CANTOS Trial Brings Unexpected CVD Promise For Novartis & Regeneron
Executive Summary
Few expected the positive top-line results from CANTOS showing the Phase III cardiovascular disease study using canakinumab met the primary endpoint. Most want to see the full details being unveiled later in 2017.
The hypothesis of targeting inflammation to stabilize plaque and thereby prevent cardiovascular events has apparently been confirmed in top-line data from Novartis AG's 10,000-patient CANTOS Phase III study of its IL-1β inhibitor antibody ACZ885 (canakinumab) in atherosclerosis.
The unexpected news – that the study measured over three years had met its primary endpoint of reducing the risk of major adverse cardiovascular events – gives the Swiss company a promising asset. Investors and the science world will need to await more details from the trial to see its precise efficacy and safety data.
Top-Line Data Only Revealed So Far
"We need to fully analyze the data, after which Novartis plans to start discussions with regulators in the US and Europe for eventual filing," a spokesperson told Scrip, without elaborating.
The top-line results are also promising for US-based Regeneron Pharmaceuticals Inc. from whom Novartis licensed the compound, and which receives royalties from its sales.
"ACZ885 is the first and only investigational agent which has shown that selectively targeting inflammation reduces cardiovascular risk." – Novartis CMO Vas Narasimhan
Novartis June 22 said its Canakinumab Anti-Inflammatory Thrombosis Outcomes Study, or CANTOS, met the primary endpoint, demonstrating that when used in combination with standard of care ACZ885 reduces the risk of major adverse cardiovascular events, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke (MACE), in patients with a prior heart attack and inflammatory atherosclerosis. Full data from the study will be unveiled at a medical congress later this year.
The medical need behind the study is clear: despite standard treatment, people with a prior heart attack live with a higher ongoing risk of having another event or dying. In about four in 10 people, this risk is directly related to increased inflammation associated with atherosclerosis, Novartis says.
"Despite current treatment, about 25% of heart attack survivors will have another cardiovascular event within five years, making the outcome of the CANTOS study a promising new development for patients," said Vas Narasimhan, Novartis' global head of drug development and chief medical officer.
He noted in a statement that ACZ885 was "the first and only investigational agent which has shown that selectively targeting inflammation reduces cardiovascular risk."
"Investors will likely be loath to believe that canakinumab could suddenly become a mega-blockbuster, especially because in the eyes of many, Novartis is currently a 'glass half empty' story … It will certainly be important to see the magnitude of the clinical benefit, along with the side effect profile." – Bernstein Analyst Tim Anderson
Canakinumab is an interleukin-1 beta blocker, already approved in the US as Ilaris for treating cryoporin-associated periodic syndrome and active systemic juvenile idiopathic arthritis.
Heart attack, the focus of CANTOS, occurs in about 580,000 people every year in Europe's five biggest economies and 750,000 people in the US. In 2015, there were an estimated 7.3 million heart attacks globally.
Analysts said the unexpected CANTOS news was promising for heart patients – and for Novartis investors – given the large unmet need the drug could potentially address.
"Cantos was a high-risk study, given there were no Phase II data upon which to base expectations, and as a result, expectations for success have been low," analysts at Jefferies said, adding that "the positive headline represents a significant incremental positive for the stock."
ACZ885 is thought to work by blocking the interleukin IL-1β pro-inflammatory cytokine. CANTOS evaluated three different quarterly doses (50 mg, 150 mg or 300 mg) versus placebo.
Analysts at Berenberg pointed to studies suggesting up to 50% of heart attacks or strokes occur in healthy men and women with low cholesterol or low risk of CVD.
"This has led to the hypothesis that, in these patients at least, underlying inflammation is driving the development of atherosclerosis. However, the literature has so far failed to find evidence that inflammation causes cardiovascular death. Instead, the consensus view has been that cardiovascular disease itself causes inflammation. In this context, 'inflammation' is quantified by measuring hsCRP, a non-specific inflammatory marker." They thus raised the issue of difficulties for ACZ885 fitting into standard of care for the secondary prevention of cardiovascular disease.
"HsCRP is a notoriously difficult biochemical marker for physicians; it can be raised by thousands of different pathologies ranging from the common cold to an insect bite. The premise of selecting a therapy for secondary prevention [of cardiovascular death] based on hsCRP is alien to physicians and we question how Novartis will approach this in order to have the drug prescribed. Given Novartis failed to meet expectations with its last major CV launch (Entresto), the company has much to prove with ACZ885," they concluded. (Also see "Novartis's Entresto Voyage: Hindsight Is 20/20" - Scrip, 15 May, 2017.)
Bernstein analyst Tim Anderson summed up by saying that "until full results are released later in the year - probably the American Heart Association congress in November), investors will likely be loath to believe that canakinumab could suddenly become a mega-blockbuster, especially because in the eyes of many, Novartis is currently a 'glass half empty' story … It will certainly be important to see the magnitude of the clinical benefit, along with the side effect profile," he concluded.
Regeneron Royalties Impact
Novartis's CANTOS announcement prompted Regeneron Pharmaceuticals to issue a statement clarifying its royalty rights to canakinumab if approved for sale as specified in their 2009 agreement. Regeneron said it had not reviewed the CANTOS data and could not predict whether the study would result in new indications or sales in the future. Regeneron is not involved in the development and regulatory process for canakinumab. (Also see "Novartis Ilaris Approved For Rare Autoinflammatory Disorder; Filings For More Common Diseases Planned" - Pink Sheet, 18 Jun, 2009.)
Under a 2009 agreement with Novartis, Regeneron receives a royalty on worldwide net sales of canakinumab; the royalty rate starts at 4% and reaches 15% when canakinumab annual sales exceed $1.5bn. The royalty applies to currently approved indications for Ilaris, and any potential sales for future indications, including related to the positive CANTOS top-line results.