Extensive Phase II data showing efficacy and safety for Amgen Inc.’s injectable AMG 145 is helping build a case for PCSK9 inhibitors in areas of unmet need. However, the data is short term and the candidates still face an uphill battle proving their worth, considering that other options are widely available, including cheap, highly efficacious oral generics supported by long safety track records.

Along with Sanofi/Regeneron Pharmaceuticals Inc., Amgen is at the lead of development of drugs aimed at PCSK9 inhibition, a new way of treating high cholesterol. Members of the class inhibit plasma proprotein convertase subtilisin/kesin type 9, which binds to and degrades LDL receptors, making it harder to clear LDL cholesterol. In studies to date, the PCSK9 inhibitors have demonstrated substantial reductions in LDL, a trusted surrogate endpoint for cardiovascular outcomes.

In addition to the Amgen studies, Sanofi/Regeneron and Pfizer also released data at the Nov. 3-7 American Heart Association meeting in Los Angeles – providing an opportunity to size up the class and gauge interest in a new dyslipidemia treatment option from physician attendees.

Physicians at the AHA meeting were “surprisingly reserved” in their enthusiasm for the PCSK9 class, Barclay’s analyst Tony Butler observes.

Four Phase II studies of the subcutaneously injected AMG 145 in more than 1,300 patients were presented at the meeting and published simultaneously in peer-reviewed journals. Across the studies, the treatment demonstrated LDL-lowering effects ranging from 41% to 66%, efficacy results that analysts believe are on par with Sanofi/Regeneron’s SAR236553 (REGN727), which is now in Phase III.

AMG 145’s safety profile also looked clean in the studies, but the treatment period was only 12 weeks long – an insufficient window for a chronically treated condition such as high cholesterol. Also, there were some reports of creatine kinase elevation at five and 10 times the upper limit of normal in patients taking the test drug.

One of Sanofi/Regeneron’s older Phase II studies in the genetic disorder of heterozygous familial hypercholesterolemia also was recently published in the New England Journal of Medicine. The study is part of a smaller Phase II program that included about 350 patients ([A#14121101003]). Regeneron outlined and explained its late-stage development strategy, including an outcomes study in 18,000 high-risk patients, during a Nov. 5 investor briefing at the meeting.

Further behind in development, Pfizer aired pooled data for two Phase II studies of an intravenous formulation of its PCSK9 inhibitor RN316, given every four weeks, on Nov. 5 at the AHA meeting. A Phase IIb study of the candidate recently got under way.

Commenting on the mood at the AHA meeting in a Nov. 7 note, Barclay’s analyst Tony Butler said that the reception for the PCSK9 inhibitor class was mostly positive when it came to the efficacy profile for LDL-lowering, as well as reduction in ApoB and Lp(a) levels.

But despite reductions of 40% to 72% in LDL and minimal adverse events for members of the class, physicians at the meeting were “surprisingly reserved in their enthusiasm for this class of agents,” he wrote. Concerns include the need for outcomes studies prior to approval, longer-term safety data, questions about compliance with subcutaneous injectables for an asymptomatic disease like high cholesterol, and the cost differential of new drugs compared to generics. Reports of CK elevation also caused concern, even though the conditions resolved spontaneously.

In a Nov. 7 note, Leerink Swann’s Howard Liang flagged CK elevation as something that needs to be monitored in the future, considering that across Amgen’s Phase II studies, the rate of patients on test drug with CK greater than five times the upper limit of normal was 1.6% for those on the biweekly dosing schedule and 1.2% for monthly, versus 0.8% for placebo arms.

No cases of CK greater than 5xULN were reported for SAR236553/REGN727 in Phase II, but the program for that candidate was considerably smaller.

Targeting Unmet Needs

While clinicians appreciate the PCSK9 mechanism of action and potential for significant efficacy, the class still faces significant development and commercial hurdles.

Injectables are obviously much less convenient than small molecules and will be much more expensive than older oral drugs, particularly the highly efficacious generic statins Also see "Will New Injectables Sell In An Oral, Mainly Generic Cholesterol World?" - Pink Sheet, 9 April, 2012.. Furthermore, a range of add-on therapies are available, offering multiple routes to cholesterol management between fenofibrates, statins, niacin and Merck & Co. Inc.’s Zetia (ezetimibe).

There also are development risks. Some candidates – like AMG 145 and REGN727 – are monoclonal antibodies, which carry a known risk for immunogenicity, and safety problems could emerge in Phase III. Depending on what emerges in larger trials, that risk could limit use in larger, healthier patient populations coveted by big pharma.

But while broad use might be a challenge, the PCSK9 inhibitors seem well suited for the untapped frontier in dyslipidemia: areas of unmet need for those who can’t reach LDL targets for one reason or other, including patients with genetic disorders, notably familial hypercholesterolemia; those at high risk for cardiovascular events; and statin-intolerant patients Also see "Branded Life After Lipitor: Pharma Targets Unmet Needs In Dyslipidemia" - In Vivo, 23 April, 2012.. During its investor presentation at the AHA meeting, Regeneron stressed the focus on the millions of patients in these areas of unmet need.

Amgen’s Phase II program for AMG 145 explored the role of the candidate in a variety of patient populations with unmet need, despite a range of treatment options. A variety of doses and dosing schedules – once every two weeks versus monthly – were tested (see sidebar).

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Positive efficacy and safety results for the RUTHERFORD study in 167 patients with heterozygous familial hypercholesterolemia (HeFH) and the GAUSS trial in 160 statin-intolerant patients were presented at the AHA meeting on Nov. 5 and published in Circulation and the Journal of the American Medical Association ([A#14121105004]).

On Nov. 6, the Lancet featured positive results for lowering LDL with a good safety profile from the LAPLACE-TIMI 57 study in about 630 patients with high cholesterol and on a statin, and from the MENDEL study in about 400 patients who were not taking other lipid-lowering drugs.

In practice, PCSK9 inhibitors are expected to be added to statin therapy, and the randomized LAPLACE-TIMI 57 study of the drug with statins and/or Zetia represents the largest study so far in this patient population, according to a Lancet editorial accompanying the study publications. However, less than a third of patients in the trial were on high-intensity statins and the “frequency of coronary heart disease, cerebrovascular or peripheral arterial disease and diabetes was low,” wrote the editorial’s co-authors Andrew Tonkin of Monash University in Melbourne and Gerald Watts of the University of West Australia.

The Differentiator: Monthly Dosing

Amgen used the “ultracentrifugation” measure for LDL in its trials, which is stricter than the “Friedewald formulae” used in the Regeneron studies, making it harder to compare results for the two candidates directly. Taking this difference into account, analysts view AMG 145 and REGN 727 as having similar efficacy. AMG 145 is “roughly comparable” to RGN727 with encouraging safety, Liang concluded. Butler reached a similar conclusion.

But whereas Sanofi/Regeneron’s drug appears to require dosing every two weeks, Amgen has had positive results with dosing at every two weeks and also every four weeks. Amgen plans to take both dosing schedules into Phase III, due to kick off in early 2013. Regeneron is testing two doses – 75 mg and 150 mg – every two weeks in its Phase III ODYSSEY program of 22,000 patients.

“Despite a later Phase III start, Amgen’s differentiation could be dosing with both an every other week (q2w) and monthly (q4w) schedule in Phase III compared with REGN/SNY’s q2w dose only,” Liang said. Feedback from clinicians suggests that a monthly dose would be preferred, even if LDL lowering is slightly lower for that regimen, he reported.

The Lancet editorial about the Amgen studies pointed out that the data support effectiveness of either the two week or four week regimen.

“Low-volume, low-frequency subcutaneous injections are likely to be more acceptable, suggesting that AMG 145 420 mg, administered monthly with a microinfuser device, might be a preferred option. Self-administration will, however, require patient education and support systems,” the authors stated.

Amgen hasn’t observed inter-subject variability with the four-week dosing paradigm, Sean Harper, EVP of R&D, said during a Nov. 6 investors call at the AHA meeting.

“As we’ve studied the pharmacokinetics and pharmacodynamics of our molecule, we reached an understanding of the ability to do that in a way that we think will be very useful for patients. So we are advancing both of those dosing options forward,” he said.

During its own investor call Nov. 5, Regeneron execs faced questions about the challenges of getting patients with an asymptomatic disease to use an injectable monoclonal antibody and prospects for competing with a product that needs to be given every two weeks.

“We’re able to administer both of these doses [75 mg and 150 mg] with a single 1 mL injection that can be used with an auto-injector, so it’s very patient-friendly in terms of usage. And by using the every two week dosing regimen, we’ve got a dosage that provides consistent reductions over time, regardless of background therapy, regardless of the patients,” Bill Sasiela, VP of program direction, responded.

Ultimately, societies, health systems and patients will look at the cost-effectiveness of the reductions that are achieved, Robert Califf, vice chancellor for clinical and translational research at Duke University, commented during the call.

“If we get anything like what would be predicted, then it looks to me that this would fall within the realm of acceptability,” Califf said.

Authors of the Lancet article suggested that oral preparations need to be developed. However, when asked about this possibility during the Regeneron call, Jay Edelberg, head of Sanofi’s PCSK9 research and development unit, said that due to the biology of PCSK9, it is very difficult to develop a small molecule. “You can never say never, but I think there [are] going to be challenges to try and take an oral approach,” he said.

Instead, the companies are focusing on making delivery of the injectable as patient-friendly as possible, he noted.

Meeting Demand For More Data

Aside from dosing frequency and the delivery device, Phase III safety data could offer means of differentiation among the PSK9 candidates.

Reporting results for AMG 145 in LAPLACE-TIMI in the Lancet, Brigham and Women’s Robert Gugliano and colleagues said that rates of treatment-related adverse events were similar for the test drug and placebo, with no severe or life-threatening effects. However, the authors also acknowledged that “over 12 weeks, few patients had a serious adverse event, reducing our statistical power to detect imbalances.”

Commenting on MENDEL and LAPLACE TIMI-57 in their editorial, Tonkin and Watts wrote that serious safety concerns were not identified in the two trials, but that the duration of drug exposure was short.

“Large long-term randomized trials with precise clinical cardiovascular endpoints are needed to substantiate the promise shown by PCSK9 inhibitors and to establish safety, tolerability, acceptability and cost-effectiveness,” the editorial states.

Regeneron’s Phase III ODYSSEY program includes a total of 22,000 patients. The company is running four other Phase III studies in HeFH (n=826), statin intolerance (n=250), primary hypercholesterolemia (n=100) and high cardiovascular risk (MI, stroke, type 2 diabetes and chronic kidney disease, n=3,716). The cardiovascular outcomes study will assess 18,000 patients who have had an acute coronary syndrome, on top of standard of care. Phase III results should start to become available in 2014, and the outcomes study is slated for completion in 2018.

However, the company said that it does not expect that it will need outcomes data prior to approval. Rather, it plans to file in the U.S. and E.U. based on studies using the surrogate endpoint of LDL reduction.

“Across the globe, LDL remains a valid surrogate for approval,” Sasiela said.

Amgen also faced questions about the requirements for filing in indications of HeFH and statin-intolerant patients. Harper responded that the company’s Phase III program will cover the whole patient spectrum, mirroring the Phase II trials.

“Our view is that it will be possible to file the program. And our intent is to file based on LDL-lowering,” Harper said.

Momentum Builds For PCSK9 Class, But Proof Of Safety Still Thin

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