Why Sanofi’s arthritis biologicals lead could be short-lived

Sanofi is certain to feature in the next wave of biologicals to treat rheumatoid arthritis, but judging by today’s data with sarilumab it will have to contend with some fierce headwinds.

Looming patent expiry of AbbVie’s Humira will be one obvious hindrance, but worse is Johnson & Johnson’s competing agent sirukumab, which has set an efficacy threshold that Sanofi is struggling even to match. It could come down to the science of targeting IL-6, and right now Sanofi’s key advantage might be a few months’ lead in regulatory filings.

Both sarilumab and sirukumab are MAbs, and are the two sole phase III contenders challenging Roche’s Actemra – currently the only anti-IL-6 approved for RA. However, the Sanofi agent targets the IL-6 receptor, as does Actemra, whereas J&J’s targets the IL-6 cytokine itself.

J&J argues that RA patients have low serum and synovial levels of IL-6 relative to those of the receptor, suggesting a lower effective dose, and cites preclinical data showing sirukumab to be a vastly more potent inhibitor of IL-6 signalling than Actemra.

And clinical trials support J&J, too. Sanofi today revealed the results of a second important pivotal trial of sarilumab, showing this MAb to have efficacy barely in line with Actemra.

The key efficacy measure in RA is percentage of patients who show a 20% improvement in signs and symptoms after 24 weeks as defined by the American College of Rheumatology – the so-called ACR20 score. Depending on the dose used, sarilumab yielded ACR20 responses in 56-61% of patients, versus 34% for placebo.

This study, Target, tested sarilumab in patients unresponsive to or intolerant of TNF-alpha inhibitors like Humira or Amgen’s Enbrel. The earlier Mobility trial, in inadequate methotrexate responders, showed 24-week ACR20 responses in 58-66% of patients.

On Target, but underwhelming

The trouble for Sanofi is that these data, while statistically and clinically significant, barely match Actemra, whose label cites ACR20 responses across five trials of between 48% and 70%.

Even more alarming is the threat of J&J’s sirukumab, which in phase IIb yielded an ACR20 in 83% of patients. True, cross-study comparisons need to be treated with caution – for one thing baseline characteristics differ – but still, this shows what Sanofi and its partner Regeneron are up against.

In its defence the French group says it never intended to beat Actemra, and rather has mooted the importance of participating in the overall growth of the biologicals space. Just 5% market share would render sarilumab a blockbuster, Bryan Garnier analysts reckon.

Earlier in development there is Ablynx/AbbVie’s ALX-0061 – though this is a receptor-targeting agent it has the possible benefit of being smaller than a normal antibody (Ablynx another beneficiary of AbbVie’s pay-to-fund approach, September 23, 2013).

The competitor pipeline has had a couple of setbacks, Pfizer dropping PF-04236921 for RA, and Bristol-Myers Squibb ditching a deal with Alder Biopharmaceuticals covering clazakizumab. Humira comes off patent next year and the entry of biosimilars should bring some pricing pressure, though anti-IL-6 agents will initially be targeting the post-Humira setting.

For those who think first-mover advantage matters it will be important that Sanofi says it will file sarilumab in the US in the fourth quarter. For its part, J&J has slated a 2016 submission, but before that it will report the first phase III data with sirukumab.

If phase II is anything to go by, J&J's results could blow both Actemra and sarilumab out of the water.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter