The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted to recommend approval of Pargluva ( Muraglitazar ), an investigational oral medicine for the treatment of type 2 diabetes, for use as monotherapy and in combination with Metformin.
The Committee voted not to recommend its use in combination with a sulfonylurea.

Pargluva is a dual alpha/gamma PPAR ( peroxisome proliferator-activated receptor ) activator.
Activation of PPAR-gamma is associated with reductions in plasma glucose levels, while activation of PPAR-alpha is associated with reductions in plasma triglyceride levels and increases in high-density lipoprotein cholesterol ( HDL-C ) levels.

Bristol-Myers Squibb and Merck & Co are collaborators in the global development and commercialization of Pargluva.
The New Drug Application ( NDA ) for Pargluva was submitted to the FDA in late December 2004.

A phase 3, head-to-head study, showed that Muraglitazar significantly outperformed Pioglitazone ( Actos ) in reducing levels of hemoglobin A1c ( HbA1c ) and fasting plasma glucose, while also improving lipid measures.

Investigators in this double-blind, randomized, active-controlled trial enrolled 1159 subjects with type 2 diabetes who had inadequate glycemic control on Metformin monotherapy.

Subjects were randomized to Muraglitazar 5 mg once daily ( n = 587 ) or to Pioglitazone 30 mg once daily ( n = 572 ) for 24 weeks. They continued on mean daily Metformin doses of 1854 mg ( Muraglitazar cohort ) and 1851 mg ( Pioglitazone cohort ).

At week 24, the Muraglitazar group achieved a mean reduction of hemoglobin A1c of 1.14% compared to 0.85% in the Pioglitazone group ( p < .0001 ).
Also, 60% of Muraglitazar subjects achieved the ADA suggested HbA1c target of less than 7%, compared to 45% of Pioglitazone subjects (P < .0001).

Muraglitazar subjects also achieved a significant mean reduction in fasting plasma glucose ( -44 mg/dL ) compared to Pioglitazone subjects ( -33 mg/dL, P < .0001 ),

At week 12, Muraglitazar subjects achieved a mean decrease in triglyceride levels of 28% versus 14% in the Pioglitazone group ( p < .0001 ), and subjects with triglyceride levels above 150 mg/dL at baseline showed a 35% decrease with Muraglitazar and a 19% decrease with Pioglitazone ( p < .0001).

Among Muraglitazar subjects, levels of high-density lipoprotein cholesterol decreased 6% and of apolipoprotein B fell 12%, and free fatty acids decreased 30%, compared to 1%, 6% and 21% with Pioglitazone, respectively ( p < .0001 for all ).

The clinical safety of Muraglitazar has been comprehensively evaluated in the NDA, providing clinical information in over 3200 subjects ( 2969 diabetic subjects ) treated with Pargluva.

In a placebo-controlled, double-blind, 24-week Phase 3 monotherapy study, edema related events were reported in 8.1%, 11.4%, and 7.8% of subjects treated with Muraglitazar 2.5 mg, Muraglitazaer 5 mg and placebo-treated subjects, respectively.
Across all 24-week controlled clinical studies that studied Muraglitazar 2.5 mg and 5 mg doses, Muraglitazar-treated subjects in combination therapy studies with Metformin or sulfonylurea reported edema with an incidence broadly in line with rates seen in the monotherapy study.
In an active-controlled combination study of Muraglitazar versus Pioglitazone on a background of metformin, the incidence of edema at 24 weeks was 9.2% for Muraglitazar 5 mg and 7.2% for Pioglitazone 30 mg.
Most of these edema-related events were considered mild or moderate in intensity and few subjects discontinued treatment due to this adverse experience.

The mean weight gain observed in 24-week Phase 3 studies with Muraglitazar was between 1.1 kg to 4.3 kg.
In the active-controlled Metformin combination study of Muraglitazar 5 mg versus Pioglitazone 30 mg in addition to Metformin, the mean weight gain at 24 weeks was 1.4 and 0.6 kg from baseline, respectively.
In the combination study with sulfonylurea, mean weight gain from baseline was greater ( 2.7 kg for 2.5 mg and 4.3 kg for 5 mg vs 0.4 kg for placebo ), presumably due to increased endogenous insulin levels associated with administration of a sulfonylurea.

Hypoglycemic events were reported in < 1% of subjects in all other studies not involving concomitant treatment with a sulfonylurea.
In the placebo-controlled combination study with a sulfonylurea, confirmed hypoglycemia ( documented by symptoms such as dizziness, shakiness, sweating, hunger, and a finger stick blood glucose measurement ≤ 50 mg/dL ) was, as expected, reported in more subjects treated with Muraglitazar and sulfonylurea than with sulfonylurea alone.

Heart failure adverse events were monitored closely during the Muraglitazar clinical program.
The clinical presentations, underlying risk factors, management and outcome of heart failure events were in line with the clinical experience gained with the TZDs Pioglitazone and Rosiglitazone over the past several years.
Across all 24-week controlled clinical studies that studied Muraglitazar 2.5 mg and 5 mg doses, seven adverse events of heart failure were reported by investigators, yielding incidence rates of 0.19%, 0.34%, and 0.17% for subjects on Muraglitazar 2.5 mg, Muraglitazar 5 mg, and Pioglitazone 30 mg, respectively.
Although the incidence rates of heart failure events demonstrated a dose relationship trend through the full dose range studied, which included the higher 10 mg and 20 mg doses studied in Phase 2, it is apparent that the propensity to experience a heart failure event depended on underlying CV risk factors. Such risk factors included prior cardiovascular disease history, including prior heart failure.
These same underlying CV disease features have also been associated with events of heart failure in type 2 diabetes subjects treated with the TZDs Pioglitazone or Rosiglitazone.
Overall, for Muraglitazar, heart failure cases were of mild to moderate severity and most events resolved within days after administration of diuretics and study drug discontinuation.

Source: FDA, 2005


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