Early evidence has built excitement for the investigational class of PCSK9 inhibitors, which have shown robust efficacy at cutting “bad” LDL cholesterol down to size. But positioning and pricing these biologicals in a market largely dominated by cheap and popular oral generics is sure to be a tough balancing act.

In recent months, new PCSK9 inhibitors have quickly captured the imagination of investors, clinicians and the media. Proprotein convertase subtilisin/kexin type 9 is a protein thought to cause the destruction of LDL receptors, making it harder to clear LDL cholesterol. Genetic studies indicate that low levels of PCSK9 are associated with lower levels of LDL and dramatically lower risk for cardiac events. The target has been validated in animal studies, which showed that taking out PCSK9 increases the number of LDL receptors in the liver clearance of LDL-C particles.

Regeneron Pharmaceuticals Inc./Sanofi SA,Amgen Inc. and Pfizer Inc. are among the companies developing PCSK9 inhibitors.

The most advanced data for the class was presented at the American College of Cardiology meeting in March: Phase II data for Regeneron/Sanofi’s subcutaneous injectable REGN727/SAR236553, a monoclonal antibody candidate that has been on a fast development track Also see "Regeneron/Sanofi’s Long-Term Alliances Begin Bearing Fruit" - Pink Sheet, 2 April, 2012.. In the Phase II trial of 183 patients already stable on Lipitor, Sanofi/Regeneron’s antibody was shown to reduce LDL cholesterol by 40% to 72%, depending on the dose (([A#14120326006]). The results suggest dosing every two weeks is optimal.

Also at the ACC meeting, Amgen released a Phase Ib dose ranging study of its PCSK9 inhibitor AMG 145, a monoclonal antibody, which was shown to reduce LDL by up to 81% compared to placebo in patients taking low to moderate doses of statins. Patients dosed every four weeks had a reduction of 66%, suggesting monthly administration could be possible.

“We believe there is life beyond statins and the next 10 years will be as exciting and hopefully as beneficial to patients as the statin era has been,” said Evan Stein, director of the Metabolic and Atherosclerosis Research Center at the University of Cincinnati, summarizing the results for the PCSK9 inhibitors during a session on treating difficult patients at the ACC meeting.

Stein was also the lead author of an article reporting three Phase I studies on SAR236553 in the New England Journal of Medicine on March 22.

Even though it is still in the early days, analysts are bullish – Cowen & Co. analyst Phil Nadeau estimates Sanofi/Regeneron candidate’s worldwide revenue potential at $1 billion.

Sitting Ducks

As the products are biological, high pricing is expected. Developers could target a high cost, highly effective agent at a narrow population, but alternatively they may want to make a product more affordable if they are going for a broad population, commented Ed Schoonveld, principal and market pricing and practice leader at ZS Associates.

Among other factors that will affect the pricing are the specific patient populations targeted and the value of the candidates, as demonstrated in additional, more advanced trials. An obvious target for new drugs is patients with rare types of familial hypercholesterolemia, a genetic condition that predisposes patients to high cholesterol and is associated with premature heart disease and death.

An estimated 600,000 people in the U.S. have FH. Those with severe types of FH have cholesterol levels two to four times higher than recommended targets, despite treatment with multiple cholesterol medications. In fact, levels may be so high that patients need regular apheresis treatments to remove excess lipids from their blood. In the U.S. about 3,000 patients have homozygous hypercholesterolemia (hoFH), meaning the disease was inherited from two parents, and 15,000 to 17,000 have severe cases of heterozygous hypercholesterolemia (heFH), meaning one parent passed on the disease.

HoFH is an obvious target that offers an easier regulatory path than other patient populations. The patient population is so small and unmet need is so high, that clinician experts, industry execs and consultants do not expect outcomes studies will be needed to secure approval, and the label could be expanded later on. From the payer perspective, treating these patients effectively could avoid expensive events and associated hospitalization costs.

Casting PSCK9 Net Wide

But the PCSK9 developers have their sights set a lot higher than merely rare types of FH.

Regeneron’s Phase II program included three trials in about 350 patients, including one study in heFH and two in primary hypercholesterolemia (one as a therapy co-administered with statins and the other as add-on therapy in patients on stable atorvastatin). Regeneron is also recruiting patients at high cardiovascular risk for a long-term Phase III safety study, according to clinicaltrials.gov.

Amgen’s Phase II program includes six trials in about 1,900 patients. One trial tests the drug in heFH and another as an add-on therapy in patients with and without coronary heart disease or risk factors that in combination equate to a risk as high as a history of CHD (CHD risk equivalent). Amgen’s program also tests the drug in patients who are intolerant to an effective dose of statins against ezetemibe (Merck & Co. Inc.’s Zetia), and as a monotherapy in patients with high cholesterol but nevertheless a low risk of cardiovascular events.

“We are looking at a wide variety of patients that have hypercholesterolemia and trying to understand the benefit/risk profile of AMG 145 in these patients,” said Amgen’s Scott Wasserman.

“We are looking at a wide variety of patients that have hypercholesterolemia and trying to understand the benefit/risk profile of AMG 145 in these patients. Phase III depends on what those studies demonstrate,” said Scott Wasserman, global project leader for cardiovascular medicine at Amgen.

Amgen expects to have all of the Phase II results in hand by late 2012.

And in the lead of PCSK9 development, Regeneron/Sanofi also appears to be planning to cast its net wide. The companies are expected to unveil their Phase III program in the second quarter.

Speaking in an interview after a press conference at the ACC meeting, Regeneron exec Bill Sasiela said that statins are now and will remain the “foundation of therapy.” But a number of key populations could benefit from PCSK9 treatment, including those who can’t get to LDL targets because they maxed out on statins and still had elevated cholesterol, or can’t tolerate moving up to a higher dose. The company estimates 1.4 million people in the U.S. are refractory or intolerant to statins.

“And there are patients with genetic forms of hypercholesterolemia who when you throw everything at them are still very far away from treatment goals. And they are not that rare, there are 600,000 with familial hypercholesterolemia in the US alone,” said Sasiela, vice president of Regeneron’s cardiovascular and metabolic division.

The market for secondary prevention, meaning treatment of those who have had a cardiovascular event, or who are CHD risk equivalent looks sizeable and LDL targets are more aggressive. Every year, an estimated 785,000 Americans have a new coronary attack and 470,000 have a recurrent attack. Furthermore, another 195,000 have a silent myocardial infarction.

A High Bar

PSCK9 inhibitors, among other new dyslipidemia efforts in development, face a market dominated by easy-to-take, popular and proven oral medications. And with the patent expiration of the top statin brands, the options are getting cheaper.

Once the most popular statin, Pfizer’s Lipitor (atorvastatin) went generic in November 2011. Merck’s Zocor (simvastatin) had previously gone generic in 2006 and in terms of volume sold, is the leader in the U.S. statin market. AstraZeneca PLC’s Crestor (rosuvastatin) will join the club in 2016, adding yet another low-cost, high-potency treatment option Also see "AstraZeneca Prepares For U.S. Statin Market Shake-Up As Lipitor Goes Generic" - Pink Sheet, 27 October, 2011..

Statins represent a highly evidence-based group of medicines, with outcomes studies documenting a dramatic reduction in risk for events of up to 50%. New drugs will need to show a significant further reduction in risk on top of optimal therapy, including high-dose statins.

Outside of rare patient populations, outcomes studies will be needed to secure FDA approval. With partners Genzyme Corp. and Sanofi, Isis recently submitted an application for the antisense apolipoprotein-b inhibitor Kynamro (mipomersen) in hoFH and upon FDA’s request is running a 12-month safety study to support approval in severe heFH Also see "Sanofi/Genzyme And Isis Submit Kynamro For Lowering Cholesterol" - Pink Sheet, 30 March, 2012.. The company expects that an outcomes study would be needed to expand to broader populations.

Outcomes trials will also be needed to succeed commercially. History shows that LDL is a surrogate endpoint that does not always equate to a survival benefit, Schoonveld commented, referring to the failed ENHANCE study of Merck’s Vytorin in 2008 Also see "No Surprises From ENHANCE At ACC Mean Vytorin Hopes Hang On IMPROVE-IT" - Pink Sheet, 7 April, 2008.. Across the therapeutic board, there is increased scrutiny, particularly in Europe, about whether a new drug is actually providing a long-term benefit, as shown by the Germany’s Institute of Quality and Evidence in Health Care’s recent determination that Merck’s hepatitis C drug Victrelis (boceprevir) did not produce sufficient added benefit. Schoonveld expects added-benefit reviews to be tough.

Outcomes studies are costly and time-consuming and present a big hurdle with respect to getting drugs to the market, though when it comes to drugs that show a very dramatic impact on surrogate markers, the sample size may be smaller than usual for outcomes trials, he said.

After the data for Regeneron/Sanofi’s Phase II trial were presented at the ACC meeting, the session co-chair Karol Watson stressed the need for outcomes studies. “This [PCSK9] could obviously be a very beneficial adjunct to get to goal, but we need outcomes studies,” explained Watson, co-director of the Cholesterol and Lipid Management Center at UCLA, in an interview after the meeting.

Dean Kereiakes, cardiologist at Christ Hospital in Cincinnati and an investigator on one of the Regeneron trials, commented that he will be looking for studies in statin intolerant patients, and high-risk populations not able to reach targets with high-dose statins plus other available therapies, including Zetia.

During a press conference at the ACC meeting about the Regeneron results, Mayo Clinic cardiologist Rick Nishimura called PCSK9 a “game changer,” but when asked afterward about the appropriate patient population, he commented that many patients will do well on statins.

“A 30, 40, 50% reduction in cardiac events … I’d say that’s working. Statins work better than any medications we have,” Nishimura said. “If your cholesterol can be controlled with conventional meds, take it and run with it and don’t go to something investigational. Anything investigational could have potential side effects 10 or 20 years down the road that we don’t know about.”

Watson also raised concerns about the side effect profile, given that a number of the PCSK9s are monoclonal antibodies, they carry a risk for immune effects.

A case of leukocytoclastic vasculitis (rash) was noted as a drug-related serious adverse event in the Regeneron study, though investigators said that the exact cause could not be determined. Leukocytoclasitic vaculitis is listed as a side effect on labels of monoclonal antibodies.

“That sounded like an immune reaction to me. Until we know it’s safe, you have to worry about that,” Watson said.

Whereas the side effects of monoclonal antibodies might be acceptable in a patient with another condition like rheumatoid arthritis, questions could arise in hypercholesterolemia, depending on the patient population targeted, commented Michael Rice, senior consultant at Defined Health. For an otherwise healthy patient with high cholesterol, those may not be acceptable risks, he said.

Sasiela said Regeneron is trying to get to the bottom of the report.

“An external expert looked at the case and doesn’t feel strongly that it is truly drug related. But it’s very much an open question as to whether it’s something related to this form of antibody therapy or any of the antibody therapies,” he said.

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