Riding High, Victoza Hopes To Gain Ground Over Popular DPP-4s With Label Change

FDA label now notes superior efficacy and greater weight loss for Novo Nordisk’s injectable GLP-1 receptor agonist Victoza vs. Mercks’ DPP-4 inhibitor Januvia. Superiority would be expected for a GLP-1, but label still has potential to encourage earlier use of the class.

Novo Nordisk AS’s popular injectable GLP-1 receptor agonist Victoza (liraglutide) for type 2 diabetes should get a bit of a boost from a label change that adds a claim of superior blood sugar control and greater weight loss compared to Merck & Co. Inc.’s oral DPP-4 inhibitor Januvia (sitagliptin).

Based on results from two randomized controlled studies, Victoza’s label was revised April 6 to note superior efficacy compared to Januvia, as well as superior efficacy when used in combination with Levemir (insulin detemir) and metformin in patients who can’t reach targets with Victoza and metformin alone.

Results from the two open label 26-week trials in each of these settings outline the significantly improved blood sugar lowering, but also an increase in gastrointestinal side effects.

A once-daily subcutaneous injectable, Victoza has taken off since winning FDA approval as a second-line therapy for type 2 diabetes in January 2010, despite a warning in labeling of thyroid tumors, among other risks. Sales reached about DKK 6 billion, or just over $1 billion, in 2011, up 159% from the previous year. At the time Victoza was approved, the only other drug approved in the class was Amylin Pharmaceuticals Inc.’s twice-daily Byetta (exenatide). But Victoza now faces competition against Amylin’s once-weekly extension form of exenatide, Bydureon, which cleared FDA in late January.

The GLP1 market was worth about $1.7 billion in 2011, or about 6% of the worldwide market for diabetes drugs, compared to about $6 billion for DPP-4 inhibitors, which have 23% of the total, according to Cowen and Company estimates.

Label Brings Home Class Comparisons

The question now is just how far can GLP-1s go – and that depends partly on the extent of use earlier on in treatment.

Oral generics like metformin represent the standard of care for first-line treatment of type 2 diabetes. When blood sugar lowering isn’t good enough with generics, it’s a natural to add on an oral DPP-4 inhibitor like Januvia, which has for the most part a clean safety record, but offers only modest efficacy for lowering blood sugar. The dominant DPP-4 inhibitor, Januvia brought in $3.3 billion in worldwide sales in 2011, up from $2.3 billion the previous year. Added to that are the sales of Merck’s combination of Januvia and metformin, Janumet: $1.4 billion worldwide in 2011, up from about $950 million the previous year.

Developers of subcutaneous injectable GLP-1 analogs would like to bump their candidates up in the treatment line-up, ahead of the oral DPP-4s, based on superior efficacy and significant weight loss (DPP-4s are weight neutral).

Proving superiority over a DPP-4 inhibitor would be expected as the GLP-1 class is known for more potent blood sugar lowering. But having this explicitly conveyed in the labeling could bring that point home more clearly and possibly have a favorable marketing impact. At the time the head-to-head study results against Januvia were published in the Lancet, in April 2010, Novo Nordisk execs said that it’s important to have data supporting the perception of superior efficacy (Also see "Novo Nordisk's GLP-1 Victoza Off To A Good Start" - Pink Sheet, 27 Apr, 2010.).

Data comparing the GLP-1s head to head against other diabetes therapies “provides more convincing evidence” for clinicians that these are “potent therapies that deserve a place alongside the orals in the early management of diabetes,” Cowen and Company analysts wrote in their annual Therapeutic Categories Outlook report for 2012.

Better Blood Sugar, More Weight Loss

The head-to-head study against Januvia randomized 665 patients to one of two doses of liraglutide (1.2 mg or 1.8 mg) or 100 mg of sitagliptin for 26 weeks of treatment. All patients received treatment as an add-on therapy to metformin.

Those taking Januvia experienced a significantly greater reduction in hemoglobin A1c (1.2% and 1.5% for the 1.2 mg and 1.8 mg doses respectively) compared to .9% for Januvia. And those taking Victoza also had greater weight loss of 2.7 kg (5.94 pounds) and 3.3 kg (7.26 pounds) for the 1.2 and 1.8 mg doses respectively, compared to a 0.8 kg loss (1.76 pounds) for Januvia.

The label reflects these efficacy results, but also the greater incidence of gastrointestinal adverse events in the Victoza arm. Side effects occurring in ≥5% of patients included nausea (23.9% for Victoza vs. 4.6% for Januvia), diarrhea (9.3% vs. 4.6%) and vomiting (8.7% vs. 4.1%)

The second study tested the value of adding insulin detemir (Levemir) to patients taking metformin and Victoza, but who were still not reaching the recommended hemoglobin A1c target of 7% or less. Investigators enrolled 988 patients with inadequate glycemic control and treated them in a study run-in period with Victoza (1.8 mg dose) and metformin for 12 weeks. Of the total, 498 achieved the 7% target and another 167 (17%) withdrew from the trial. One-half of the discontinuations were due to gastrointestinal adverse events, labeling notes. The 323 patients left in the study with A1c levels greater than 7% were then randomized to 26 weeks of treatment with once daily insulin detemir with Victoza and metformin, or continued therapy with Victoza and metformin.

Treatment with insulin detemir as an add-on to Victoza 1.8 mg and metformin resulted in a statistically significant further reduction in HbA1c of .5% compared to no reduction in patients who continued treatment with Victoza 1.8 mg plus metformin alone.

Furthermore 43% of patients in the Victoza/metformin/Levemir group reached the A1c blood sugar target of 7%, compared to 17% on Victoza/metformin.

The only adverse event reported in 5% or more of patients in those taking the three therapies together was diarrhea, which occurred in 11.7% taking the three-drug regimen vs. 6.9% in those taking Victoza/metformin.

In its press statement, Novo Nordisk noted that those taking a regimen including Levemir did not gain weight.

From a mean baseline body weight of 96 kg (211 pounds) after randomization, there was a mean reduction of .3 kg (.66 pounds) in the arm including insulin detemir, vs. a mean reduction of 1.1 kg (2.4 pounds) for those on Victoza and metformin alone, the label notes.

Selling Points

The commercial impact of new labeling is unclear. Weight loss is already an important selling point for the class of GLP-1s. In fact, in their annual report, Cowen analysts noted that physicians view weight loss as Byetta’s “biggest attribute,” more important than blood sugar lowering.

Bydureon’s label does not currently include comparative data against Januvia, but the drug did outperform Januvia for blood sugar lowering and weight loss in the head-to-head DURATION-2 study as an add-on therapy to metformin. In the DURATION-4 monotherapy study, patients randomized to Bydureon monotherapy had a statistically significant better blood sugar and weight loss effects compared to Januvia.

However, Bydureon also failed in the head-to-head DURATION-6 study against Victoza.

Bydureon has had a strong launch in terms of new scripts, but IMS Health data suggest that Victoza is holding its share of the GLP-1 market and that the weekly form of exenatide is taking share from the twice-daily Byetta (Also see "GSK Airs Phase III Data For Weekly GLP-1 Albiglutide, Plans To File By Year-End" - Pink Sheet, 3 Apr, 2012.).

Interviews with physicians suggest that Bydureon and Victoza will split the GLP-1 market, because “each formulation has its benefits and issues,” wrote the Cowen analysts. For example, Victoza comes in an easier-to-use pen device. Bydureon’s once-weekly dosing has pros and cons, as it’s more convenient but on the flip side, if you need to get the drug out of a patient’s system it takes longer.

The total worldwide market for GLP-1 class is projected to rise from about $1.7 billion in 2011 to $4.3 billion in 2016, while the DPP-4 inhibitor market is expected to double during that period to $12 billion in 2016, according to the Cowen report (see table).

Worldwide Diabetes Market, Sales By Drug Class
Drug Class	Worldwide Sales in 2011 and % of total market ($mm)	Sales Projections for 2016 and % of total market ($mm)
Insulins	$16,097 (60%)	$18,646 (45%)
DPP-4 inhibitors	$6,067 (23%)	$12,421 (30%)
GLP-1 receptor agonists	$1,679 (6%)	$4,279 (10%)
SGLT2 inhibitors	0	$1,215 (3%)
Sulfonylureas	$1,017 (4%)	$910 (2%)
Glitazones	$981 (4%)	$546 (1%)
Other oral agents	$954 (4%)	$3,148 (8%)
Total market	$26,794	$41,164
Source: Cowen and Company Therapeutic Categories Outlook report, 2012

The newer GLP-1s have fewer drawbacks than Byetta, for example less nausea, but side effects still exist and injectable delivery remains a barrier, Cowen analysts concluded.

At the time the head-to-head study results against Januvia were published in the Lancet, authors of an accompanying editorial noted that “the gastrointestinal tolerance profile is better with sitagliptin than with liraglutide, and one pill of sitagliptin daily might be judged as easier to administer than one subcutaneous injection of liraglutide daily.”

Furthermore, “the increased cost of liraglutide should be compared with the benefit provided by improved glucose control and weight reduction,” Andre Scheen and Regis Radermecker, University of Liege, Belgium, wrote in the editorial, which was published April 24, 2010.

Cowen reports (via third-party sources) that Victoza at 1.2 mg a day costs $3,418 per year, based on listed wholesale acquisition cost, whereas the higher dosing costs $5,122 annually. That compares to about $4,200 a year for Bydureon and $3,553 for Byetta. Based on WAC, Januvia costs about $2,558 per year.

Commenting on the prospect of using GLP-1s earlier in treatment, the Lancet editorial authors also noted that the “long-term safety” with the class “remains an open question.”

Furthermore, they observed, the disease is so “heterogeneous that treatment probably needs to be tailored to individuals rather than strictly standardized.”