Bristol Finds Biomarkers For Improved Response To Orencia In RA

Rheumatoid arthritis patients treated with Bristol’s Orencia who tested positive for two biomarkers of poor prognosis had a significantly greater response on outcomes than those who did not in a real-world data analysis presented at EULAR. The experience with TNF inhibitors was different.

Bristol-Myers Squibb Co. has evidence supporting two potential biomarkers to predict response in rheumatoid arthritis, a discovery that could have implications for Orencia (abatacept).

The firm presented the first US observational study exploring how patients with rheumatoid arthritis respond to treatment based on their baseline status for two biomarkers of poor prognosis at the annual European Congress of Rheumatology (EULAR) June 9.

The two biomarkers that were tested were anti-cyclic citrullinated peptide (anti-CCP, also known as ACPA) and rheumatoid factor (RF), biomarkers of poor prognosis, which could be associated with more severe disease progression and joint damage. The study found that patients who tested positive for the two biomarkers and were treated with Orencia had a better outcome than patients who tested negative for the biomarkers.

It is still unclear what implications the data might have in the commercial market, Bristol Head of Specialty Development Douglas Manion said in an interview.

“What the real world prescribers do in terms of leveraging these data to better target initial therapy or subsequent to initial therapy that is what we will see,” Manion said. “We have not yet made a decision as to what we will be doing in terms of registrational pathway to seek an indication around this specific biomarker-based population.”

Tests for anti-CCP and RF are already readily available on the market, though these are not specifically companion diagnostics for Orencia. Given the high level of treatment experimentation and cycling in rheumatoid arthritis, Manion said the data could be useful for more targeted cycling.

The study also evaluated the biomarkers and outcomes in patients treated with tumor necrosis factor inhibitors like AbbVie Inc.'s Humira (adalimumab), Amgen Inc.’s Enbrel (etanercept) and Johnson & Johnson’s Remicade (infliximab) and saw a different result. The study did not show a significant difference in response between anti-CCP/RF status in those treated with a TNF blocker.

Bristol believes that’s because of Orencia’s mechanism of action, which targets the immune system in a specific way. Orencia is a costimulation modulator that inhibits T cell activation by binding to CD80 and CD86, thereby blocking interaction with CD28.

“Our belief is that it has to do with the targeted pathway Orencia is hitting,” Manion said. “TNFs are a bit more of a blunt instrument in terms of which pathways in humans they are addressing.” Both RF and anti-CCP are antibodies generated by the immune system, he explained.

“The hypothesis would be that the biomarkers in fact are more reflective of that pathway,” he added.

The biomarker data could help to further differentiate Orencia at a time when some of the anti-TNFs are facing the first competition from biosimilars in the US. The first biosimilar version of Remicade, Celltrion Inc.’s Inflectra, was approved by FDA in April, although the drug hasn’t launched yet due to ongoing patent litigation (Also see "Inflectra Label Not Exactly Silent On Remicade's Orphan-Protected Claim" - Pink Sheet, 5 Apr, 2016.). Orencia continues to be an important growth driver for Bristol; the drug generated sales of $1.89bn in 2015, representing 14% growth.

Study Stratified Patients By Four Biomarker Status Types

The biomarker study, led by principal investigator Leslie Harold, associate professor of medicine and orthopedics and physical rehabilitation at the University of Massachusetts Medical School, relied on data from the Corrona LLC registry, the largest RA cohort prospectively followed in North America. Harrold is also senior medical director of pharmacoepidemiology and outcomes research at Corrona. The database includes data from 662 participating rheumatologists and currently includes more than 40,000 RA patients.

The analysis included RA patients tested for both anti-CCP and RF who received Orencia (566 patients) or a tumor necrosis factor inhibitor (1,715) between June 2002 and January 2015.

Response rates for Orencia and TNF-inhibitors were evaluated based on biomarker status: double positive (anti-CCP+/RF+), single positive (anti-CCP+/RF- or anti-CCP-/RF+) and double negative (anti-CCP-/RF-).

The primary outcome measured in the analysis was mean change from baseline in Clinical Disease Activity Index (CDAI) at six months, and secondary outcomes were achievement of low disease activity (LDA) at six months and achievement of remission at six months.

The results showed that in patients who initiated Orencia and tested positive for both biomarkers, response rate was significantly greater compared to patients who tested negative (CDAI -8.9 vs -4.5; LDA 43% vs 26%; remission 15% vs 5%). Additionally, single positive status was associated with a greater likelihood of remission compared to double-negative status for those treated with Orencia (12% vs 5%).

A similar pattern was not seen in patients treated with anti-TNFs. In patients with double-positive status versus double-negative status, for example, CDAI was -7.5% vs -6.8%, LDA was 39% vs. 35% and remission was 16% vs. 14%.

Informing Future Research

Orencia was approved more than 10 years ago in 2005, but Bristol believes its growing expertise in immunology, including the expansion into immuno-oncology, is giving the company a competitive advantage when it comes to developing treatments for autoimmune diseases. The company recently reorganized its research group so that the autoimmune researchers and immuno-oncology researchers are more aligned, Manion said.

“We think that this is going to be a virtuous realignment to allow more cross talk,” he said. Orencia, for example, works in a mirror image to Bristol’s immuno-oncology drug Yervoy (ipilimumab). “Yervoy turns on what Orencia turns off,” Manion said.

The company believes the biomarker research will help inform future research in autoimmune disease too – even more specifically as it relates to the technology it acquired with the $225m buyout of Padlock Therapeutics Inc. in March (Also see "Bristol Makes Major Investment In Padlock's Autoimmune Platform" - Pink Sheet, 23 Mar, 2016.). Padlock’s protein/peptidyl arginine deiminase (PAD) inhibitor technology platform produces enzymes that produce autoantigens that could prevent progression of autoimmune diseases earlier. Bristol believes in patients identified as being at high risk with pre- and early-RA, PAD inhibition could be paradigm changing.

“If you have a predictive biomarker, one that identifies people who are at greater risk of getting imminent joint erosion but have preserved joints, then that is the optimal place to be,” Manion said.

The Padlock programs are still in preclinical development and Bristol said it was too early to say when a lead program would be ready for the clinic.