Bristol-Myers Squibb's Glucovance (metformin/glyburide) is emerging from FDA in time to give Bristol a half a year or more to transfer the market from its $1.9 bil. single-agent product Glucophage to the new combo.

Approved by FDA July 31, the new fixed combination of metformin and glyburide was approved far enough in advance of the expiration of exclusivity on Glucophage to give Bristol a chance to build the replacement product before metformin becomes available as a generic.

Bristol's oral anti-diabetic Glucophage (metformin) loses exclusivity in September, after a six-month pediatric exclusivity extension.

FDA will begin to accept generic metformin applications after the expiration of the exclusivity period so there will presumably be a period before the introduction of generics. Bristol also has an NDA pending (with a mid-November user fee deadline) on a once-daily formulation of metformin.

Glucovance will be available in mid-August with an initial three years of exclusivity. The FDA approval letter notes that the requirement for submission of pediatric studies for the product is deferred until July 31, 2002 which could affect the future exclusivity.

The NDA for Glucovance received a 10-month standard review from FDA. The application was filed Sept. 30, 1999.

Bristol previously estimated that approximately 1.25 mil. diabetics take a combination of metformin and a sulfonylurea class drug like glyburide as separate products (¹ [A#00620210014]).

Glucovance is indicated as an initial treatment for new type 2 diabetes patients and as a second-line therapy for patients currently on single-ingredient therapy with metformin or a sulfonylurea product with inadequate blood sugar level control.

In presentations publicized from this year's American Diabetes Association scientific sessions meeting in mid- June, proponents of the new fixed combination called it a potential "paradigm shift."

A June 12 press release from the Columbia University Health Sciences Division reported the comments from a Columbia researcher and study investigator in the Glucovance Phase III trial.

Daniel Donovan, MD, noted that as a first-line therapy, the fixed combination achieved ADA target blood sugar levels in "a significant number of patients." The Columbia researcher also noted that "in many cases, the required dose was lower than the doses of single agent glyburide or metformin."

Glucovance comes in three fixed dosage combinations: 1.25 mg glyburide/250 mg metformin; 2.5 mg glyburide/500 mg metformin; and 5 mg glyburide/500 mg metformin.

In the clinical trial data summarized in approved labeling, the lowest dose combo (1.25 mg/250 mg) resulted in a -1.48 mean change in hemoglobin A1c compared to -1.03 change for metformin 500 mg alone or -1.24 for glyburide 2.5 mg. alone.

A June 12 press release from the lead investigator in the Phase III trial, Baylor College of Medicine professor Alan Garber, also stressed the ability of the combination to manage blood sugar levels more effectively at lower doses than the single ingredients.

"Most importantly," Garber said, "we were able to help more patients reach the goals of blood sugar management recommended by the American Diabetes Association with lower doses of metformin and glyburide than we would have previously used when prescribing either medication alone."

Garber also claimed a side effect advantage for the combination over the single ingredient doses. "Patients treated with the glyburide 1.25 mg/250 mg tablet had fewer gastrointestinal side effects than metformin patients and fewer symptoms of hypoglycemia than those treated with glyburide therapy," the Baylor researcher said.

Also stressing the potential impact of a fixed combination product as the new starting point for diabetes drug therapy, Garber said: "The [Phase III] study results clearly demonstrate the benefits of treating patients with a single combination tablet as initial therapy."

The effort to show the advantages of the fixed combination will be key to Bristol's attempt to keep a dominant brand in the metformin class past the arrival of generic versions of the single ingredient.

Skepticism about the re-emergence of fixed combination products as a way to extend brand positions was expressed by outgoing New England Journal of Medicine Editor-In-Chief Marcia Angell, MD, in a recent issue of the journal.

Angell questioned the "medical soundness" of fixed combinations "as opposed to flexible combinations of separate drugs." In her article, she specifically focused on two joint product development projects between Merck and Schering-Plough in the asthma and cholesterol classes (² Also see "Comparative Trials Urged By NEJM Departing Editor To Deter "Me-Too" Drugs" - Pink Sheet, 26 June, 2000.).

Bristol also ran into difficulty earlier this year in gaining approval for a fixed combination of the cancer treatment regimen uracil/tegafur and leucovorin under the brand name Orzel. Bristol withdrew the branded combination but has resubmitted an application for uracil/tegafur.

Bristol may face one other complication as it attempts to make the Glucovance combo the starting therapy in the diabetes field. The company is already involved in a co-marketing effort with SmithKline on the glitazone product Avandia (rosiglitazone).

Avandia was originally approved for use as a single agent or in combination with metformin. In April, it received a supplemental FDA approval (NDA 21-071/S-001) for use in combination with a sulfonylurea. It is unclear whether Bristol can move co-marketing efforts with Avandia to the new metformin/glyburide combination. SmithKline's upcoming merger with Glaxo could lead to a re-evaluation of the Avandia agreement.

Pricing for the new product may be easier, even with the upcoming generic availability of the separate ingredients. Bristol may have created pricing flexibility for the Glucovance launch from recent pricing activity on Glucophage.

Bristol has been aggressively raising the price on Glucophage, including a 6.9% increase in May. The raises on the single-ingredient product may give Bristol more room to find a price for Glucovance that will make it attractive even when the generics to the single ingredient become available.

The importance of Glucovance as a replacement for Glucophage is indicated by a careful handling of the introduction. Bristol issued a press release on the product on Aug. 2, two days after FDA approval. The press release again emphasizes the theme of a "paradigm shift" in diabetes treatment to use two ingredients as initial therapy, but otherwise is very terse.

On Bristol's website, the company highlighted the approval of the hair removal product Vaniqa, to be promoted with Gillette (³ Also see "Bristol/Gillette Vaniqa To Be Launched In September For Facial Hair Removal" - Pink Sheet, 7 August, 2000.). The Glucovance approval, however, is not featured, implying that Bristol is trying to maintain a quiet period on Glucovance until it can stage a launch to explain why the combo should replace the successful Glucophage franchise.

The strong statement of Glucovance's activity compared to single ingredients and placebo in labeling should help Bristol define the usefulness of the combo. "Treatment with Glucovance resulted in significantly greater reduction in [baseline hemoglobin A1c] and postprandial plasma glucose compared to glyburide, metformin or placebo," labeling states.

Approval was based on results from two double-blind clinical trials. The first-line therapy trial involved 806 patients with a baseline fasting plasma glucose level < 240 mg/dL and baseline hemoglobin A1c between 7% and 11%.

Glucovance 1.25 mg/250 mg resulted in a -20.3 difference from metformin. The higher dose of Glucovance produced a -18.9 difference.

Glucovance therapy produced a greater reduction in FPG compared to glyburide and metformin, but the differences were not statistically significant, according to the FDA-approved labeling.

As second-line therapy, the combo was studied in 639 patients who were receiving at least half the maximum dose of a sulfonylurea. Patients were randomized to receive a fixed dose of glyburide 5 mg, metformin 500 mg, Glucovance 2.5 mg/500 mg or Glucovance 5 mg/500 mg. After 16 weeks, Glucovance "resulted in significant lowering of HbA1c, FPG and PPG from baseline compared to glyburide or metformin alone."

The recommended dosage for Glucovance as initial therapy is 1.25 mg/250 mg once or twice daily with meals. Dosage for second-line therapy is 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals.

BMS Counting On Initial Combo Use For Glucovance To Supplant Glucophage

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