One of the hottest races in biotech is the PCSK9 drug development program aimed at lowering bad cholesterol (LDL) and thereby reducing heart disease.
These drugs are intended for a mass market like Lipitor, but unlike Lipitor, they are complicated biological drugs for which FDA approval is hard to get, and setting up manufacturing for is even harder. But the billions of dollars to be made are too attractive for many companies to miss out on, so the race is on.
Trials are run on a truly mass scale around the globe. Patients with stubbornly high levels of LDL continue to sign up, desperate to find something that will finally limit their risk of heart disease.
Like insulin for diabetes, the drugs are injected, but the injection is done once or twice a month.
In the lead is alirocumab or REGN727 or SAR236553 from Sanofi/Regeneron. Some of its seven Phase III trials will begin reporting later this year.
With dosing every two weeks, alirocumab has also been formulated in a pen device. Designing and using injection pens is a specialty skill for Sanofi, a giant in the insulin business.
Next in line is Amgen's AMG145, which is recruiting patients for most of its twelve Phase III trials. AMG145 could boast more flexible dosing and is progressing with once-monthly, as well as bi-weekly dosing. However, analysts note that once-monthly dosing results in a modest loss of efficacy and requires two separate injections.
Amgen is thinking ahead.
The ability to manufacture a complicated biological product for the mass market is a formidable task. Amgen is preparing three factories in Colorado, Puerto Rico and Rhode Island to make the drug. It is anticipating production on a scale never attempted before with a monoclonal antibody, a costly wager for a drug still being tested and likely years away from approval.
At every stage of production, the equipment has been blown up to a huge scale. Antibody-producing cells are going to be grown in gigantic stainless steel tanks. Amgen clearly wants to be ready with large quantities of its versions of the drug at the time when it is approved.
This is not just a race for approval, but also about who can do it, said Dr. Joseph P. Miletich, the head of translational sciences at Amgen, in a New York Times article.
Phase IIb data on the subcutaneous (injected) formulation of Pfizer's anti-PCSK9 antibody, called RN316, also known as PF-04950615, are expected in the coming months.
The phase IIb study is conducted with 356 patients with high cholesterol, already on statins, testing the effect of the injected version of the drug on LDL, or "bad" cholesterol. Dosing consists of 50mg, 100mg and 150mg every two weeks or 200mg or 300mg every four weeks, and the primary endpoint is an absolute change from baseline in LDL-C at 12 weeks.
Pfizer's drug proved highly effective in its intravenous formulation at lowering LDL in patients with high cholesterol, according to Phase IIa data released at last year. At the most successful dose level, 6mg/kg monthly, there was an 80 percent reduction in LDL-C from baseline with a 56 percent reduction at week 12.
A dose interruption occurred in 29 percent of the patients at week four when they reached abnormally low LDL-C levels, defined as below 25mg/dl.
Deutsche Bank (DB) analysts note that the FDA will probably not require such a stopping in future Phase III trials. However, there remains uncertainty over the implications of profoundly low LDL for patients.
For Pfizer, the subcutaneous formulation needs to perform as well as its intravenous counterpart, as competitors testing this method of administration are further ahead.
Why are new cholesterol lowering drugs needed in the first place?
Statins like Lipitor, Crestor and others work well, have been on the market for over a decade, are taken by hundreds of thousands of patients around the world, and are generally regarded as safe. But statins don't work for everyone, nor are they tolerated by all patients.
Also, there are people with genetic abnormalities who have LDL levels well above 400mg/dL and for whom statins are not nearly potent enough to lower their LDL levels to recommended levels.
For these type of patients, the solution may come from the new PCSK9 inhibitors.
The PCSK9 gene provides instructions for making a protein. However, the PCSK9 protein is not good news: it destroys LDL (bad cholesterol) receptors, which are important for the removal of LDL cholesterol from the bloodstream. This action results in high LDL cholesterol levels, which can build up in artery walls, leading to atherosclerosis and heart trouble.
The new experimental drugs are monoclonal antibodies, blocking the PCSK9 protein from binding to the receptor. The idea originally came from observing people who were born with a genetic defect that prevents them from producing PCSK-9. These people have very low LDL cholesterol levels and little evidence of atherosclerosis. They also don't seem to suffer any consequences from missing this protein.
Inhibitors of PCSK-9 have been pursued for almost a decade. The clinical data are just now emerging and highly promising.
How low is too low?
In the trials so far, people with stubbornly high cholesterol levels who are taking the new drugs have seen their LDL levels plunging from levels well over 100 to 50, 40, or even lower.
Dr. Barry Gumbiner, who is directing Pfizer's studies, said the company had to decide whether to set a floor for patients' LDL levels. Pfizer is interrupting treatment when LDL levels reach 25 or lower. The people seemed fine, but the company got nervous.
"There is not a lot of experience treating people to LDL levels this low," Dr. Gumbiner said in a New York Times article.
The PCSK-9 inhibitor program is a huge enterprise. The drugs are intended for a mass market, for usage for a lifetime, like Lipitor, and the FDA places a high bar on safety on these types of drugs.
To avoid surprises later, tens of thousands of patients have to be treated over a prolonged period of time to prove to the regulators that they are safe. If any of the trials cannot deliver solid efficacy combined with a clean bill of safety, they will be dropped in a heartbeat.
As an example, just one of Sanofi's Phase III trials ((NCT01663402)) is conducted at 349 sites with 18,000 patients enrolled. This study alone will likely cost about half a billion dollars. Obviously, the companies are hoping that the addition of REGN727 will be superior to statin therapy alone in a sense that the REGN727 cohort has impressively fewer heart attacks and strokes.
Also, the cost of production. The monoclonal antibody is made in living cells at an enormous expense, like some new cancer drugs that are already burdening the medical system. Amgen plans to make metric tons of its drug, much more, the company says, than any other biologic.
Insurers generally pay for drugs approved by the FDA, but the number who might benefit from these cholesterol drugs dwarfs those who are helped by the biologic cancer drugs.
The annual cost of such drugs to the patients will be at least $10,000 per year, and maybe even 2-3 times that. The annual cost of the generic statins is a fraction of that.
Most likely these agents initially will be reserved for people at high risk and for whom statins are not very effective, or for whom statins are not tolerated.
Although the trials are promising, there are some question marks.
While the drugs lower cholesterol, it has not yet been shown that they actually reduce the risk of heart attacks, strokes or other cardiovascular problems. The critical large-scale studies that would prove that are only starting. Also, the drugs have to be injected, typically every two to four weeks, as opposed to statins, which are pills. That may limit their wider appeal.
Despite major gains over the past half-century, heart disease remains the leading killer of Americans, causing nearly 600,000 deaths a year. Statins, the cholesterol-lowering drugs that went on the market in 1987, were a huge breakthrough, but far from a panacea.
Dr. Gary H. Gibbons, the director of the National Heart, Lung, and Blood Institute, estimates that even if the new drugs were expensive and injected, as many as two million Americans might be candidates. But if they could eventually be made affordable and in pill form -- two very big ifs at this point -- they might be used by one in four adults.
If and when approved, the market for these PCSK9 inhibitors may be at least $10 billion, according to Adnan Butt, an analyst with RBC Capital Markets in San Francisco. In the U.S. alone, about 1 million people cannot take statins because of side effects such as muscle soreness.
$10 billion is the kind of revenue potential usually reserved for a new Alzheimer's drug.
But there are also analysts who say that figure is wildly inflated. And Novartis (NVS), as well as a few biotechs like Alnylam (ALNY), have been working on new drugs in this field, raising the prospect of multiple drugs diluting the market share of the leaders.
The Sanofi/ Regeneron product is slated to be launched in 2015, and sales are forecast to reach $621m by 2018, according to EvaluatePharma.
Amgen's drug could be launched a year later than Sanofi's, according to Deutsche Bank's projection and may have 2018 sales of $140 million.
This leaves Pfizer's drug in third place, with an expected launch in 2017. Roche is hot on Pfizer's heels, with Phase II data on its subcutaneous project RG7652 due later this year.
The PCSK-9 inhibitor program is one of the biggest gambles in pharma today. The millions of people around the world with heart complaints can only hope that it succeeds.