Homozygous familial hypercholesterolemia (hoFH) is a rare disorder caused by mutations in the low density lipoprotein (LDL) receptor associated with severe hypercholesterolemia (cholesterol >500 mg/dL), premature atherosclerosis and death. HoFH patients are relatively unresponsive to available lipid lowering agents and are typically managed with low density lipoprotein (LDL) apheresis, which can temporarily lower LDL by up to 50%, but is expensive, inconvenient, not widely available, and only slows atherosclerosis development. Thus, there is a need for effective new agents that can substantially lower cholesterol in this disorder. Microsomal triglyceride transfer protein (MTP) is a protein responsible for transferring lipids onto apolipoprotein B (apo B) in the assembly of intestinal chylomicrons and hepatic very low density lipoprotein (VLDL). The genetic absence of MTP causes abetalipoproteinemia, characterized by the absence of VLDL and LDL in plasma and markedly reduced levels of cholesterol. MTP is a target for inhibition as novel strategy for cholesterol reduction. BMS-201038 is a potent inhibitor of MTP that has been extensively studied in Phase 1 and 2 studies. Although highly effective, its development was halted because the association with potential gastrointestinal (GI) and hepatic-related side effects. The investigators believe, however, that GI side effects could be managed with low fat diet and a dose-titration design. They currently hold the IND for this compound and recently completed a Phase 2 study to determine the dose, safety and efficacy of BMS-201038 in hoFH. Six hoFH subjects received once daily dosing of 4 doses of BMS-201038 (0.3, 0.1, 0.3, and 1.0 mg/kg) for 4 weeks each while on a very low fat diet. All subjects tolerated the drug up to the maximal dose with little to no steatorrhea. Three of the six subjects had substantial increases in liver transaminases, but levels rapidly decreased without a reduction in dosage in 2 of 3 patients. At the highest dose, the mean percent changes in LDL cholesterol and apo B were -51% and -55% (p<0.001), respectively. These data indicate that MTP inhibition is tolerable and highly effective in hoFH and supports the performance of a longer-term Phase 3 trial. This application proposes a multicenter, Phase 3 trial consisting of a 26 week randomized, placebo-controlled phase followed by a 52-week active, open label phase to evaluate the long-term efficacy and safety of BMS-201038 assessed by clinical and laboratory data as well as adverse events. This study would serve as basis for approval of BMS-201038 for hoFH.
| Raper, Anna; Kolansky, Daniel M; Cuchel, Marina (2012) Treatment of familial hypercholesterolemia: is there a need beyond statin therapy? Curr Atheroscler Rep 14:11-6 |
