SPIRE Trials: Immune Response Thwarts PCSK9 Inhibitor Bococizumab

March 17, 2017

Results of the clinical-trial program with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor bococizumab (Pfizer), including final data from the major outcome trials SPIRE 1 and 2, show that antidrug antibodies developed in a large proportion of patients and significantly attenuated the LDL-lowering effect[1,2].

On the other hand, a new analysis of data on another PCSK9 agent, alirocumab (Praluent, Sanofi/Regeneron) suggest that immunogenicity is not such an issue for that drug and possibly also for evolocumab (Repatha, Amgen).

Data on antibody formation and LDL-cholesterol–lowering effects from six trials of bococizumab in a total of 4300 patients, as well as final outcome results from the SPIRE 1 and 2 trials, were presented today at the American College of Cardiology (ACC) 2017 Scientific Sessions and simultaneously published online in the New England Journal of Medicine.

The SPIRE 1 and 2 studies were stopped early after Pfizer made the decision to stop development of bococizumab because of the immunogenicity issues with the drug.

New data on alirocumab[3], also published today in the New England Journal of Medicine, show that antidrug antibodies develop in just 5% of patients and neutralizing antibodies in 1.3%, with evolocumab said to show even lower rates of immunogenicity.

The reason for the difference between bococizumab and the other two agents is probably due to the fact that bococizumab is a partially murine monoclonal antibody, whereas alirocumab and evolocumab are both fully humanized, the reports note.

Bococizumab in SPIRE 2 reduced cardiovascular events in patients with higher LDL levels at baseline (>100 mg/dL) who were followed for a longer duration (median 12 months), with a hazard ratio [HR] of 0.79 (P=0.02). But the drug had no effect on cardiovascular events in SPIRE-1 (HR 0.99, P=0.94), which included patients with lower LDL levels at baseline (>70 mg/dL) who were followed for a shorter duration (median 7 months).

In the whole bococizumab program, antidrug antibodies developed in almost half (48%) the patients who received bococizumab and neutralizing antibodies developed in 29%. The authors say this substantially attenuated LDL lowering over time in some affected patients. They also point out that there was wide variability in the LDL lowering achieved with bococizumab even among patients who did not develop antibodies.

Dr Paul Ridker

Lead investigator of the SPIRE 1 and 2 studies and lead author of both papers on bococizumab, Dr Paul Ridker (Harvard Medical School, Boston, MA) commented to heartwire from Medscape: "Despite antidrug antibody development, bococizumab nonetheless significantly reduced vascular events by 21% among those with higher risk and higher LDL levels. Further, those with the greatest LDL reductions got the greatest benefits. Thus, our data strongly support the class overall and the general concept that lower LDL levels result in lower event rates."

He added: "Importantly, we also found in our data that there was wide individual variation in LDL response among those without antidrug antibodies. Whether this is also true of evolocumab and alirocumab needs to be determined, as this individual variation has implications for care."

Alirocumab Antibody Data

The latest alirocumab data are reported in a letter to the same journal by a team led by Dr Eli Roth (Sterling Research Group, Cincinnati, OH).

Roth commented to heartwire : "PCSK9 monoclonal antibodies are the most important advance in lipids in 30 years. Because the bococizumab data are being published we wanted to get our data on alirocumab out there too so people can see immunogenicity is not necessarily such a big problem with the other drugs."

He and his colleagues report data from 10 trials with alirocumab in a total of 4747 patients (3039 who received active drug), in which antidrug antibodies were observed in 5.1% of alirocumab patients vs 1.0% of control patients. Patients were treated for various durations up to 78 weeks.

Persistent antidrug antibodies (two or more consecutive samples over 12 weeks) were found in 1.4% of alirocumab patients and 0.2% of controls. And neutralizing antibodies were detected in 1.3% of alirocumab patients.

Dr Roth explained to heartwire that antidrug antibodies are those generated against any part of the foreign protein, which don't necessarily interfere with the binding to its target. But neutralizing antibodies bind to the drug at the point at which it interacts with its target and so have a higher likelihood of prevent its action.

However, in the latest alirocumab data even in the patients with neutralizing antibodies, LDL reductions were maintained over time. But injection-site reactions were more frequent in those who developed antidrug antibodies.

Roth suggested that the antibody titers seen with alirocumab were much lower than those observed with bococizumab and probably not high enough to have any meaningful effect on LDL reduction.

"The LDL lowering was similar in patients with and without antidrug antibodies, transient antibodies, persistent antibodies, or neutralizing antibodies. They were all the same," he said.

"Our data suggest that the antibodies seen with alirocumab had no effect on its LDL lowering. But the numbers of patients are still quite low, and we need to wait for the larger outcomes trials to know more," he concluded.

Commenting on the studies for heartwire , Dr Jeffrey S Berger (New York University School of Medicine, NY) said: "In light of the data demonstrating antidrug antibody formation with bococizumab and its mitigating effect on the reduction of LDL-cholesterol levels, the alirocumab data are timely and important and are certainly reassuring."

He added, however, that "these data are derived from small populations with antidrug antibodies, and thus caution needs to be applied. Further monitoring of immunogenicity (antibody formation and its effect on cholesterol levels and cardiovascular outcomes) should be done in larger populations receiving drug."

Dr Steven Nissen MD, (Cleveland Clinic, OH), who is a coauthor on the bococizumab papers, told heartwire that he didn't think the antibody response reported in the new data on alirocumab would be clinically significant. "It doesn't look like a showstopper, but few patients in this report were treated for more than a year, so we still need to be cautious."

Nissen also pointed out that evolocumab appears to have even less immunogenicity than alirocumab. "In the FOURIER trial, evolocumab doesn't seem to have an issue with immunogenicity at all. The LDL reduction over the 26 months was as flat as a pancake—no attenuation at all, and there were practically no neutralizing antibodies."

But Roth cautioned that comparisons should not be made between different trials using different assays. He elaborated: "We used a particularly sensitive assay to look for antibodies as advised by the FDA. The fact that we are seeing a 1% rate of antibodies in the control group (which are false positives) shows how sensitive the assay was. Each drug will use a different assay, and they cannot be compared."

Nissen said the bococizumab data did not necessarily preclude the development of other partially murine PCSK9 agents. "These drugs are effective, but they are expensive. If a partial murine-based agent were developed that had only a little immunogenicity then it could be viable if priced competitively."

Dr Roth explained that bococizumab may have had particular problems, as the mouse protein is located at the most important point of the drug—the variable region that binds to PCSK9. "So this makes it more likely that the antibodies would interfere with drug's therapeutic effect."

Ridker reports grant support and personal fees from Pfizer during the conduct of this study; grant support from Kowa and Amgen; grant support and personal fees from Novartis; and personal fees from Sanofi outside the submitted work. In addition he reports royalties from patents related to the issue of inflammatory biomarkers in cardiovascular disease and diabetes held by Brigham and Women's Hospital and licensed to Siemens and AstraZeneca. Disclosures for the coauthors are listed on the journal website. Nissen reports grant support from Pfizer during the course of this study and from AstraZeneca, Amgen, Esperion, and the Medicines Company outside the submitted work. Roth reports grants, personal fees and nonfinancial support from Regeneron and Sanofi. Disclosures for the coauthors are listed on the journal website.

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