Trulicity, which was approved for T2D in September 2014, made $2.03bn in global sales in 2017. Analysts forecast it could reach $4.9bn by 2022. An analyst report also noted that Lilly’s cardiovascular outcomes trial (CVOT), dubbed REWIND, has a longer follow-up duration than competitor Novo Nordisk’s successful LEADER study for Victoza (liraglutide), which could give Trulicity a boost. But REWIND’s healthier trial population could be risky. If REWIND does succeed, though, it could mean a larger market for Trulicity.
Trulicity’s demonstrated effect on HbA1c and weight as well as its similarity to agents that have already shown benefit provides potential for REWIND to succeed. Trial results are expected in late-2018, according to the company’s 4Q17 investor call.
Lilly did not respond to a request for comment.
HbA1c, weight-loss data impresses
It is highly unlikely the REWIND trial will show CV harm based on evidence from other CVOTs of drugs that belong to the same class as Trulicity known as GLP-1 agnoists, agreed Dr Zachary Bloomgarden, clinical professor, Icahn School of Medicine at Mount Sinai, New York, and Paul O’Hare, associate clinical professor, Warwick Medical School, UK. Both of Novo’s GLP-1s — Victoza and Ozempic (intravenous semaglutide) — showed significant CV protection, and while AstraZeneca’s GLP-1 Bydureon (exenatide once-weekly) failed to show statistically significant CV risk reduction, it did not show CV harm either. Sanofi’s (EPA:SAN) Lyxumia (lixisenatide) showed that it was noninferior to placebo for cardiovascular safety.
Despite its failure to show statistically significant CV risk reduction, Bydureon did show an all-cause mortality reduction and a trend toward CV benefit, Bloomgarden noted. There were reportedly 839 CV events observed in the Bydureon arm (11.4%) versus 905 in the placebo arm (12.2%). Trulicity is comparable to Bydureon and thus similar positive trends are anticipated, he said.
In fact, Trulicity could even show benefit, because it seems to be highly effective at HbA1c reduction and weight reduction, added Bloomgarden and Steve Bain, professor in medicine (diabetes), Swansea University Medical School, UK. In its Phase III AWARD-6 study, which compared the drug to Victoza, Trulicity’s mean Hba1c reduction was -1.42% versus Victoza’s -1.36%, with Trulicity patients losing 2.9 kg on average at 26 weeks (Dungan et al. 2014 The Lancet;384(9951):1349-57).
Trulicity could also show benefit, because the potency of its receptor agonism is comparable with Victoza and Ozempic, O’Hare said. The 9,340-patient LEADER trial demonstrated that Victoza reduced the risk of cardiovascular death, nonfatal heart attack or nonfatal stroke by 13% versus 14.9% for placebo (p=0.01), with an absolute risk reduction of 1.9%. In the 3,297-patient SUSTAIN 6 study, cardiovascular death, nonfatal myocardial infarction or nonfatal stroke occurred in 6.6% of Ozempic-treated patients and 8.9% of the placebo group. REWIND is a 3,176-patient trial with the same primary endpoint as LEADER and SUSTAIN 6 of time from randomisation to the first occurrence of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke.
Doubts on GLP-1 class effect linger
Still, Bain and O’Hare noted, success spoilers can still happen due to Trulicity’s underlying differences to Victoza. Although a meta-analysis of multiple studies argue CV benefits are a class effect (Bethal et al Lancet Diabetes Endocrinol. 2018 Feb;6(2):105-113), looked at individually, some GLP-1s show only neutrality in their CVOTs, they noted.
Additionally, experts noted differences between REWIND and LEADER. It indeed makes sense that REWIND has a higher chance of success, as its six-year follow-up provides more time for Trulicity to demonstrate superiority, given that LEADER’s median follow-up of 3.8 years was sufficient for positive results, agreed Bloomgarden, Bain and O’Hare.
LEADER, however, only showed significance in less healthy, higher-risk patients, O’Hare and Bain noted. REWIND’s healthier demographic decreases its chance of success, noted Bloomgarden, Bain and O’Hare.
Still, if REWIND can account for this risk with its longer follow-up duration and show convincing protection in healthier patients, this will open up a larger market for Trulicity, O’Hare said. Whilst O’Hare and Bloomgarden said the perceived GLP-1 class-effect may have already encouraged uptake, O’Hare added that he still would not prescribe Trulicity for CV protection until the evidence is there. If it does demonstrate CV benefit, it has additional competitive advantages in its once-weekly formulation, its amicable application device and its weight-loss properties, experts said.
LEADER included patients with chronic renal failure, but these patients are excluded from REWIND, according to ClinicalTrials.com. Furthermore, unlike LEADER, REWIND excludes patients with HbA1c higher than 9.5%, those with acute coronary or cerebrovascular event within the past two months, those with a planned or anticipated revascularization procedure and those with a history of pancreatitis, hepatic insufficiency or C-cell thyroid disorder, while none of these are listed as exclusion criteria for LEADER. While LEADER included patients with chronic heart failure, REWIND did not but it did include patients with subclinical vascular disease.
Furthermore, the underlying mechanism of GLP-1s’ CV benefit is still unknown, which feeds uncertainty, O’Hare noted. One theory is increased pulse-rate seen in GLP-1s’ multiple T2D trials — previously considered detrimental — may in fact be linked to CV benefit, he said. It seems that those who have their CV system stimulated the most might be getting the most benefit, he explained. If this is the case, Trulicity may be just as good as Victoza, O’Hare said. According to public information, Trulicity has been shown to increase patient heart rates by 2-4 beats/minute, and in information on AWARD-6 data seen by this news service, Trulicity increased patient pulse rate by an average of 2.37 beats/minute while Victoza’s increase was an average of 3.12 beats/minute (p=0.25).
Additionally, the link between high blood glucose and CV risk is not direct, noted Dr William Winter, professor, Pathology & Pediatrics, University of Florida Diabetes Institute. People with diabetes have high cholesterol and high blood pressure, which can cause CV risk without high blood glucose, he explained. An ideal study would recruit patients with well-controlled cholesterol and blood pressure to see if lowering glucose can itself have an effect on CV risk, he said.
Hannah Wilgar is a reporter for GlobalData’s investigative journalism team, which is focused on breaking exclusive news and providing nuanced, forward-looking analyses. A version of this article originally appeared on 3 May in the Insights module of GlobalData’s Pharmaceutical Intelligence Center. GlobalData also provides unique and market-leading data and insights into the global pharmaceutical industry and is pharmaceutical-technology.com’s parent company. To access more investigative news like this article, visit GlobalData.