EMA approves Novo Nordisk’s Victoza for the reduction of CV events – July 28, 2017

Novo Nordisk announced yesterday that the EMA has approved a new CV indication for GLP-1 agonist Victoza (liraglutide). Based on positive results from the LEADER trial (including 13% risk reduction for three-point MACE – non-fatal MI, non-fatal stroke, CV death – and 22% risk reduction for CV death specifically), the European label for Victoza will now include an indication to prevent CV events in type 2 diabetes patients facing high CV risk. Victoza is the first GLP-1 agonist and the second diabetes drug to have a CV indication added to the label, after Lilly/BI’s SGLT-2 inhibitor Jardiance (though this latter product is indicated specifically for the reduction of CV death). While we wait for the FDA to decide on a similar indication for the US Victoza label (expected very soon, in August 2017, following last month’s Advisory Committee meeting), we think this news from the EU is certainly something to celebrate. CV disease remains the leading cause of death for people with diabetes, so anti-hyperglycemic therapies that also protect against CV morbidity and mortality are tremendously valuable in our treatment arsenal. As the needle on best practice diabetes care moves beyond glucose-lowering to really preventing complications and improving outcomes, it’s important for busy healthcare providers (endos and PCPs alike) to have ready access to information on demonstrated CV risk reduction, indicated clearly on a product label. We hope this encourages greater uptake of Victoza, so that more patients at high-risk for CV morbidity/mortality reap the cardioprotective benefits. We also eagerly anticipate the payer response to this expanded indication – our fingers are crossed that this label change improves reimbursement prospects for the GLP-1 agonist, as this therapy class remains out of reach for many patients. As Dr. John Buse so eloquently articulated at the recent Keystone conference, “it is immoral that as a society we mandate a certain set of trials be done from a regulatory perspective, and then not require that insurance companies cover these drugs if they’re shown to reduce mortality. We’re not talking about reducing toenail fungus. We’re talking about reducing mortality.” Yes, indeed. Conducting a CVOT is a massive investment, and it feels unacceptable to then keep life-saving benefits out of the public eye, or off product labels. Our fingers are so very crossed for similar news on Victoza’s US product label from the FDA.  

• The European label will indicate Victoza for the prevention of CV events in high-risk patients (although it will also include overall LEADER data which showed a benefit for the total enrolled population) – we mention this again, because it was one focus of debate at the recent FDA Advisory Committee meeting. Panelists voted 17-2 in favor of a new CV indication for Victoza on the US product label, but also largely agreed that liraglutide only demonstrated very compelling cardioprotection in the subset of LEADER participants at very high CV risk. This opinion was based primarily on a subgroup analysis of higher-risk vs. lower-risk study participants: The hazard ratio point estimate for three-point MACE was 0.83 in favor of liraglutide for the higher-risk subgroup (95% CI: 0.74-0.93) vs. 1.2 in favor of placebo for the lower-risk subgroup (95% CI: 0.66-1.67, which crosses the line of unity, meaning this finding is not statistically significant). The criteria for “higher-risk” included ≥50 years-old with type 2 diabetes and established CV or renal disease at baseline (history of MI, stroke, peripheral vascular disease, or class II-III heart failure, arterial stenosis >50% or symptomatic/asymptomatic ischemia, and eGFR <<60 ml/min/1.73m²). This cohort was more inclusive than the typical “secondary prevention” definition of previous history of CV events, but still, based on the majority opinion of the Advisory Committee, it seems likely that any FDA-approved indication for Victoza will also be restricted to diabetes patients at high CV risk. We’ll be curious to see the precise language used to describe “high CV risk” following these discussion points at the Ad Comm, if the FDA approval comes through. Jardiance’s CV indication in the US also applies to high-risk patients, and we’ll likely have to wait for CVOTs with a higher number of “primary prevention” participants before we see broader indications for cardioprotection.
• We’ll be interested to see how Novo Nordisk spreads awareness of this label update among diabetes care providers and cardiologists. In educating patients and HCPs about Jardiance’s CV indication, Lilly/BI are taking strides in the effort to increase understanding of the diabetes/CV disease overlap more generally – we think this is such an important goal, and we’re excited to see how Novo Nordisk contributes. We look forward to management’s commentary to this end during Novo Nordisk’s 2Q17 earnings call on August 9. Further out, we wonder how the company will present this label revision at the annual European Society for Cardiology (ESC) congress (this year from August 26-30 in Barcelona). Novo Nordisk (and diabetes therapy on the whole) had a noticeably larger presence at ESC 2016 than in years past, a sign of increasing crossover between endocrinology and cardiology practices. We suspect ESC 2017 will feature even more content related to diabetes, especially with anti-hyperglycemic drugs like Jardiance and Victoza now explicitly indicated for CV risk reduction, inviting cardiologists to prescribe them.
• The Committee for Medicinal Products for Human Use (CHMP) recently endorsed the inclusion of LEADER data on the European label for Saxenda (liraglutide 3.0 mg for obesity) as well. This was somewhat unexpected, since LEADER only investigated 1.2 mg and 1.8 mg doses of liraglutide in people with type 2 diabetes. That said, a label update that adds new clinical trial data is not as strong as one that reflects a brand new, explicit indication. CHMP previous concluded that LEADER trial results would be sufficient to support the CV safety of Saxenda, meaning Novo Nordisk isn’t required to conducted a separate, dedicated CVOT for its higher-dose formulation of liraglutide. We see this is as good news overall: Liraglutide has clearly demonstrated potency, both in glucose-lowering and in weight loss, and data from the SCALE program has even found Saxenda to delay new-onset type 2 diabetes (the prevention piece is quite meaningful). There is convincing published evidence in support of liraglutide’s safety (if not superiority over placebo). Because Saxenda is priced proportional to dose, its list price is rather high, and reimbursement prospects are poor. We hope having LEADER data on the label makes a more compelling case to payers, and sparks greater coverage.

-- by Payal Marathe and Kelly Close