The association between serum trigclyeride (TG) levels and cardiovascular (CV) risk remains a controversial one. While case control population studies tend to support an independent association between TG levels and CV risk, the correlation breaks down in many prospective cohort studies, when adjustments are made for TC, LDL-C and HDL-C levels. Clinical trial data is equally mixed, with the two major TG modifying drug classes currently in use the prescription omega-3 fatty acids (POMs) and the fibrates failing to consistently and robustly demonstrate CV outcomes benefit to date.
The U.S. NCEP ATP III guidelines recommend that a TG reducing agent be considered only if a patient is at LDL-C goal, with high serum TG (200- 499 mg/dL). For patients with very high serum TG (500 mg/dL), TG reduction is recommended, irrespective of LDL-C levels, to protect against pancreatitis. In practice, however, the lack of clarity regarding the status of serum TG level as an independent CV risk factor has led to some ambivalence among the specialist physician community as to the merits of treating it.
However, the untested nature of TG levels as an effective disease modifying target for the prevention of recurrent CV events, and the relatively inconsistent use of such agents, has done little to dent the aspirations of drug developers. In recent years there has been something of a renaissance in the development of agents to treat hypertriglyceridemia. In January 2013, Amarin's POM (Vascepa) launched in the United States for the treatment of very high TG levels, and is expected to gain an additional label for use in the considerably larger high TG population. A second novel POM, AstraZeneca's Epanova, is set to launch early in 2014, with a similar launch strategy on the cards.
Novel drug classes for the treatment of hypertriglyceridemia are also in the works, albeit at an earlier stage of development. At the 2013 ESC, Isis presented impressive interim Phase II data for ISIS-ApoCIII Rx, an oligonucleotide delivered by weekly subcutaneous injection. The highest dose of ApoCIII Rx (300 mg) was shown to reduce TG by up to 75 percent in monotherapy, in patents with average baseline TG above 500 mg/dL. Further Phase II data is anticipated in the next few months, and a Phase III trial is planned for next year.
While Amarin and AstraZeneca are looking to expand the use of their POMs into the broader dyslipidemic patient population with high and even potentially borderline serum TG levels in their sights, Isis is taking an entirely different approach. ApoCIII Rx will initially be launched for a section of the very high TG population those with serum TG levels above 880 mg/dL with severely high TG levels. ApoCIII Rx will likely be priced at a considerable premium relative to other TG lowering therapies, owing to its oligonucleotide nature and small target population, effectively eliminating any opportunity for extensive population expansion.
Given the market potential of Epanova and Vascepa, ApoCIII Rx is ostensibly a much less lucrative player in the hypertriglyceridemia space. However, we believe that the success of the novel POMs will be entirely contingent on a demonstration of CV outcomes benefit. The success of ApoCIII Rx, in contrast, is merely dependent on a continued demonstration of potent TG reduction in patients with severely high TG, and if the initial data is anything to go by, is a much surer prospect.
Paramjit Narang is a business insights analyst on the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources Group.