As part of its ongoing effort to develop drugs for metabolic disease, Boehringer Ingelheim is gearing up for a filing within the next few months of its first diabetes drug - the DPP-4 inhibitor linagliptin.

Following the release of four Phase III studies involving more 3,200 patients of the dipeptidyl peptidase-4 inhibitor at the 2010 American Diabetes Association meeting, a filing will come "very soon," confirmed Giora Davidai, executive director and medical leader of cardiovascular/metabolic medicine, at the private German pharma.

Boehringer has emerged as a potential diabetes player somewhat by stealth. As a private company, it is not required to provide regular updates to investors about the status of its development nor provide any comment on its R&D outlays.

At this year's ADA meeting, the company released 18 posters, including the four Phase III trials on linagliptin. That compares to just three posters last year. Overall, the Phase III program includes about 5,000 patients and an additional long-term cardiovascular safety study of 10,000 patients is set to get under way shortly.

Currently, two DPP-4s are FDA-approved - Merck's first-to-market blockbuster Januvia (sitagliptin) and Bristol/AstraZeneca's struggling medicine Onglyza (saxagliptin). Novartis' Galvus (vildagliptin) is cleared outside the United States but was never approved stateside because of skin toxicity signals (¹ Also see "Galvus Safety Trial Reconsidered In Light Of Novartis Cost Concerns" - Pink Sheet, 21 January, 2008.).

Linagliptin will be differentiated based primarily on the way the drug is metabolized, Davidai explained. Very little linagliptin is excreted through the kidneys (5 percent), and this could prove to be an advantage for safety, in the company's view. About 60 percent of patients with type 2 diabetes have some form of renal impairment and an estimated 25 percent have severe renal impairment.

Members of the DPP-4 class sometimes get criticized for lackluster efficacy, but a strong safety profile can go a long way, as experience with Januvia attests. In 2009, Januvia and Janumet (sitagliptin/metformin combination) reaped sales for Merck of almost $2.6 billion.

The enormous publicity recently over potential cardiovascular safety problems with GlaxoSmithKline's type 2 diabetes drug Avandia (rosiglitazone) could further spur sales. As Avandia was being scrutinized in FDA advisory committee meetings, the mainstream media ran stories for consumers exploring safer options and outlining the pros and cons of each diabetes class, including DPP-4.

Boehringer currently devotes about 20 percent of its profits to R&D, but does not disclose how much of this figure goes to diabetes in particular. Boehringer had about $12.7 billion in sales in 2009 and Davidai indicated that the diabetes research staff has been growing rapidly.

Two of the company's best-selling drugs are due to go off patent this year - Mirapex / Sifrol for Parkinson's disease and restless leg syndrome, and Flomax for benign prostatic hyperplasia - making the need for pipeline development more imperative. The company's novel anti-coagulant Pradaxa (dabigatran)for atrial fibrillation is expected to help save the day. The company already markets the antihypertensive Micardis (telmisartan).

Davidai said the company's strong program in cardiovascular medicine is a good background for diabetes drug development: "There's always a debate between endocrinologists and cardiologists about whether diabetes is a cardiovascular disease. Be that as it may, they are tightly linked together. Diabetes complements our cardiovascular research program very well."

For a company that came into diabetes only in 2001, Boehringer has put together a respectable pipeline (² Also see "Boehringer Ingelheim: Privacy Has its Virtues" - In Vivo, 1 October, 2009.). In addition to linagliptin, its diabetes portfolio also includes compounds with three novel mechanisms of action that are attracting a lot of attention nowadays: a Phase III-ready SGLT-2 inhibitor, an 11beta-HSD1 inhibitor, and GPR119 agonists. The 11 beta-HSD1 inhibitor was acquired through a 2009 deal with Vitae while the GPR119 compounds were snapped up in a recent tie-up with Neurocrine (³ Also see "Neurocrine Inks $575 Mil. Deal With Abbott To Develop and Sell Gynecologic, Elagolix" - Pink Sheet, 16 June, 2010.).

A number of factors suggest the company should continue to "invest massively" in diabetes, Davidai said. The disease is becoming increasingly prevalent around the world and yet there is still unmet need. Many patients still struggle to get their blood sugar levels under control, despite the availability of many different kinds of drugs. According to the International Diabetes Federation, about 285 million have the disease worldwide and this figure is set to increase to 438 million in 2030. During a Boehringer webcast at the 2010 ADA meeting, the IDF VP Jonathan Brown said that both of these figures are very conservative estimates. The current figure is probably closer to 335 million and by 2030, the total could rise by almost 100 percent to more than 600 million, he said.

In its March 2010 "Therapeutic Categories Outlook" report, Cowen & Company estimated that the worldwide market for DPP-4s was worth about $2.8 billion in 2009, or 12 percent of the total $23 billion diabetes market. Insulins, DPP-4s and GLP-1 inhibitors are expected to be the main drivers of market growth. In 2014, the DPP-4 share is expected to rise to $5.1 billion, or 14 percent of the $37.5 billion diabetes market.

Efficacy Similar To Other DPP-4s

The four, 24-week randomized Phase III studies on linagliptin released at the ADA meeting show how Boehringer's linagliptin performs in a range of settings, including as a monotherapy, and in combination with other drugs.

The studies showed statistically significant reductions in blood glucose with linagliptin monotherapy versus placebo and for the test drug in combination with the commonly used oral anti-diabetes drugs sufonylureas and metformin.

A placebo-adjusted reduction in HbA1c of .69 percent was noted in the monotherapy study. Overall, efficacy was on roughly on par with other DPP-4 inhibitors. Significant improvements were also seen in beta cell function and the drug was very well-tolerated, in line with the class.

In patients with mild and moderate renal impairment, linagliptin blood plasma levels were comparable to those seen in diabetes patients with normal renal function. According to a company statement, this suggests that "linagliptin, which has a primarily non-renal route of excretion, may have distinct pharmacological features not yet seen in this novel class of drugs."

Data so far suggest that no dose adjustment would be required for linagliptin regardless of the degree of renal impairment, according to the company.

Januvia is excreted mainly through the kidneys and requires two downward dose adjustments, noted Cowen analysts in their March report. Onglyza requires only one dose adjustment based on status of kidneys, which could be considered an advantage. However, unlike Januvia, Onglyza is metabolized by the CYP 3A4/5 pathway, increasing the potential for certain drug-drug interactions, the Cowen analysts noted.

It's unclear how much of an advantage use in renally-impaired patients with no dose adjustments will prove to be for linagliptin. A label for these patients could help the product stand out. But by focusing on this niche, Boehringer is shrinking its potential market at the outset, commented analysts at the UK research firm Decision Resources.

Phase III Designed With Global Market In Mind

Boehringer also endeavored to test linagliptin in distinct ethnic groups, including participants from China and Japan. One of the Phase III studies presented at the ADA meeting specifically compared linagliptin to Ranbaxy's Voglibose , a popular type 2 medicine in Japan. Decision Resources notes that with $2.4 billion in diabetes drug sales for 2009, Japan is the second largest of the seven Big Pharma markets after the U.S., with about $14 billion. Manufacturers of Januvia, Galvus and Onglyza have been battling to win over the diabetes market in India (⁴ Also see "Big Brand Fights Come To India As Januvia, Galvus And Onglyza Vie For Market Share" - Pink Sheet, 4 June, 2010.).

According to IDF figures, in absolute terms, diabetes is most prevalent in the Western Pacific region, with 77 million adults affected. That compares to 37 million in North America. However, in relative terms, only about 4.7 percent of adults in the Western Pacific region have diabetes, versus 10.2 percent in North America.

Of the $2.6 billion in sales for Januvia and Janumet in 2009, $1.87 billion derived from the U.S. market.

Experience with Onglyza suggests Januvia still has a strong hold on the market overall. Reporting that Onglyza generated only $10 million in the first quarter of 2010, Bristol executives acknowledged that sales had been disappointing (⁵ Also see "For Bristol, Onglyza Disappoints And Health Care Reform Takes A Toll" - Pink Sheet, 3 May, 2010.). The weak entry has been chalked up to a lack of differentiation compared to Januvia, which is supported by a growing safety database in a highly safety-conscious therapeutic space.

Writing in a June 28 note, Leerink Swann's Seamus Fernandez observed: "At the ADA meeting, we spoke with several endocrinologists who stated that they do not view Onglyza or Onglyzamet [Onglyza and metformin] as having any efficacy or safety advantages over Januvia/Janumet."

Originally, it was assumed that the overall pie for DPP-4 sales would be large enough for a second and third to market player, commented Decision Resources analyst Donny Wong. But now, based on Onglyza performance, the picture looks a bit different, with Januvia firmly entrenched.

"Most of the pie belongs to Merck," Wong said.

Typically, type 2 diabetes patients are given metformin as a first-line drug and then moved on to a DPP-4 inhibitor like Januvia. Companies are seeking to break into the first-line space with combinations of DPP-4s with metformin. Decision Resources estimates that based on research with insurance claims databases, about 20 percent of the market for first-line combinations is penetrated.

Takeda's Alogliptin May Be Back On Track

In a move that some took as a sign of the commercial challenges in the DPP-4 space, Forest Laboratories recently dropped a partnership with the biotech Phenomix for the Phase III dutogliptin (⁶ Also see "FDA Is Listening: Adolor Cited For Downplaying REMS At Conference" - Pink Sheet, 26 April, 2010.). Phenomix confirmed that it is currently looking for a new partner and no timeline for an FDA filing has been set.

Takeda meanwhile hit a major bump on the road to the DPP-4 market when the FDA requested cardiovascular safety data as a condition for approval of alogliptin (⁷ Also see "Takeda's Alogliptin Suffers Major Setback, Delaying Drug Launch Until 2012 Or Later" - Pink Sheet, 30 June, 2009.). The company had indicated that it was performing a cardiovascular risk study that would finish in 2014 but that the drug could be approved before then based on interim data. At the 2010 ADA meeting, Takeda presented a poster presentation of a pooled analysis of trials indicating the risk of a CV event was low, similar or less than the rate associated with placebo. Therefore, it's possible that this application will move forward and that alogliptin will get on the market soon, creating more competition for linagliptin.

"They are probably gearing up for a submission to FDA soon. That would push linagliptin back one more in order of entry into the U.S. market," Wong said.

Wedding Bells For SGLT-2 And DPP-4?

Meanwhile, Boehringer also sees potential in its SGLT-2 inhibitor BI 10773, now through Phase II and ready for Phase III. Data for the drug were aired along with results from Bristol/AstraZeneca's dapagliflozin, as well as other compounds. Efficacy for the class was viewed as acceptable, but there are still concerns about urinary tract infections, which are thought to be a class side effect linked to excretion of sugar in the urine (⁸ Also see "New Data Help Size Up Novel Class Of SGLT-2 Inhibitors In Diabetes" - Pink Sheet, 5 July, 2010.). Trial data suggest the problem is manageable and not too severe, but the rates are still a cause for concern.

"The urinary infection issue is an issue that needs to be resolved; it's a question regarding the whole class," Davidai said. "The fact that you excrete a lot of sugar through the kidney, through the urinary tract definitely raises the question if these would be conducive to both fungal and bacterial infections. I don't think any of the SGLT-2 compounds yet has resolved this issue. We are looking very closely into [it]."

Nevertheless, Davidai expressed optimism overall about SGLT-2, with particular interest in possibily combining a SGLT-2 with DPP-4 to take advantage of complementary mechanisms of action. Hypoglycemia rates are low for both drugs. A DPP-4 inhibitor stimulates insulin and the release of the hormone glucagon in the pancreas. In contrast, the SGLT-2 inhibitor works by eliminating glucose from the body through the urine. DPP-4s are weight neutral, while SGLT-2s offer modest weight loss benefits.

"They are tremendously complementary. I don't want to be a prophet but I do believe co-administration of those two classes of drugs is from a medical point of view very, very attractive," Davidai said.

- Emily Hayes ( ⁹ e.hayes@elsevier.com )

Boehringer Ingelheim Plays Catch-Up In Diabetes, Close To Filing DPP-4 Drug

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