Amgen Keeping Dosing Options Open For Cholesterol Buster AMG 145

A monthly dose of Amgen’s PCSK9 inhibitor lowers LDL significantly with a good tolerability profile in two Phase II studies. Reporting results for the RUTHERFORD trial in the journal Circulation, investigators compare AMG 145 favorably for heterozygous familial hypercholesterolemia to a range of rivals, including Sanofi’s REGN 727, Genzyme’s mipomersen and Aegerion’s lomitapide.

Amgen Inc.is still keeping its options open with respect to dosing schedules for the PCSK9 inhibitor AMG 145 after releasing two positive Phase II studies in different patient populations – RUTHERFORD and GAUSS – at the American Heart Association annual meeting in Los Angeles.

Amgen and Sanofi/Regeneron Pharmaceuticals Inc. are leading the new field of development with monoclonal antibodies to inhibit plasma proprotein convertase subtilisin/kesin type 9, which binds to and degrades LDL receptors, making it harder to clear LDL cholesterol.

A late-breaking clinical trial session on Nov. 5 featured data on AMG 145 from the RUTHERFORD study of patients with the genetic condition heterozygous familial hypercholesterolemia (HeFH) and from GAUSS in at-risk patients who are intolerant to statins and not able to reach cholesterol targets. The candidate looks efficacious in harder to treat patients, with a manageable safety profile and amenable to once-monthly dosing, but late-stage data is needed to fully evaluate tolerability. Two other Phase II studies called LAPLACE-TIMI and MENDEL are slated for presentation and publication Nov. 6.

Convenience of dosing is considered an important competitive advantage. Phase II data for Sanofi/Regeneron’s SAR236553 (REGN727) in HeFH suggested that a two-week dosing schedule would be optimal for the most robust and durable effect (Also see "Regeneron/Sanofi’s PSCK9 Inhibitor Might Need Two-Week Dosing Schedule" - Pink Sheet, 30 May, 2012.)

AMG 145 looks competitive, in terms of the four-week dosing results, UBS analyst Andrew Peters said in a Nov. 5 analyst note. However the analyst added, “We wonder if AMG 145 could deliver even greater lowering with 2-week dosing since 2-weeks post dosing showed maximal response.”

Asked to comment on the prospect for monthly dosing in an interview after results were presented, Amgen’s global CV lead Scott Wasserman said the firm is committed to looking at both every-two-week and monthly regimens as it moves into Phase III.

Amgen’s AMG 145 demonstrated reductions in LDL by up to 81% compared to placebo in patients taking low to moderate doses of statins in a Phase Ib dose-ranging study presented at the American College of Cardiology meeting in March (Also see "Will New Injectables Sell In An Oral, Mainly Generic Cholesterol World?" - Pink Sheet, 9 Apr, 2012.). Those dosed every four weeks had a reduction of 66%, suggesting monthly administration was possible.

RUTHERFORD: LDL Down 43% To 55%

The RUTHERFORD study presented at the AHA tested two doses of AMG 145 (350 mg and 420 mg) given once every four weeks in a “large and diverse cohort” of 167 HeFH patients whose LDL was over 100 mg/dL and with triglycerides over 400 mg/dL despite available treatments, including statins, ezetimibe (Merck & Co. Inc.‘s Zetia) and niacin.

About one-fifth of the patient population had existing coronary artery disease, despite intensive statin use, lead author Frederick Raal, University of the Witwatersrand in South Africa, wrote in reporting results in the journal Circulation on Nov. 5.

After 12 weeks of treatment, LDL was down by 43% in the 350 mg arm compared to 55% in the 420 mg group, and up 1% for placebo. The candidate reduced LDL in a dose-responsive manner, researchers reported. After 12 weeks of treatment, most taking the test drug reached the LDL target of 100 mg/dL and 60% attained the 70 mg d/L target, which is advised for patients at especially high risk.

Raal and colleagues compared AMG 145 to other cholesterol management options, including drugs that are in development – Sanofi’s SAR236553 (REGN727) – and pending FDA review – Genzyme Corp.’ mipomersen and Aegerion Pharmaceuticals Inc.’s lomitapide (Also see "Cholesterol Endpoints Draw Scrutiny At HoFH Panels" - Pink Sheet, 22 Oct, 2012.).

“Although moderate further reduction in LDL-C can be achieved with other drugs under development, such as the ApoB antisense therapeutic mipomersen and the microsomal triglyceride transfer protein inhibitor lomitapide, these drugs have significant side effects and neither can achieve the substantial reduction in LDL-C seen with AMG 145,” the authors state.

As for REGN727, they pointed out “a number of differences” between trials. Regeneron’s drug “appeared to show” better reduction in LDL-C of up to 57.9% compared to placebo with dosing every two weeks in a trial in this patient population. But, they argued, the measure used in that study – the “Friedewald formulae” – “significantly underestimates” LDL-C in some patient subsets compared with the “ultracentrifugation” measure used in RUTHERFORD. In RUTHERFORD, reductions at two weeks with the ultracentrifugation method were over 60% for both doses, they added.

As for safety, researchers reported that there were no “clinically significant safety findings” related to AMG 145. The most common treatment-related side effects for the 350 mg and 420 mg doses respectively were injection site pain (7.3% and 3.6%) and headache (5.5% and 1.8%), as well as a skin burning sensation (1.8% and 3.6%).

Researchers also reported an increase in creatinine kinase in one patient who had normal creatinine kinase at baseline.

Aside from injection site pain, there were no notable differences between the AMG 145 and placebo arms in areas of interest, like hypersensitivity and immunogenicity, liver enzyme elevation and liver disorders. No binding or neutralizing antibodies against AMG 145 were reported.

Tapping Into Intolerance, Nipping At Zetia’s Heels

The second Phase II study of AMG 145 presented and published on Nov. 5 was GAUSS, in statin-intolerant patients. Statin intolerance represents an attractive market opportunity for pharma, especially in light of the blockbuster success of Zetia, which has successfully tapped into this market segment (Also see "Seeing Dollar Signs In Statin Intolerance" - In Vivo, 23 Apr, 2012.).

Out of about 20 million patients treated with statins, some 10% to 20% are unable to tolerate any statins or the higher doses necessary to achieve current LDL-C goals, primarily because of muscle-related side effects, reported David Sullivan of the Royal Prince Alfred Hospital in Australia in the Journal of the American Medical Association online Nov. 5. Results were presented the same day at the AHA meeting.

The randomized GAUSS trial tested various doses of the drug alone (280 mg to 420 mg) and also the highest 420 mg dose given with Zetia, against Zetia and placebo. The trial also permitted use of low doses of statins, in line with real-world practice.

Fatigue, muscle fatigue or muscle spasm were reported in fewer than 5% of patients taking AMG 145, they reported. But the most common side effect overall was myalgia (muscle pain), which occurred in from 3.1% to 15.6% taking various doses of AMG 145 alone and 20% in the arm that included AMG 145 with Zetia. That compares to 3.1% for placebo/Zetia.

Sullivan and colleagues noted that patients reported higher rates of muscle effects, using the term myalgia. Nevertheless, they said that the muscle tolerability profile of AMG 145 in the study, if confirmed, “provides a potential therapeutic option for high-risk patients who currently have few treatment options.”

The subjective nature of statin intolerance was a limitation of the study, researchers acknowledged.

But myalgia rates did not correlate to dosing. For example, five patients (15.6%) taking the 280 mg dose got the side effect compared to only 1 patient (3.1%) taking 420 mg. Wasserman explained that this lack of dose relationship suggests that the effect is not real. “There’s no trend there,” he said. “This is probably an issue of small numbers.”

No liver function alterations or development of binding or neutralizing antibodies to the test drug were reported in the trial.

As for efficacy, there was a dose-dependent reduction in LDL ranging from -41% in an arm taking 280 mg of the drug, -51% in those taking 420 mg alone, and -63% for those on 420 mg of AMG 145 with Zetia. That compares to -15% for patients on placebo/Zetia.

However, “the overall reduction in LDL-C achieved with AMG 145 alone or in combination with ezetimibe was quantitatively similar to reductions reported with the most highly efficacious statins,” the article states.