Boehringer/Lilly's Linagliptin Approved: Can Renal Flexibility Unlock The DPP-4 Market?

Tradjenta's label supporting use in renally-impaired patients, with no need to adjust dose, could help differentiate the product's safety profile in a competitive space.

With Tradjenta (linagliptin) newly approved in diabetes, partners Eli Lilly & Co. and Boehringer Ingelheim GMBH are poised to make a play for the growing market for DPP-4 drugs, which is now locked up by Merck & Co.' s Januvia (sitagliptin).

Linagliptin was approved May 2 at a 5 mg dose as an adjunct to diet and exercise, for improving glycemic control in patients with type 2 diabetes. Approval was supported by eight double-blind placebo-controlled studies of about 3,800 patients. The program included studies of the drug as a stand-alone therapy and in combination with other type 2 diabetes drugs including metformin, glimepiride and pioglitzaone.

Linagliptin is a member of the dipeptidyl peptidase-4 inhibitor class, which is not exactly known for fantastic efficacy in terms of lowering blood sugar, but is thought to offer a relatively clean safety profile and has the advantage of an oral formulation. Safety has become an extremely important attribute considering how many diabetes drugs with different mechanisms of action have been criticized for risk of various adverse events.

Linagliptin emerged rather by stealth in recent years by the private Boehringer, which has a background in cardiovascular medicine but is relatively new to diabetes (Also see "Boehringer Ingelheim Plays Catch-Up In Diabetes, Close To Filing DPP-4 Drug" - Pink Sheet, 19 Jul, 2010.).

Most recently, Boehringer tapped into one of the most lucrative new markets for Big Pharma, with the successful launch of the novel anticoagulant Pradaxa (dabigatran).

A veteran in diabetes, Lilly came on board through a January partnership deal that also involved other drugs in the space, including Boehringer's Phase III-ready sodium-dependent glucose co-transporter -2 inhibitor BI10773 (Also see "In Deal With BI, Lilly Gets Late-Stage Diabetes Drugs" - Pink Sheet, 17 Jan, 2011.)

The DPP-4 market is now dominated by Merck's first-in-class Januvia. The drug brought in $739 million in sales for the first quarter of 2011, up by 45% from the same time last year, while the combination line-extension product Janumet (sitagliptin/metformin) had $305 million during the same period, up by 52%. In 2010, these two products together raked in about $3.4 billion.

In fact Merck has done so well that some analysts have questioned whether newcomers can compete, barring some clear point of differentiation or else very competitive pricing. Bristol-Myers Squibb/AstraZeneca's Onglyza (saxagliptin) -the second to market in the U.S. -has not had an easy time breaking in (Also see "AstraZeneca/Bristol's Onglyza Gains Approval, But Now Has To Face Januvia" - Pink Sheet, 3 Aug, 2009.).

Bristol reported sales of $81 million for Onglyza and the sister combination product Kombiglyze (saxagliptin/metformin) in the first quarter of 2011, having reported $158 million for the whole of 2010.

As a whole, the DPP-4 class has sales of $3.9 billion 2010, worth about 16% of the total worldwide diabetes drug market, which is expected to rise to $7.8 billion in 2015, or 20% of the total in 2015, according to Cowen & Co.' s Therapeutic Categories Outlook Report from March 2011.

Label Supports Advantage For Renally-impaired

Linagliptin's sponsors in the past have pledged to differentiate the drug, among other ways, as a drug that is safe for renally-impaired patients. Very little of linagliptin is excreted through the kidneys (5%), and the companies have noted that about 60% of patients with type 2 diabetes have some form of renal impairment and an estimated 25 percent have severe renal impairment.

However, some consultants have noted that this approach would need to be taken with caution so as not to limit the addressable market to a niche population from the outset. And they have questioned whether this would be enough to battle a powerful brand such as Januvia.

According to the Tradjenta label granted on May 2, no dose adjustment is recommended for patients with renal impairment. The clinical pharmacology section of the label notes that this advice is supported by results of an open-label pharmacokinetic study of 39 patients with varying degrees of renal function and also by population pharmacokinetic analyses. No dose adjustment is needed for patients with liver impairment either.

In contrast, the warnings and precautions section warns of the Januvia label notes risk for acute renal failure, which sometimes results in the need for dialysis.

Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD (end-stage renal disease), according to the Januvia label, and assessment of renal function is recommended prior to initiating Januvia and then periodically. The acute renal failure notification follows a warning about postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis.

As for Onglyza, the label advises that a lower approved dose be used in patients with moderate or severe renal impairment or ESRD. Renal function should be assessed prior to initiation of the drug and periodically thereafter. No dose adjustment is needed for patients with mild renal impairment.

The Tradjenta adverse reactions label notes that side effects reported in more than 5% or more patients treated with Tradjenta include nasopharyngitis and that hypoglycemia was more commonly reported in patients treated with Tradjenta and sulfonylurea compared with placebo and sulfonylurea. Also, pancreatitis was reported more often in patients randomized to linagliptin.

-Emily Hayes ([email protected])