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Lipid Changes with Sirukumab Called 'Anti-Atherogenic'

— Looking for silver-lining in cloudy trial data

MedpageToday

SAN DIEGO -- Increases in blood lipids have been a nagging problem for rheumatology drugs targeting interleukin-6, including the market leader tocilizumab (Actemra). Now, developers of a new anti-IL-6 drug are making a bold claim: that the lipid changes it induces may actually inhibit atherosclerosis development.

In a at the American College of Rheumatology (ACR) annual meeting, they put it right in the title: "LDL and HDL Changes with Sirukumab Treatment Suggest an Anti-Atherogenic Profile." The on the ACR website is even more direct, declaring the changes "Are Anti-Atherogenic" with no weasel words.

Action Points

  • Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

The basis for their claim, according to post-hoc analysis of phase III trial results with the drug in rheumatoid arthritis (RA) patients, stems from the drug's apparent effect on cholesterol particle sizes, particularly "decrease in small LDL particles and increase in small HDL particles." These, the study's authors said, "suggest a shift towards a more anti-atherogenic" overall profile of blood lipid parameters.

They noted, too, that other markers of cardiovascular risk including ApoB/ApoA1 ratio remained unchanged and that HDL increases accounted for most of the increase in total cholesterol.

In a by the same authors, and using the same trial data, they reported a positive association between these lipid changes and suppressed RA inflammation.

Whether the altered lipid profile with sirukumab -- which remains investigational after the -- actually inhibits atherosclerosis is uncertain, as the current studies did not assess vascular plaque. Rather, they simply tied the blood test results to theories that LDL/HDL particle-size profiles are more important in plaque development than overall levels.

The issue of lipid effects has gained special importance for sirukumab because those clinical trials showed a dose-dependent increase in all-cause mortality among patients receiving the drug versus placebo, and cardiovascular events were the leading causes of death. Those data led an FDA advisory committee last August to recommend overwhelmingly against approval. In late September, the FDA sent the drug's main sponsor, Janssen, a Complete Response Letter requesting "additional clinical data" on the drug's safety before it could be approved, the firm said.

In the lipid particle-size analysis reported at ACR, Matthew Loza, PhD, associate director of the Janssen Pharmaceutical Companies of Johnson & Johnson in Spring House, Pennsylvania, and colleagues looked at changes over time in HDL cholesterol by small, medium, and large particles, and in LDL cholesterol by very small, small, medium and large sizes. They also looked at VLDL cholesterol by small, medium, and large sizes. Changes with sirukumab were compared with those seen in the trials' placebo groups.

The poster included a tremendous amount of detail, but the overall picture was that concentrations of large LDL particles increased with the drug relative to placebo whereas medium, small, and very small particle levels decreased. For HDL, increases in small particles accounted for virtually all the overall rise in HDL levels. Both of these results, Loza's group argued, should tend to inhibit rather than promote atherosclerosis formation.

But still uncertain, they conceded -- and not addressed in the current studies -- is how the lipid changes may correlate with the cardiovascular events seen in the trials.

The second poster by Loza, Bidisha Dasgupta, PhD, also an associate director at Janssen, and colleagues, linked lipid levels to inflammatory activity. The researchers found correlation coefficients (r) in the range of -0.30 to -0.43 for various lipid subspecies (e.g., total cholesterol, small VLDL particles) with inflammation markers C-reactive protein and serum amyloid A.

The researchers' interpretation: that the lipid increases somehow reflect the anti-inflammatory effect of sirukumab treatment. But they did not offer a mechanistic connection between the phenomena.

Disclosures

The studies were funded by Janssen and GlaxoSmithKline (GSK). Loza, Dasgupta, and several co-authors are employees of Janssen or GSK.

Primary Source

American College of Rheumatology

Loza M, et al "LDL and HDL changes with sirukumab treatment are anti-atherogenic: Results from two phase 3 trials in patients with rheumatoid arthritis" ACR 2017; Abstract 548.

Secondary Source

American College of Rheumatology

Dasgupta B, et al "Increases in lipid levels following sirukumab treatment are associated with suppression of inflammation in rheumatoid arthritis: Results from two phase 3 trials" ACR 2017; Abstract 549.