木瓜直播

BARCELONA -- Long-awaited evidence that targeting an inflammatory pathway can reduce heart attacks and stroke independent of lipids is now in hand -- canakinumab (Ilaris) reduced events by 15% compared with placebo.

But there is a two-fold catch: Because canakinumab is an immunotherapy, the drug carries a high price tag and use was associated with an increased risk of fatal infections.

Canakinumab is a human monoclonal antibody that targets the interleukin-1beta innate immunity pathway and it is currently approved as an orphan drug for treatment of two rare pediatric conditions -- systemic juvenile idiopathic arthritis and cryopyrin-associated periodic syndromes for which it is administered monthly and carries an annual price tag of $200,000.

Thus, the reception was mixed: Anthony DeMaria, MD, of the University of California San Diego School of Medicine, called the results "really big because it is a totally new mechanism." But while Stanford cardiologist Robert Harrington, MD, agreed that CANTOS provides evidence to validate the inflammation hypothesis, he suggested it is too soon to strike up the band.

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), 150 mg of canakinumab every 3 months reduced high-sensitivity C-reactive protein (hs-CRP) levels by an average of 37% compared with placebo and achieved a 15% reduction in cardiovascular events -- mostly MIs -- compared with placebo, Paul Ridker, MD, reported here at the European Society of Cardiology 2017 congress.

The CANTOS findings were simultaneously published online by the.

After a median follow-up of 3.7 years, the event rate was 4.5 per 100 person-years in the placebo group versus 3.86 events per 100 person-years in the canakinumab 150 mg group. Two other arms -- canakinumab 50 mg and 300 mg -- also achieved reductions in events (4.11 and 3.90 per 100 person-years, respectively) but only the 150-mg dose achieved a statistically significant reduction. There was no reduction in mortality.

The trial recruited patients who had a history of MI and a hs-CRP level of 2.0 mg/L or higher.

Reflecting on the finding, Ridker told 木瓜直播 that he had spent roughly 25 years investigating "one fundamental question: Why do half of all heart attacks and strokes occur in people with no known risks?"

His timeline for proving the inflammation hypothesis began more than 20 years ago, "when we published the first paper that said if you checked an inflammatory marker, what we now call CRP, you could identify people at high risk for heart attacks ... 19 years ago we published a paper showing that statins reduced inflammation, and about 8 or 9 years ago we published a paper that showed if you had high CRP and low LDL, you had better be on a statin.

And through that whole process the fundamental question we asked remained: Can we lower event rates by reducing inflammation?"

The answer, based on CANTOS, is yes, Ridker concluded.

Moreover, he noted that, although there was no cardiovascular mortality benefit, there was 30% reduction in need for bypass surgery, angioplasty, and heart failure -- all of which means a significant improvement in quality of life. And treatment was also associated with a reduction in gout, rheumatoid arthritis, and osteoarthritis, he said.

Interestingly, the treatment had no effect on lipids, which suggests that the benefit was all attributable to the anti-inflammatory activity. But Ridker added that the inflammatory hypothesis in no way competes with the lipid hypothesis. "I think statins are the miracle drugs of the century, and all of these patients [in CANTOS] were on aggressive statin therapy."

Cancer Benefit

And canakinumab treatment had yet another benefit: There was an apparent decrease in risk of cancer, a finding that was elucidated in a paper also published today. In the cancer analysis, also authored by Ridker, total cancer mortality was lower only in the 300-mg group, but "[i]ncident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0.61 [95% CI 0.39–0.97]; P=0.034) and 300 mg groups (HR 0.33 [95% CI 0.18–0.59] P<0.0001."

And now the bad: Canakinumab was associated with a higher incidence of fatal infection than placebo -- the rate was 0.18 in the 3,344 patient placebo group versus 0.32 among the 6,717 patients who received any dose of the drug, which worked out to 23 deaths versus 78 deaths (P=0.02).

There was no significant difference in all-cause mortality (HR for all canakinumab doses versus placebo, 0.94; 95% CI 0.83-1.06; P=0.31).

"Despite the scientific and clinical excitement associated with having a new mechanism of action to attack in the treatment of coronary artery disease," Harrington wrote, "a better understanding of the risks and benefits of this form of therapy is needed. Given that there was no observed effect on cardiovascular mortality in this trial, more information about the details of the myocardial infarctions (infarct size, Q-wave versus non–Q-wave, and spontaneous or procedure-related) is needed to better assess the clinical benefit of canakinumab. We also need additional information about the fatal infections encountered in CANTOS. Furthermore, any discussion of the use of canakinumab in patients with a previous myocardial infarction must consider cost. Given monthly for approved indications, canakinumab is priced at approximately $200,000 per year in the United States. Such pricing may be suitable for rare diseases, but not for a common indication such as coronary artery disease, even if given every 3 months."

Price vs Benefit

Harrington is not the first to point out this difficulty with CANTOS -- on June 28 heart failure specialist Milton Packer, MD, wrote this in his 木瓜直播 blog: "My prediction: [canakinumab] may cost $64,000 for a 15-20% reduction in the risk of a major cardiovascular event, without decreasing cardiovascular death by itself.

"Is it worth it? If there was push back from payers for [evolocumab] Repatha, I can just imagine what will happen if Ilaris receives a cardiovascular indication."

Repatha is a PCSK9 inhibitor that aggressively lowers lipids and is approved for patients who fail statin therapy, including patients with heterozygous or homozygous familial hypercholesterolemia. But while the lipid reductions with the PCSK9 therapy are impressive, and the FOURIER trial found a 15% reduction in events with treatment, neither evolocumab nor alirocumab (Praluent), a PCSK9 inhibitor from Sanofi/Regeneron have achieved wide uptake as payers balk at the high price tags for the drugs.

Speaking at an ESC press briefing, Ridker said, "This is what personalized predictive medicine is all about." Once a patient has experienced an MI, there is always residual risk of recurrence. Thus, he suggested that residual risk can be divided into residual lipid-driven risk and residual inflammatory-driven risk.

Co-investigator, Peter Libby, MD, of Massachusetts General Hospital, put it this way: 30 days after an MI, when a patient is on statin therapy and stable, physicians could check LDL and then initiate more aggessive statin therapy if it is not well-controlled. Similarly, physicians should check hs-CRP, and if it is elevated -- 2.0 mg/L or higher -- initiating anti-inflammatory therapy targeting interleukin-1 beta would be an option.

That said, Libby noted that he was not recommending off-label use of canakinumab. "We need to wait for guideline committees to assess the evidence."

Ridker told 木瓜直播 he believed canakinumab might prove to be most useful if it were given to an identified high-responder group. He noted that after a single injection responders have a significant reduction in highly sensitive-CRP and it is those patients who would benefit from continuing on treatment. At that point, "I believe the benefit would outweigh the toxicity risk," he said.

"Maybe that first dose could be free," Ridker added.

And while canakinumab is the first anti-inflammatory agent to demontrate benefit, there may be others, Ridker said. For example, "we have a [National Heart, Lung, and Blood Institute] trial of methotrexate that is on-going. If that proves to be effective, it would be only pennies per treatment." At the press conference, Ridker said the methotrexate trial has "randomized about 4,000 patients, and we will need to get to 7,000 so it will be a few years before we have results."

Novartis, which developed canakinumab, may be sympathetic to that approach. Novartis Global Head Drug Development and Chief Medical Officer Vas Narasimhan, MD, and Jay Bradner, MD, president of the company's Institutes for BioMedical Research, told reporters that the company planned to go ahead with a filing with the FDA as early as October.

"We plan to move ahead with a cardiovascular filing" based on the CANTOS results, Narasimhan said. And while the filing will be based on the total results, "we plan to bring the findings in the hs-CRP responders to our meeting with the FDA." The company also plans to proceed with a phase III trial in non-small cell lung cancer in the first quarter of 2018.

Narasimhan said that, in CANTOS, patients whose hs-CRP declined to 1.8 mg/L or less had a much more robust response. In that subgroup, the number needed to treat to prevent a primary endpoint event was 50 at 2 years and 30 at 3.7 years.

Comment