It is now a given that glucose-lowering drugs need to show that they can also prevent cardiovascular complications and death, since heart disease is so prevalent among diabetics. Two upcoming events will show just how important a cardiovascular claim is.
Johnson & Johnson’s Invokana is due a decision in July on adding data from the Canvas trial to its label, a move that could help it stop sales from shrinking even more. Astrazeneca, meanwhile, expects results later this year from the Declare-Timi58 trial of Farxiga, and hopes that this will show a specific benefit in heart failure.
Of the three SGLT-2 inhibitors approved so far for type 2 diabetes just one, Lilly and Boehringer Ingelheim’s Jardiance, has been permitted to boast a cardiovascular benefit. Jardiance’s lead in sales over Invokana and Farxiga shows the need for these rivals to catch up with their labelling.
Invokana, of course, has an additional problem in that post-marketing surveillance identified a risk of lower-limb amputations, leading to a black box on the label (Amputation risk adds another cut to Invokana, May 30, 2017). This looks likely to demote the drug from the blockbuster club from next year, according to EvaluatePharma’s consensus of sellside analysts.
|Outlook for SGLT-2 diabetes pills|
|Global sales ($m)|
|Invokana||Johnson & Johnson/Mitsubishi Tanabe||1,020||916||890||836|
|Steglatro||Merck & Co||49||238||414||572|
|Lusefi||Taisho Pharmaceutical Holdings||60||97||126||155|
This is why getting the cardiovascular claim is so important. Without the ability to market on a level playing field with Jardiance – on cardiac benefit at least – Invokana will become a harder sell. Fortunately for J&J, the data from Canvas are pretty good; Invokana reduced the risk of cardiovascular death, or non-fatal myocardial infarction or stroke by 14% versus placebo (ADA – Canvas paints a mixed picture for J&J’s Invokana, June 12, 2017).
As with many of these cardiovascular outcomes studies, the picture behind that endpoint was mixed, with the individual components of the composite missing statistical significance. The same was true of Jardiance, which missed on such secondary endpoints as prevention of myocardial infarctions in the Empa-Reg Outcomes study.
Where both have really shone is on heart failure-related endpoints. Researchers have hypothesised that SGLT-2s' mechanism of action – excretion of blood glucose through the urine – has a diuretic effect that benefits heart failure patients. Indeed, Lilly and Boehringer are testing this with a phase III trial enrolling chronic heart failure patients that have no diabetes diagnosis.
Failure is an option
Astra looks like it learned from the earlier-to-market drugs when it designed the Declare-Timi58 trial. In addition to the cardiovascular death, MI and stroke composite endpoint, Declare has a four-point co-primary composite that includes hospitalisation for heart failure, the only SGLT-2 outcomes study that has done so.
Declare is expected to read out in the second half of 2018. Obviously, showing a benefit is essential for Farxiga to remain relevant – although even without the cardiovascular claim it has caught up to Invokana thanks to the latter’s amputation risk.
However, a specific claim on heart failure hospitalisation could give it an edge against Jardiance. Certainly, when payers are looking at the cost-effectiveness of a drug, prevention of expensive hospital stays is one consideration; the average cost of a heart failure hospital stay for US Medicare beneficiaries is more than $14,000, and 40% are re-admitted within 90 days.
Astra has already pushed hard on the idea that a cardiovascular benefit is a class effect across all SGLT-2 pills. It has funded the CVD-Real “real world” analysis of patient registries demonstrating that SGLT-2s broadly prevent cardiovascular death and hospitalisations – this should have readied payers and physicians for Astra’s marketing message if Declare is positive (ACC – Jardiance heart benefit looks like a class effect, March 20, 2017).
It is possible, of course, that CVD-Real’s results were biased by the benefit of Jardiance and Invokana, which is why regulators will want to see the results of Declare before making a label change. If Astra hopes to keep Farxiga from suffering a decline like Invokana, it needs Declare to be positive.