Thanks to genomic sequencing, some heart-healthy mutants and billions of dollars spent on R&D, rival drug developers are bearing down on a promising new way of treating the scourge of high cholesterol. And with the first FDA applications likely coming in the next year, the nascent field's trailblazers are vying for the top spot with blockbuster aspirations.

Leading the way is Amgen ($AMGN), whose drug evolocumab (AMG 145) has already come out the other end of 6 Phase III studies with stellar results, followed by alirocumab from partners Sanofi ($SNY) and Regeneron ($REGN), which performed well in the first of 14 planned late-stage studies, and Pfizer's ($PFE) bococizumab, which entered Phase III in October.

The drugs, which help the body get "bad" LDL cholesterol out of the bloodstream, were the toast of the American College of Cardiology's annual scientific meeting, heralded as perhaps the biggest advance in cardio treatments since statins--tried and cheap stalwart therapies that, despite their ubiquity, don't work for every patient. An estimated 71 million Americans have high cholesterol, and analysts figure the in-development new drugs, whether used on top or in lieu of statins, could bring about a $10 billion market.

"We look at this a game changer for patients," Scott Wasserman, Amgen's executive medical director for global development, said in an interview. "We believe this is going to put a significant stranglehold on cardiovascular disease."

But despite an early coronation from many investors and analysts, a host of hurdles stand before the leaders in what has become a late-stage arms race, including regulatory uncertainty, looming safety concerns and the daunting prospect of convincing already-testy payers to shell out for costly biologics therapies.

Naturally, such discoveries tend to draw a crowd, and a bevy of biotech and pharma outfits have since developed investigational monoclonal antibodies designed to home in on PCSK9 and keep it from binding to LDL receptors, thereby freeing up the liver to do its job on bad cholesterol. Lagging behind Amgen, Sanofi, Regeneron and Pfizer are earlier-stage efforts from Roche ($RHHBY), Bristol-Myers Squibb ($BMY), Alnylam ($ALNY) and others.

How well they work

According to pretty much all the available data, the PCSK9 pathway is a winner. Across Amgen's late-stage results on more than 4,000 patients, evolocumab on its own reduced mean LDL cholesterol by 57% compared to placebo. That number swelled to as high as 75% after combining the drug with statin therapy. Furthermore, the drug easily beat out Merck's ($MRK) Zetia--which is designed to block intestinal absorption of bad cholesterol--and has performed well when paired with other cardio treatments.

Sanofi and Regeneron hit a similar mark in their first Phase III trial of alirocumab, which also topped Merck's small-molecule therapy, and the pair are planning to report 9 more late-stage trials in 2014, unveiling data on roughly 6,000 patients, according to Bill Sasiela, vice president of program direction at Regeneron.

And Pfizer has found itself in the same ballpark of LDL reduction with bococizumab's Phase II results, lighting the way for a late-stage program that will enroll more than 22,000 patients, the company said.

On the safety side, each company has said its therapy has been well tolerated, pointing to similar safety profiles in the treatment and placebo arms of each trial. The most common adverse events across the whole class include headache, diarrhea, nausea and urinary tract infection. 

Amgen, Sanofi, Regeneron and Pfizer have all laid out plans for expansive late-stage programs involving more than 40 trials and about 75,000 patients, testing their drugs in a wide range of populations, including those with rare genetic disorders and statin intolerances, and seeing how well the treatments complement existing therapies at various dosages, all in an effort to prove that shutting down PCSK9 leads to a meaningful, durable and reliable drop in LDL cholesterol.

Deducing just what "work" means

But whether that reduction spells a better life for patients is a different matter altogether. The FDA accepts a reduction in LDL as a biomarker for improvement in cardiovascular function, but not everyone is convinced 2 + 2 = 4 when it comes to PCSK9 drugs. Payers may hold out for long-term data before accepting the new drugs, which could cost thousands of dollars per year, and physicians, long since used to the predictable benefits of statins, will likely want a better grasp on PCSK9 blockers before prescribing them to all but the most desperate of patients.

And so each of the class leaders has committed to massive, multiyear studies with hopes of connecting the dots between lowering cholesterol and improving the rates of heart attack, stroke and other serious events. Pfizer's longitudinal trial, which will include more than 20,000 patients, should report out in 2017, the company said, while Amgen and Sanofi and Regeneron expect to have long-term data ready by 2018.

"Ultimately, the proof of the pudding is in the long-term outcomes studies to show efficacy and show safety," Libby said. "The human mutants show us a lot of assurance, but we really require the outcomes data."

Amgen's Wasserman agrees, saying the early days of PCSK9 blockers will likely be a two-tier story, starting with the approval of the first drug and followed by the emergence of outcomes data, which have the chance to "change the discussion" about cardiovascular treatment.

Like Wasserman, Regeneron's Sasiela is betting the new class of drugs can prove itself in the outcomes study, pointing to the discovery of the pathway as evidence. In the first registry analysis of "human mutants" who had lost PCSK9 function, the group experienced a solid improvement in LDL but an even more impressive reduction in long-term cardiovascular risk, Sasiela said--all without any serious side effects.

The neurocognitive specter

Of course, as tends to be the case in biotech, with hype comes a pervasive fear of a letdown. For PCSK9 blockers, that has come in the form of potential neurocognitive impairments tied to the drugs, the fear of which has already led to a few sky-is-falling hours on Wall Street.

Earlier this month, Sanofi revealed that the FDA is looking into the potential for cognitive impairment with the new class of drugs, asking the drugmaker and its partner to keep an eye on the issue through their 12-study Phase III program. Amgen later confirmed that it got the same notice, leading jittery investors to dump shares in all three companies, sending shares down as much as 10% over worries that the FDA might hold out for long-term outcomes data before approving any PCSK9 drugs or that a previously undisclosed safety issue could derail high-dollar expectations for the drugs.

But that minicrisis has since subsided, as each of the leading developers has reported no safety signals for cognitive impairment across data from thousands of patients. Despite its inescapability just weeks before, the neurocognitive question didn't play much of a role in any of the PCSK9 sessions at ACC. (Sasiela quickly confirmed that Regeneron doesn't see the issue as an impediment to alirocumab development, and Wasserman, who has clearly had to address this topic more than once, can rattle off each of the few reported neurocognitive problems across Amgen's entire PCSK9 program and promptly explain the non-evolocumab cause of each.)

Still, the earlier skittishness over safety demonstrates that the market isn't quite all-in on the new therapies, and, thanks to some recent share-crushing disasters for the likes of Sarepta ($SRPT), Ariad ($ARIA) and PTC Therapeutics ($PTCT), it's not surprising that many biotech investors are waiting around for some second shoes to drop.

A new era for cardiology

Whether PCSK9 drugs can live up to their billing likely won't be decided for at least three years, but their short-term promise heralds the grand entry of biologics into the cardiology world, Libby said. As anyone inundated with TV ads for Enbrel and Humira can attest, TNF-blocking biotech drugs have revolutionized rheumatology, according to Libby, and the same thing has taken place in cancer. But for cardiology, an area long focused on small-molecule therapies with varying rates of success, drugs like evolocumab, alirocumab and bococizumab signal a new way forward.