in diabetes is not dead yet, October 5, 2018).

But that same trial also showed high rates of nausea, vomiting and diarrhoea, particularly with the highest dose studied, 15mg, which was also the most efficacious. And these side effects were not incidental, leading to high rates of discontinuations.

In an attempt to combat the adverse events Lilly is trying various dose-escalation schedules; the company’s ADA presentation with tirzepatide featured data from a 12-week phase II titration study.

While it claimed that the new dosing schedules had led to improved tolerability, a look at the numbers shows that the incidence of gastrointestinal effects was still high.

Side effects with tirzepatide
  Phase IIb, NCT03131687 Phase II dose titration, NCT03311724
Side effect 10mg 15mg 12mg schedule 15mg schedule 1* 15mg schedule 2*
Nausea 22% 40% 24% 39% 36%
Diarrhoea 24% 32% 31% 36% 32%
Vomiting 16% 26% 17% 18% 18%
Disc. at 12 wks 10% 32% 7% 21% 7%
Treatment-related disc. 6% 25% 3% 4% 0%
*Escalation from 2.5mg to 5mg to 10mg to 15mg over 8 wk; **Escalation from 2.5mg to 7.5mg to 15mg over 8 wk. Source: company releases, Evercore ISI note, June 10, 2019.

Brad Woodward, the leader of Lilly’s incretins division, stressed on a conference call yesterday that the number of patients discontinuing tirzepatide because of these adverse events had dropped to less than 4%.

He added that the lower drop-out rate could be explained by the fact that a mild classification could be applied to most gastrointestinal events: nearly two thirds of the total, versus less than half of those in the phase IIb trial.

Still, even if Lilly has cracked the tolerability issue, weight loss looks much less impressive in the dose-titration trial, although reading across from one trial to another is always somewhat risky.

Efficacy with tirzepatide
  Phase IIb, NCT03131687 Phase II dose titration, NCT03311724
Endpoint 10mg 15mg 12mg schedule 15mg schedule 1* 15mg schedule 2*
HbA1c reduction 2.0% 2.4% 1.7% 2.0% 1.8%
Weight loss 8.7kg 11.3kg 5.3kg 5.5kg 5.7kg
*Escalation from 2.5mg to 5mg to 10mg to 15mg over 8 wk; **Escalation from 2.5mg to 7.5mg to 15mg over 8 wk. Source: company releases, Evercore ISI note, June 10, 2019.

Perhaps this will all be academic – Lilly has already started several trials in the Surpass phase III programme of tirzepatide in type 2 diabetes, using yet another dosing schedule. This sees patients take four weeks to achieve the 5mg dose, 12 weeks to get to 10mg, and 20 weeks to reach 15mg.

Lilly hopes to see a decrease in gastrointestinal events in phase III, presumably without too big a drop-off in efficacy.

When asked how patients might deal with the long titration period, Enrique Conterno, president of Lilly’s diabetes division, noted that the company was also pursuing 5mg and 10mg doses, which also “showed significant benefit”. Indeed, the Evercore ISI analyst Umer Raffat believes that the 10mg dose will become the most commercially relevant.

The Surpass programme is set to conclude in 2021, and all being well Lilly plans to submit tirzepatide to regulators in 2022.

The group’s ambitions do not end there; it plans to start a phase III programme in obesity, Surmount, and the phase II studies in Nash, known as Synergy, later this year.

Somewhat surprisingly, Lilly’s diabetes arch-rival Novo Nordisk is not developing a dual GIP/GLP1 agonist. The Danish group does have a triple therapy comprising a glucagon, GLP1 and GIP agonist, known as tri-agonist 1706, but this is focused squarely on obesity, where the project is in phase I.  

Lilly’s stock ended yesterday down 4%. Although much of this drop will have been down to the Rewind disappointment, uncertainty around the group’s next big thing will not have helped.

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