November 06, 2012

LOS ANGELES — Three new phase 2 studies with two anti-PCSK9 monoclonal antibodies, all showing large reductions in LDL cholesterol, were presented here today at the American Heart Association 2012 Scientific Sessions.

These antibodies, although still relatively early in clinical development, are generating much excitement, as their large effects on LDL reduction appear to be additive to that of the statins, and the hope is that they may enable the vast majority of patients to get to LDL goals.

We don't really know very much about their safety profile yet.

The antibodies work by inhibiting the PCSK9 protein. This PCSK9 protein binds to LDL receptors, resulting in their degradation, so that fewer are available on liver cells to remove excess LDL-C from the blood. Moreover, traditional LDL-lowering therapies such as statins actually stimulate the production of PCSK9, which limits their own ability to lower LDL-C. By blocking the PCSK9 pathway, these antibodies upregulate the recycling of LDL receptors and therefore represent a potentially novel mechanism for lowering LDL.

There are many of these antibodies in development, with the most data having been presented on the Regeneron/Sanofi product, REGN727/SAR236553. But phase 2 data on two other antibodies from Amgen and Pfizer were reported today, showing broadly similar effects, with LDL lowering of 40% to 60%, as well as moderate reductions in Lp(a).

Biologics for Hypercholesterolemia

Summing up the findings, designated discussant of the studies, Dr Peter Wilson (Emory University School of Medicine, Atlanta), said the information presented today added data on anti-PCSK9 antibodies in another 450 to 500 patients. "We now have biologics now to treat hypercholesterolemia. The lipid effects with these antibodies are really quite good. They are very effective and extremely promising." But he added: "All eyes will now be on safety and long-term outcomes."

He noted that adverse events so far reported suggest some myalgia and creatinine-kinase (CK) elevation signals, but risks appear quite low. "I would say myalgia may occur in 5% to 10% of patients, and CK elevations may also occur. These may be a concern if patients are also on statins." He also pointed out that some antidrug antibodies were detected in one of the studies, "and this will need some vigilance in the future." He added, "We haven't seen much yet about liver-function abnormalities so far. I would like to see more about that."

If you believe in LDL lowering, then these drugs will really help us.

Much more information on all these issues will become available from large-scale phase 3 trials that are now starting with both the Regeneron/Sanofi and Amgen products in post-ACS patients.

Both these agents are given by subcutaneous injection, the Regeneron/Sanofi agent once every two weeks and the Amgen product once every four weeks. The Pfizer antibody was given by IV infusion once every four weeks in the studies reported, but Wilson said he hoped this would also become a subcutaneous injection in future.

Commenting on prospects for these antibodies for heartwire , lipid researcher Dr Alan Tall (Columbia University, New York) said: "These antibodies are very good at lowering LDL. It is likely that they will find a place especially for patients intolerant to statins. Clearly they are going to be efficacious. Their success will hinge on their safety, and in that regard it is still very early days. We don't really know very much about their safety profile yet."

Dr Frederick Raal (University of Witwatersrand, Johannesburg, South Africa), who presented one of the studies with the Amgen product, said: "If you believe in LDL lowering, then these drugs will really help us." He said they would first be targeted at familial-hypercholesterolemia (FH) patients, and then patients intolerant to statins and those who can't get to goal on statins.

Two studies were presented at the meeting with the Amgen drug AMG-145: GAUSS and RUTHERFORD.

GAUSS in Statin-Intolerant Patients

The GAUSS study was presented by Dr Evan Stein (Metabolic and Atherosclerosis Research Center, Cincinnati, OH) and published online simultaneously in the Journal of the American Medical Association [1].

In the study, 160 patients unable to tolerate statins due to muscle-related side effects were randomized to three different doses of AMG-145 (given by subcutaneous injection once every four weeks), a combination of AMG-145 plus ezetimibe 10 mg daily, or ezetimibe alone. Treatment was given for 12 weeks (three injections). Mean LDL at baseline was high at 193 mg/dL. AMG-145 was associated with large reductions in LDL, the greatest effect being seen in the group receiving combination therapy with ezetimibe.

GAUSS: Results at 12 Weeks

Outcome AMG-145 280 mg AMG-145 350 mg AMG-145 420 mg AMG-145 420 mg + ezetimibe Ezetimibe alone
Change in LDL from baseline (%) -41 -43 -51 -63 -15
Patients reaching LDL goal of

<100 mg/dL (%)

47 53 61 90 7
Patients reaching LDL goal of

<70 mg/dL (%)

9 17 29 62 0

Four patients suffered a serious event--acute pancreatitis, coronary artery disease, hip fracture, and syncope, but none of these were considered treatment related.

In terms of side effects, Stein said muscle issues occurred in "roughly 3% of patients on monotherapy, similar to that with ezetimibe," but this was increased to 5% to 6% on combination treatment." Stein described the tolerability as "good, considering all patients had had muscle side effects on statins."

Two patients had CK elevations over 10 times the upper limit of normal, one of which was adjudicated as myopathy event. No liver abnormalities were seen.


A second study with AMG-145, RUTHERFORD, this time in heterozygous familial-hypercholesterolemia patients, was presented by Raal and published simultaneously in Circulation [2].

In the study, 168 patients already on statins but with high LDL levels (average 158 mg/dL) were randomized to one of two doses of AMG-145 (again given once a month for three months) or placebo. Similar results as in the GAUSS study were seen.

RUTHERFORD: Results at 12 Weeks

Outcome AMG-145 350 mg (n=55) AMG-145 420 mg (n=56) Placebo (n=56)
Change in LDL from baseline (%) -43 -55 +1
Patients reaching LDL goal of

<100 mg/dL (%)

70 89 2
Patients reaching LDL goal of

<70 mg/dL (%)

44 65 0

Two patients had a serious event (atrial fibrillation and acute appendicitis), neither of which were considered treatment-related.

Three patients given AMG-145 had CK elevations, all related to strenuous exercise, which resolved spontaneously. Other side effects were nasopharyngitis (12%), injection-site pain (3% to 9%), and headache (5%).

Kastelein Upbeat; More Positive Data on AMG-145

November 6, 2012 - In a discussion of two further studies with AMG-145 presented here at the American Heart Association 2012 Scientific Sessions, Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) described the anti-PCSK9 antibodies as a "triumph of LDL lowering and goal attainment." He added: "We are truly witnessing the birth of a novel therapy."

In terms of reaching target LDL levels, Kastelein said: "We have never seen such high levels of goal attainment as when these agents are added to statin therapy."

He said that there was "an urgent unmet need" for new treatments to lower LDL, particularly in familial-hypercholesterolemia patients, with a recent study in the Netherlands showing that only 20% of such patients manage to get their LDL levels below 100 mg/dL.

In terms of safety, Kastelein commented: "I have been involved in more defeats in my lifetime than successes in terms of drug development, but I have never seen so many empty boxes in adverse-events tables in phase 2 studies before. So far I can see no relevant safety issues with these agents."

LDL Levels Under 30 Mg/Dl Will Be Seen

Kastelein also dealt with the issue of very low LDL levels (<30 mg/dL), which he said will be seen in the large-scale trials of the anti-PCSK9 antibodies. He does not believe this will be problematic. Noting that Brown and Goldstein have stated that physiological LDL should be around 25 mg/dL, Kastelein presented his own meta-analysis (as yet unpublished) of seven large statin trials suggesting that events continue to be reduced with LDL lowering right down to 30 mg/dL. "Lower levels of LDL seem to confer cardiovascular protection right down to physiological levels of under 30 mg/dL," he said.


The two further phase 2 studies with AMG-145 presented today add another 1000 patients to the information on anti-PCSK9 antibodies. The LAPLACE-TIMI 57 and MENDEL studies, which were simultaneously published online today in the Lancet, showed broadly similar results to the other phase 2 studies presented Monday, with LDL reductions of around 50% to 60%.

In the LAPLACE-TIMI 57 study [3], the largest phase 2 study of the drug, 631 stable patients already on statins (and 10% also on ezetimibe) were randomized to six different dose regimens of AMG-145 or placebo. These included both two weekly and four weekly injections. Average baseline LDL was 120 mg/dL. At the end of the 12-week treatment period, LDL levels had fallen by 42% to 66% with AMG-145. No treatment-related serious adverse events occurred. No antibodies were detected.

In an analysis of 284 patients in the LAPLACE study defined as at high risk of cardiovascular events, 90% of those receiving the higher dose of AMG-145 achieved LDL levels <70 mg/dL.

The second study, MENDEL, addressed the use of AMG-145 monotherapy in patients with LDL >100 mg/dL but in whom lipid-lowering therapy was not mandated [4]. In total, 406 patients were assigned to six different dose regimens of AMG-145, ezetimibe, or placebo. Highest doses brought about a 48% to 51% reduction in LDL and a 30% reduction in Lp(a). Safety data was said to be "encouraging" with "no signal of toxicity." CK increases occurred in four AMG-145 patients, all associated with strenuous activity, and resolved spontaneously.

Pfizer's RN-316

A third presentation included pooled data from two phase 2 studies with Pfizer's RN-316 in 136 patients already taking high-dose statins (with average baseline LDL of 123 mg/dL). They were randomized to one of four doses of RN-316 (given by IV infusion once every four weeks) or placebo. Best results were seen with the two higher doses--3 and 6 mg/kg--which brought about LDL lowering of around 46% and 56%, respectively.

In these two dose groups, over half the patients had treatment interrupted when LDL levels fell to below 25 mg/dL (as specified in the protocol). Patients who received all three doses of the agent in the 3-mg/kg and 6-mg/kg groups had higher baseline LDL levels and saw reductions of LDL of 75%.

In terms of adverse events, one patient had an increase in liver enzymes, and there was one report of CK elevation. In addition, there were five reports of myalgia and eight of arthralgia, and 5% of patients showed antidrug antibodies, but these did not appear to be related to efficacy.

There were three serious adverse events--depression, abdominal pain, and noncardiac chest pain--but these were not said to be drug related.


Also today, Sanofi and Regeneron announced the start of a phase 3 outcomes trial with SAR236553/REGN727. The ODYSSEY Outcomes trial will enroll approximately 18 000 patients who recently suffered an ACS and are not at their LDL goal, testing the efficacy and safety of SAR236553/REGN727 (a 75-mg subcutaneous injection once every two weeks) added to maximal doses of statins in reducing cardiovascular events.

Stein reported having received consulting fees from Amgen, Adnexus Therapeutics, and Sanofi related to PCSK9 inhibitors, and his institution has received research funding related to PCSK9 clinical trials from Amgen, Sanofi, and Regeneron. Disclosures for the coauthors are listed in the paper. Raal has received consulting fees from Amgen and Sanofi related to PCSK9 inhibitors, and his institution has received research funding related to PCSK9 inhibitor clinical trials from Amgen and Sanofi. Disclosures for the coauthors are listed in the paper.