Better than Statins

If there is any drug class that has retained its stronghold in the cardiovascular disease market, it undoubtedly has to be statins. Atorvastatin(brand name Lipitor by Pfizer) and Simvastatin(brand name Zocor By Merck) together account for 57 percent of the cholesterol market itself. Patent expiration and the resulting erosion of the statin market by generic versions might have reduced the value but has hardly reduced the market share of these cholesterol lowering drugs. However, the future is open for debate even as efforts are on to develop drugs with new mechanisms to achieve better clinical results, and also develop combination drugs including polypills that combine statins with other drugs.

Lipid modulators, new mechanisms

It is estimated that the dyslipidemia(abnormal cholesterol) patient population will grow steadily in the future increasing the need for cholesterol lowering drugs. While statins have so far been efficacious in addresing this need, so much so that it has been almost impossible for others to break their hegemony, there has also been noise on the side effects of statins, which is cited as one of the key reasons in the quest for non-statin options.These include CETP (Cholesteryl Ester Transfer Proteins) inhibitors and PCSK9 inhibitors, both lipid modulators just like statins, albeit with different action mechanisms. While the former are plasma proteins that mediate the transfer of triglyceride and cholesteryl ester between lipoproteins by inhibiting this pathway and as a result elevating high-density lipoprotein cholesterol (HDL-C). In contrast, PCSK9 inhibitors aim to lower the low density lipoprotein cholesterol (LDL-C) in plasma.

Late-stage trial failures of Pfizer’s torcetrapib and Roche’s dalceptrapib have dampened enthusiasm on CETP inhibitors alongwith doubts on whether a rise in HDL-C could actually result in reduction of cardiovascular events. However, not all is lost. “Merck’s anacetrapib and Eli Lilly’s evacetrapib are currently in the pipleline with anacetrapib considered to be more promising for its impact on both HDL-C (increasing) and LDL-C (decreasing),” says Vijaya Vulapalli, Senior Analyst, GBI Research. Pam Narang, analyst from Decision Resources expects them to gain blockbuster status in the next ten years. “CETP inhibitors will launch with long term outcomes data, and will likely be the most potent HDL-C raising agents available at this time. Furthermore, their ability to substantially reduce LDL-C levels somewhat offsets concerns about the therapeutic merits of raising HDL-C, on the back of dalcetrapib’s Phase III data,” she explains.

PCSK9 antibodies work by inhibiting a protein by the same name, that reduces the ability of liver to remove LDL-C from the blood. Regeneron’s alirocumab and Amgen’s AM145, posted promising results in Phase II and just entered into Phase III trials. Interviewed thought leaders by Decision resources as part of their report titled ‘Dyslipidemia’are highly enthusiastic about this category with a convincing mechanism of action on the back of impressive Phase II results and the effect on LDL-C levels. “We expect the drugs to launch initially for high risk cardiovascular patients, with a broader label contingent on long-term cardiovascular outcomes data. Their injectable administration and high cost, however, may restrict their use to high risk patients, and prevent them from usurping the statin strong-hold,” opines Narang on a caustiously optimistic note. However, some suggest to reserve any judgement, given that even CETP inhibitors looked promising early on, until results from bigger trials trickle in.

Statin plus drugs?

Even as drugs with new mechanisms are under clinical trial, statins remain undisputable as first line agents for their use in primary and secondary cardiovascular risk prevention. The wealth of clinical data till now that further supports that the drug improve long term outcomes is the reason why some are betting on combination therapies which use a statin as opposed to simply using a statin. For example, the HPS2-THRIVE study investigated the efficacy of Merck’s Tredaptive (fixed dose combination of modified release niacin and laropiprant) on a statin background in more than 18,000 high cardiovascular risk patients but failed to show long term cardiovascular outcomes relative to placebo while increasing HDL-C modestly. It also led to significantly higher rate of adverse effects relative to placebo, including skin reactions, gastro-intestinal side effects, new-onset diabetes, and myopathy. Earlier this year European Medical Agency(EMA) recommended the drug be suspended, after which Merck withdrew the drug from markets worldwide.

Physicians are keeping a close eye on IMPROVE-IT, that received a go-ahead from an independent data safety monitoring board (DSMB) recently. The study is investigating the efficacy of Merck’s Vytorin, a combination of ezetimibe (Zetia) and simvastatin (Zocor) relative to simvastatin treatment in more than 18,000 high cardiovascular risk patients. It is one of the most awaited trials in the market as it acts on both HDL-C and LDL-C. “Given that ezetimibe primarily acts by raising LDL-C, a failure for the drug to show benefit here could be bad news for the LDL-C hypothesis, and so for drugs in development which also act in this way (the statins are known to have an anti-inflammatory effect, in addition to LDL-C lowering, which could contribute to their efficacy),” pontificates Narang. Vallupalli doesn’t see Vytorin gain a major share in the market due to cost efficiencies of the genric versions , one already off patent and one to go off patent soon. “Simvastatin is already in the statins market as one of the key drugs and the Vytorin trial is to prove if combining both is going to yield better outcomes. Even if it gets approved, it may not gain in the market on the potential entry of new class of drugs that have different mechanism of action or pathways,” she postulates.

The polypill

The UMPIRE trial published recently in the Journal of the American Medical Asociation has demonstrated increased adherence in patients with cardiovascular events who take the fixed-dose combination pill or a polypill( statin, aspirin, and two anti-hypertensive drugs). In 2004 participants in the UK, Ireland, the Netherlands and India with an average age of 62 years of which 80 percent were male, either the polypill, or their normal combination of medicines was randomly assigned. 90 percent of the patients had experienced a previous heart attack, stroke or serious blockages in arteries in the legs while the remaining had one or more risk factors (blood pressure, cholesterol, diabetes, smoking) that placed them at high short-term risk of experiencing one of these cardiovascular events. While both versions of the polypill contained simvastatin, 70 percent of those in the usual care group were prescribed either atorvastatin or rosuvastatin. Corroborating the results, Professor Vivekanand Jha, Executive Director, The George Institute for Global Health India says, “Switching to a fixed dose combination can improve blood pressure and cholesterol control as seen in the polypill group, who reported 30 percent increased use of appropriate medicines. It is important to provide this type of evidence so that governments, doctors and patients can make the right decisions about medication use.”

Professor Jha fiercely supports statins and even goes a step ahead , perhaps shedding a light on what could be the next frontier for statins when he says, “Statins themselves are highly effective, but are being used very ineffectively – the biggest challenge is to get them to those individuals who need them the most. Achieving this is as, if not more, important than developing new drugs. This was the reason behind the UMPIRE trial.” While the polypill does indicate that giving medicine at prescribed doses does make prescribing easier and even improve adherence, but critics might still say that better clinical outcomes are needed. So clearly, the cholestrol drug market is witnessing a plethora of activity, be it through new mechanisms of action, or fixed drug combinations. However, statins remain a formidable marker in terms of the outcomes even as the target is to move beyond. But till the time that does not happen, they will rule even after generisation.

shalini.g@expressindia.com