Approval of Novartis' dipeptidyl peptidase-4 inhibitor Galvus (vildagliptin) is up in the air following a Feb. 23 FDA "approvable" letter requesting an additional clinical study in patients with renal impairment.

In a conference call with analysts Feb. 26, Novartis Head of Pharma Development James Shannon explained that the requested trial relates to a concern previously voiced by the agency over the potential development of skin lesions seen in primate studies of DPP-4 inhibitors.

"The FDA's concern is that in certain patient populations - and renal impairment may be one of those - plasma levels may get to a level which may predispose patients to skin lesions similar [to those seen in] the monkeys even though we have not seen that in the trials," he said.

FDA began requesting in November 2005 that all sponsors of DPP-4 inhibitors conduct three-month oral toxicity studies in monkeys to assess their respective compounds' potential for necrotic skin lesions.

According to Shannon, a key Phase II/III study submitted as part of the NDA included about 900 renal failure patients, most of whom he characterized as "moderate," who were given the highest study dose (100 mg). He added that the adverse event profile of the renal failure group was no different from patients without the ailment.

FDA is concerned that in "certain patient populations who may have a combination of factors" those patients "may have a moderate to severe renal failure as well as other factors which might influence exposure to the drug, namely other drugs, which would potentially interact with renal clearance, or gender effect or age effects. [FDA] is concerned that we may see in ... some patients plasma exposures which may reach four to six times the exposure which we see in normal patients."

The letter is the second major setback for Novartis in the last three months: The firm was poised to put the second DPP-4 inhibitor on the market, following a user fee date extension in November to examine primate skin data (¹ Also see "Galvus Review Delayed For Safety Analysis Of Primate Skin Data" - Pink Sheet, 13 November, 2006.).

Several analyst notes issued Feb. 26 indicated that conducting the additional study would likely delay approval of Galvus for at least another year.

The Galvus delay is a major boon to Merck, which has the only DPP-4 inhibitor on the market, Januvia (sitagliptin), which was approved by FDA in October. Merck anticipates European approval in early April (² Also see "Merck Gains Positive Opinion For Januvia In EU" - Pink Sheet, 26 January, 2007.). Bristol-Myers Squibb and partner AstraZeneca plan to submit their DPP-4 inhibitor saxagliptin in 2008 (³ Also see "Bristol Aims To Be First To Market With Novel Diabetes Drug Class" - Pink Sheet, 11 January, 2007.).

In response to an analyst's question as to how long the additional study would take, Shannon responded, "I don't think they're looking for a two-year study to look at the safety over the long term of high doses of Galvus. I think what they're looking for is for a rather small number of patients with different factors to look to see does the plasma exposure go to very high levels which may predispose patients to skin lesions."

He added that Merck was also required to do an additional Januvia study with kidney patients that ended up lasting only 12 weeks.

During FDA's review of Januvia, the agency noted that sitagliptin, unlike other DPP-4 inhibitors that go unnamed in review documents for that product, does not cause skin lesions and that the effects could be due to activity relating to other DPP subtypes. However, labeling does recommend renal function tests prior to initiating Januvia treatment (⁴ Also see "Skin Toxicity Seen In Other DPP-4 Inhibitors Missing In Januvia NDA – FDA Review" - Pink Sheet, 22 January, 2007.).

In response to an analyst's question, Shannon noted that the Division of Metabolism and Endocrinology Products may have issued the approvable letter in response to generalized public pressure over safety concerns.

"It is the same division who was very heavily criticized in a paper last month in the [New England Journal of Medicine] for too rapidly approving diabetes drugs. ...And it is this same division who over the last few months has been dealing with [thiazolidinediones], with the PROACTIVE and DREAM studies which didn't alleviate concerns over TZDs and also issued the 'Dear Doctor' letter for [GlaxoSmithKline's TZD] Avandia on osteoporosis. I think there is an awareness within this division that safety concerns are important."

- Jonathan M. Block (j.block@elsevier.com)

Galvus “Approvable” Letter Requests Additional Study In Renal Failure Patients

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