GSK Pushing For ADOPTion Of Avandia For First-Line Type 2 Diabetes Therapy

GlaxoSmithKline plans to use the results of its ADOPT study to establish its thiazolidinedione Avandia as the standard first-line treatment for type 2 diabetes.

In the A Diabetes Outcome Progression Trial, Avandia (rosiglitazone) demonstrated superior glycemic control maintenance compared to the biguanide metformin and the sulfonylurea glyburide, significantly reducing the risk of monotherapy failure.

"Based upon the clinical evidence, ADOPT provides new evidence to support a new standard of treatment for type 2 diabetics," GSK Senior VP-U.S. Pharmaceuticals/Vaccines David Pernock said during a Dec. 4 call.

Results of ADOPT, which compared daily doses of 5 mg rosiglitazone, 500 mg metformin and 2.5 mg glyburide in 4,360 recently-diagnosed, drug-naive type 2 diabetics over five years, were published in the Dec. 7 issue of the New England Journal of Medicine.

Avandia reduced the risk of monotherapy failure, defined as fasting plasma glucose level of more than 180 mg/dL, at five years by 32% over metformin and 63% over glyburide. Cumulative incidence of treatment failure at five years was 15% for Avandia, 21% for metformin and 34% for glyburide.

Achieving clinical acceptance of Avandia as the first choice for initial treatment for type 2 diabetes will require GSK to overcome the clinical practice recommendations from the American Diabetes Association. The recently-updated treatment guidelines recommend metformin as first-line therapy for newly diagnosed patients; thiazolidinediones, sulfonylureas and basal insulin are included as possible second-line medications (¹ (Also see "Symlin And Byetta Excluded From American Diabetes Association Guideline" - Pink Sheet, 28 Aug, 2006.), p. 24).

Although rosiglitazone is approved as a monotherapy to improve glycemic control in patients with type 2 diabetes mellitus in conjunction with diet and exercise, the majority of Avandia and Avandamet (rosiglitazone/metformin) business comes from second- and third-line combination therapy.

GSK is proposing that rosiglitazone should be used earlier in the treatment flow at all stages of the disease and plans to undertake a new marketing push to highlight ADOPT results.

GSK's marketing efforts to elevate Avandia on the treatment continuum will be supported by a 3,600-rep sales force. Promotional efforts for the franchise have been hampered by a lack of product samples due to manufacturing issues, but the company expects to be "back to our full support" in the first half of 2007.

The company believes that, by increasing rosiglitazone use as initial therapy and earlier use as an add-on, it can effectively double the market for its rosiglitazone franchise from five to 11 million patients.

GSK suggests that rosiglitazone should be used as initial monotherapy for new patients with glycated hemoglobin (HbA1c) levels of less than 8%, initial combination therapy for new patients with HbA1c levels of more than 8% and as an early add-on for current patients.

GSK is confident that Avandia/Avandamet use as initial therapy is consistent with the goals of the ADA treatment guidelines, if not the recommended treatment algorithm.

"In the ADA guidelines, I think there is a strong recommendation to get patients to goal, and to do that [physicians] may blow by even the ADA's recommendation of starting with metformin and end up very quickly on an Avandamet combination, which makes all of the sense in the world," GSK Pharmaceuticals President David Stout said.

However, the author of the ADA guidelines called into question the clinical significance of the ADOPT results in an accompanying opinion piece in NEJM.

"The choice of time to failure based on a confirmed fasting glucose level of more than 180 mg per deciliter as the primary outcome, rather than one based on glycated hemoglobin levels, seems anachronisitic," David Nathan (Harvard University) says. "Glycated hemoglobin is the measure of glycemia that correlates best with the risk of complications and has been used as the metabolic target for therapy for more than a decade."

ADOPT study authors Steven Kahn (University of Washington) et al. note that "the glycated hemoglobin level was not chosen as the primary outcome because the guidelines at initiation of the study focused largely on fasting plasma glucose levels."

"Despite the reduction in time to failure...the glycated hemoglobin results suggest a clinically less impressive effect," Nathan states. Glycated hemoglobin levels were evaluated as a secondary endpoint of ADOPT.

After six months of treatment, the rate of increase in HbA1c levels was 0.24% for glyburide, 0.14% for metformin and 0.07% for rosiglitazone. At a four-year evaluation, 40% of the rosiglitazone arm had glycated hemoglobin levels of less than 7% (the ADA goal for HbA1c levels) compared to 36% in the metformin group and 26% in the glyburide group.

"Although these differences are statistically significant, the relatively small difference in glycated hemoglobin levels achieved over four years in the rosiglitazone group as compared with the metformin group is of questionable clinical significance," Nathan said.

Citing an economic analysis of antidiabetic therapy, Senior VP-Cardiovascular & Metabolic Medicine Development Lawson Macartney maintained during the ADOPT presentation that, if the rate of increase in HbA1c levels could be reduced to 0.075...the net lifetime costs of treating diabetes would be reduced by 14%. "While this is a modest delta in absolute terms, I think the annualized slope of the lines is a key piece of the data to look at overall patient benefit."

Avandia was able to maintain a mean glycated hemoglobin level of less than 7% for the five year duration of the trial while HbA1c levels were maintained 45 months in the metformin group and 33 months in the glyburide group.

In its renewed marketing push, GSK may also try to distinguish rosiglitazone from other classes of antidiabetic agents based on its effect on the underlying pathophysiology of the disease.

In ADOPT, Avandia demonstrated significant improvement in maintaining ß-cell function. Evaluated as a secondary endpoint, ß-cell function declined at an annual rate of 2.0% after six months in the rosiglitazone group compared to 3.1% for metformin and 6.1% for glyburide.

While GSK asserts that ß-cell function data confirms that Avandia can "address the underlying pathology of type 2 diabetes and so impact disease progression," Nathan disputes that conclusion in the opinion piece.

"The hope that thiazolidinediones may affect the underlying pathophysiology of type 2 diabetes by protecting ß-cell function and may alter the course of the disease is only weakly supported by ADOPT," Nathan said, adding that "improved insulin sensitivity appears to be the most durable effect of rosiglitazone."

At five years, insulin sensitivity in patients receiving rosiglitazone had improved 77% compared to baseline; the metformin and glyburide groups showed improvement of 54% and 23% respectively.

"There were no unexpected adverse events in any of the treatment groups," the authors note. "Rosiglitazone was associated with weight gain, increased levels of LDL cholesterol (and more use of statins), more frequent edema, and a reduction in hemocrit."

Based on Nathan's analysis of ADOPT results, it is unlikely that ADA treatment guidelines will be amended to include Avandia for first-line use. "Given the modest glycemic benefit of rosiglitazone (with the risk of fluid retention and weight gain) and higher cost (including the need for more statins and diuretics), metformin remains the logical choice when initiating pharmacotherapy for type 2 diabetes," he concludes.

In its effort to dislodge metformin as the standard initial therapy, GSK will also have to contend with a recent Agency for Healthcare Research & Quality report that concludes that oral diabetes medications have similar effects on glycemic control (² (Also see "Metformin Is Most Effective Diabetes Drug At Reducing BMI – AHRQ Report" - Pink Sheet, 14 Aug, 2006.), p. 22).

Nonetheless, GSK will put "a lot more resources" behind Avandia, Pernock said. "Based upon the excitement that we've seen from the exciting results of ADOPT, GSK is treating this as a new product launch opportunity with resourcing available across all aspects of our promotion."

The rosiglitazone franchise is taking on increased importance for GSK's diabetes portfolio following the detection of a safety signal for its DPP-4 inhibitor Redona (denagliptin) in Phase III development (³ (Also see "GSK Plays Up Avandia As Diabetes “Engine” After DPP-4 Program Stalls" - Pink Sheet, 6 Nov, 2006.), p. 20).

The franchise will also benefit from results from the DREAM study, which shows a 60% reduction in progression to diabetes or death compared to placebo and could support approval of Avandia for prevention of type 2 diabetes (⁴ (Also see "GSK’s DREAM Of Diabetes Prevention Claim May Come True, But Not For King" - Pink Sheet, 2 Oct, 2006.), p. 23).

- Brian Marson