PDUFA: March 31 – Invokana

The US Food and Drug advisory panel has voted for the preliminary approval of Invokana (canagliflozin), Johnson and Johnson’s new type 2 diabetes drug, in a 10 to 5 vote. On the table during the discussion for this potentially innovative drug was the concern that it has significant cardiovascular risks associated with its design.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, in a separate 7 to 8 vote, moved that they had significant concern over these risks. Thus, insiders have labeled the advisory panel decision as ‘surprising’ at the most, and interesting at the least.

“There are clearly some unmet needs in diabetes to get glucose control. Hypoglycemia is a big limitation and right now we don’t have effective weight loss therapy, so this class of drugs clearly provides clinical benefits,” said Dr. William Cefalu, the primary researcher on the Invokana study.

Canagliflozin is an oral inhibitor of the sodium glucose cotransporter 2 (SGLT2). SGLT2 is a low-affinity transport system that is specifically expressed in the kidney and plays an important role in renal glucose reabsorption in the proximal tubule. Type 2 diabetes is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. SGLT2 is responsible for at least 90% of the glucose re-absorption in the kidney. Should it be approved, canagliflozin would be the first and only SGLT2 inhibitor agent on the US market, giving it a significant edge for at least 6-9 months before other inhibitors also come under vote.

The SGLT-2 drug class arguably dates back 178 years. In 1835, French chemists first isolated a substance known as phlorizin from the bark of apple trees, and in 1886, German physician and early diabetes pioneer Joseph von Mering demonstrated that the ingestion of high doses of phlorizin caused people to expel glucose in their urine (glucosuria). It would take over a century for researchers recognized the potential usefulness of a substance that induces glucosuria for the treatment of type 2 diabetes.

The producers report that Invokana causes weight loss by reducing re-sorption of glucose in the kidney, resulting in increased urinary glucose excretion. Invokana has proven to have a higher rate of success in improving quality of life for type 2 diabetes patients and has shown great promise in clinical trials for lowering blood sugar. Many more companies are now jumping on the canagliflozin bandwagon because of Invokana’s success, such as LX4211, which is produced by Lexicon. Johnson and Johnson currently do not have any other diabetes drugs on the market, or in their immediate pipeline.

Whereas Invokana succeeded, other SGLT2 inhibitors that have come under vote by the FDA failed to reach approval. In January 2012 the FDA denied the inhibitor drug, FORXIGA (dapagliflozin), produced by Bristol-Myers Squibb and AstraZeneca, due to concerns about the product having signals for cancer. Specifically, data showed an increased risk factor for bladder and breast cancer as well as liver damage – whether there is an actual increased risk for these side effects remains unclear.

The European Union did not share the FDA’s view of these facts, and in November 2012 Bristol and AstraZeneca began roll-out.

Invokana was also submitted for approval in Europe on June 26, putting a potential approval sometime in the middle of 2013. It has been established that Invokana does not share the same risks for malignancy as its predecessor. As with other SGLT-2 inhibitors, however, Invokana was associated with higher rates of urinary tract infections and genital infections – although these side effects caused few participants to discontinue from the trial.

The major point of concern for Invokana – which kept the vote so close – are the heightened risk of stroke; in several data published, the hazard ratio was elevated, at 1.5 (95% CI, 0.8 – 2.6). Despite concerns, the board vote shows members did not accept conclusive evidence that Invokana led to significant risk for stroke.

The decision day for Invokana’s FDA approval is in late March, according to Johnson & Johnson.

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