Lipid-lowering drug development continues to thrive and regulatory approval moves toward disease endpoints


  Recently,the development of lipid-lowering drugs is very hot.On Oct.1,a new lipid-lowering drug from Esperion Therapeutics,ETC-1002,not only outperformed Merck's Zetia(generic name:Ezetimibe)in a mid-stage clinical trial,but more importantly,a combination of the two performed better.On October 2,The Lancet reported two key clinical results for Amgen's PCSK9 inhibitor Evolocumab(Rutherford-2 and Tesla PartB).In a randomized,double-blind,placebo-controlled international multi-center clinical trial(Rutherford-2),Evolocumab in combination with a statin-lowering drug or Zetia reduced LDL levels by 60% in patients with familial heterozygous hypercholesterolemia(FH).In such patients,high doses of statins combined with Zetia often fail to bring LDL levels down to recommended levels.The latter Tesla PartB trial enrolled patients with more severe and rare homozygous hypercholesterolemia,and was able to reduce LDL levels in such patients by 31%with no significant increase in adverse effects in the treatment group.In addition,clinical results(IMPROVEIT)from a head-to-head comparison of the risk of acute coronary syndrome with the statin Simvastatin(simvastatin)and Vytorin(simvastatin and Zetia combination)in 18,000 participants are expected to be reported on November 17.Forbes analysts believe these results could lead to major changes in the development of lipid-lowering drugs.

  Statins are the current first-line drugs for treating high cholesterol,which not only effectively lower the level of density lipoprotein cholesterol("bad"cholesterol or LDL),but also have demonstrated the efficacy of reducing the risk of cardiovascular disease in several large clinical trials.Since the American Heart Association(AHA)and the American College of Cardiology(ACC)released new"guidelines for the Use of drugs to lower LDL cholesterol"last November,most industry experts believe that statins will continue to be the first-line treatment for high cholesterol in the short term.It indicates the general trend of new drug research and development from blood indicators to treatment of diseases.But while statins are a major breakthrough in the field of fat reduction,about a fifth of patients have varying degrees of resistance to the drugs,and many users suffer from side effects such as muscle soreness and forgetfulness.And a very small percentage of patients can't tolerate statins at all.In addition,about a third of high-risk patients were treated with Astrazeneca's Crestor and different generic versions of Pfizer's Lipitor,but were unable to keep LDL levels within a reasonable range.Therefore,the development of new lipid-lowering drugs has been favored by manufacturers.

  At present,the most popular lipid-lowering target is the preprotein transforming subtilis 9(PCSK9)inhibitor.This class of drugs not only offers a new mode of treatment,but also lowers LDL by a high margin,about twice as much as statins.Almost all of the phase 3 data published so far have been positive,which is considered a clear advance in the field of lipid-lowering research since statins such as Lipitor and Zocor.Examples of advanced clinical development include Amgen's Evolocumab(AMG145),Sanofi's Alirocumab,and Pfizer's Bococizumab.Evolocumab has submitted a biologics license application(BLA)to the US FDA on August 28.Because Sanofi has a priority review lottery ticket from BioMarin,if it can complete the declaration by the end of the year,it also hopes to compete for the first PCSK9 inhibitor on the market.Although Pfizer's bococizumab is half a beat slower than Amgen and Sanofi's PCSK9 inhibitors,the Outcome clinical trial of bococizumab may be completed first,and it is also possible that Pfizer's experience in selling Lipitor and doctor resources may come later.

  While most people believe that PCSK9 inhibitors will be available in the United States next year,these late-stage development are monoclonal antibodies that must be injected.This opens up an opportunity for a new once-daily oral preparation,ETC-1002.In a mid-stage trial involving 348 patients with high cholesterol,the treatment group was given 180 mg of ETC-1002 per day for 12 weeks and saw an average 30%reduction in LDL levels,slightly higher than the 27%reduction in the Zetia control group,but with statistical differences.According to previous data,ETS-1002 is slightly less effective than powerful statins such as Lipitor and Crestor,and about half as effective as PCSK9 inhibitors.But the high-dose combination of ETC-1002 and Zetia lowered LDL levels by an average of 48%,and the low-dose combination lowered LDL levels by an average of 43%.

  ETC-1002,the first ATP-citrate lyase(ACL)inhibitor and its complementary AMPK agonist,reduces blood cholesterol levels by inhibiting liver cholesterol synthesis and increasing LDL receptor expression.Although ETC-1002 is slightly less effective at lowering LDL than powerful statins,it can be combined with Zetia and show better results.In addition,ETC-1002 is also expected to be cheaper than biologics PCSK9 inhibitors.And it is taken orally once a day,which has certain advantages over injections.Although it is not yet known whether ETC-1002 reduces the risk of cardiovascular disease,in this mid-stage trial,patients in the treatment group had lower levels of C-reactive protein,a marker of cardiovascular disease inflammation,than those in the Zetia control group.Common adverse reactions include common cold symptoms and upper respiratory tract infections.The incidence of muscle-related adverse reactions was similar to Zetia.According to Tim Mayleben,CEO of Esperion,a Phase 3 trial of ETC-1002 with 4,000 patients will begin at the end of next year.

  The Improved-IT clinical results,scheduled to be presented next month at the American Heart Association's annual meeting,will have a profound impact on the development of lipid-lowering drugs.Although most believe in the correlation between LDL levels and the risk of cardiovascular disease,Zetia has been on the market for 12 years and this is a large trial evaluating its cardiovascular Outcome.It is also the first large trial to directly demonstrate LDL-C and the risk of cardiovascular events.The results could influence whether the FDA uses LDL as an alternative endpoint for cardiovascular events.In any case,the shift of regulatory approval from blood indicators to disease endpoints is an unquestionable general trend.

  Source:Chinese Medicine Source