Johnson & Johnson: can canagliflozin do what dapa didn't?

New clinical trial data for canagliflozin have revealed that its blood glucose-lowering abilities show superiority to blockbuster gold-standard Januvia, with the added benefit of weight loss. The potential for first-to-market SGLT-2 inhibitor status in the US and its good safety and efficacy profile boost canagliflozin's chances for success in a crowded diabetes market.

Janssen, a subsidiary of Johnson & Johnson, presented late-stage data from several trials of its novel antidiabetic canagliflozin at the American Diabetes Association meeting in June 2012. These results have driven interest in the drug following its recent regulatory submission to the FDA and prior to its upcoming European submission.

Canagliflozin comes from the same sodium glucose cotransporter-2 (SGLT-2) inhibitor class as dapagliflozin (Bristol-Myers Squibb/AstraZeneca), which has been delayed in the US by a January 2012 Complete Response Letter following (possibly random) imbalances in cancer cases and liver injury compared to control groups, as revealed in a trial meta-analysis. Canagliflozin's complete trial data have yet to be subjected to the same sort of pooled analysis, but the presented data indicate no evidence of cancer or liver concerns. They do, however, show some evidence of superior efficacy, which will affect the risk-benefit calculation and could differentiate the SGLT-2 inhibitor class of drugs.

Canagliflozin was shown to be effective when used as monotherapy, lowering HbA1c levels by 1.16% at 52 weeks for the 300mg dose compared to placebo in a two-dose trial in 584 patients. Furthermore, 300mg canagliflozin's blood glucose-lowering abilities showed superiority to gold-standard oral antidiabetic drug Januvia (sitagliptin; Merck & Co.) when used as add-on in type 2 diabetic patients inadequately controlled on metformin and sulfonylureas. Non-inferiority and superiority, respectively, were also shown by 100mg and 300mg doses of canagliflozin compared with the sulfonylurea glimepiride. At week 52, 300mg canagliflozin reduced HbA1c levels by 1.03% vs 0.66% when compared to sitagliptin, and by 0.93% vs 0.84% when compared to glimepiride.

SGLT-2 inhibitors work in the kidneys by preventing glucose reabsorption and increasing excretion, and this mechanism means that efficacy is impeded in patients with higher levels of renal dysfunction. Because renal impairment is a common comorbidity of type 2 diabetes, determining the patient population in which these drugs can be safely and effectively used is important for commercial prospects.

Canagliflozin demonstrated some efficacy in type 2 diabetic patients with moderate renal impairment, lowering HbA1c levels at week 26 by 0.30% and 0.40% for doses of 100mg and 300mg, respectively, compared to placebo. Dapagliflozin demonstrated similar (but not statistically significant) efficacy results in moderately renally impaired patients at doses of 5mg and 10mg. This difference is likely to work in canagliflozin's favor as greater effectiveness will mean less need for change by physicians if patients do develop increasing renal impairment. However, minor HbA1c level changes in patients with reduced kidney function do not appear convincing enough to promote SGLT-2 inhibitor use in this patient population, as superior alternatives are available.

Losing calories through glucose excretion in the urine (glycosuria), leading to weight loss, is a welcome side effect of the SGLT-2 inhibitor class, while the reduction of systolic blood pressure seems to be another class-wide side effect. Both of these effects were shown for canagliflozin in the presented data, with weight loss in the range of 1.8% to 3.7% across studies (300mg dose) at week 52, and systolic blood pressure reduction between 1.6mmHg and 6.1mmHg (300mg dose) at week 26. However, as well as weight loss, glycosuria brings with it more negative side effects: a significantly increased rate of microbial genital and urinary tract infections was seen in the canagliflozin arms of the reported clinical trials when compared to the placebo or active comparator arms, with this increase in genitourinary infections considered to be class-wide.

Canagliflozin appeared to exhibit significantly higher efficacy in lowering blood glucose levels compared with the most advanced in-class competitor, dapagliflozin. In a trial with 584 participants, canagliflozin monotherapy in drug-naive type 2 diabetic patients reduced HbA1c levels by 1.16% (placebo-adjusted) at 26 weeks compared to baseline, whereas treatment with 10mg dapagliflozin reduced HbA1c levels by 0.54% (placebo-adjusted) compared to baseline at 24 weeks in a similar Phase III trial with 546 participants. These results will benefit canagliflozin, but in the absence of head-to-head trials in a matched patient population such comparisons should be treated with caution. It is unclear as yet whether physicians will see the SGLT-2 inhibitor class as largely interchangeable or whether differences - and a clear leader - can emerge.

So far none of the serious safety scares that surrounded the dapagliflozin New Drug Application have surfaced during the evaluation of canagliflozin's trial data, with no reported meaningful imbalances in cancer risks and liver toxicity. Johnson & Johnson and co-developer Mitsubishi Tanabe expect a positive decision for canagliflozin in the US, where it would become the first-to-market SGLT-2 inhibitor. The companies also have high hopes for canagliflozin in the EU and plan to file for regulatory approval at the end of June 2012. If approved, the drug would likely be second-to-market after competitor Forxiga (dapagliflozin; Bristol-Myers Squibb/AstraZeneca), which received a positive opinion from the Committee for Medicinal Products for Human Use in April 2012.

If canagliflozin gains approval, it must find a place in the crowded diabetes treatment algorithm. The comparison of canagliflozin with glimepiride and Januvia suggests that the developers are positioning it as a second-line therapy after metformin failure, presumably as an add-on therapy to other oral antidiabetics, although the novel mechanism means that the SGLT-2 inhibitors can potentially be combined with most other diabetes drugs. Data to date show canagliflozin as an efficacious, tolerable, weight-reducing therapy, but it remains to be seen how concerns about safety issues and the known genitourinary infection side effects will affect its uptake, as well as that of the other SGLT-2 inhibitors in the market.