2017 ACR Annual Meeting: Biosimilars and Recent Regulatory Setbacks

Over 16,000 people from 110 countries including healthcare providers, industry representatives, and DRG’s rheumatoid arthritis expert descended on the Convention Center in sunny San Diego for the American College of Rheumatology (ACR) annual meeting from November 3-8, 2017.

Biosimilars: A major topic of discussion during the meeting was the recent arrival of biosimilars. In addition to posters and seminars on the topic, the ACR planning committee organized a Great Debate: Biosimilars…To Switch or Not to Switch? That is the question. Biosimilar expert Jonathan Kay, MD presented the ‘Pro’ side while Roy Fleischmann, MD, MACR sought to convince the audience that biosimilars still have many unanswered questions that should lead physicians to be conservative about prescribing them.

Unlike small-molecule drugs, the production of biologics results in normal batch-to-batch variability making different batches of bio-originators biosimilar to each other. However, this variability can drift out of a proven acceptable range due to known or unknown changes in the manufacturing process and lead to effects in clinical safety, efficacy, or immunogenicity. Physicians note that variability in immunogenicity between biosimilars and bio-originators combined with patients being forced to switch agents multiple times could result in the loss of effectiveness. How biosimilar variability will be monitored post-approval is currently unclear and is complicated by the availability of multiple biosimilars for each bio-originator, all from different companies (for example: Janssen’s bio-originator Remicade (infliximab) with biosimilars: Biogen’s Flixabi, Celltrion’s Remsima/Pfizer’s Inflectra).

The biosimilar approval process is different from bio-originators, with the focus being largely on analytical studies showing sufficient similarity between a biosimilar and its bio-originator. Once approved for one indication, biosimilars may be approved for indications where it was not studied in a clinical trial but in which the bio-originator is approved. The requirement of fewer clinical trials and indication extrapolation expedites the availability of biosimilars and decreases the costs of these agents. However, some physicians have reservations about extrapolating the clinical similarity of biosimilars to multiple indications especially in cases where, for example, a biosimilar has been tested in an indication like rheumatoid arthritis but is extrapolated for use in Crohn’s disease.

With the approval and launch of biosimilar TNF-α inhibitors in the United States, Europe, and Japan, an increasing number of studies have focused on patients who switch from a bio-originator to a biosimilar. The NOR-SWITCH study, widely cited as evidence for the safety and efficacy of biosimilars, reported non-inferiority for Norwegian patients switched from Remicade to its biosimilar, Remsima/Inflectra.1 More problematic were studies looking at required patient switching to an infliximab biosimilar recorded in the Danish national registry, DANBIO, and in The Netherlands (BIO-SWITCH).2,3 Both studies attributed higher rates of biosimilar discontinuation to a ‘nocebo effect’ where patient reported outcomes worsen relative to more objective assessments of disease. While some physicians believe that education of patients will help decrease negative perceptions of switching to a biosimilar and decrease this ‘nocebo effect,’ others argue that the results are clinically important and point to the need for further studies powered for statistical significance on the effects of switching in multiple indications. In addition, while work has investigated switching from a bio-originator to a biosimilar, no work has yet tackled how multiple switches between different biosimilars is tolerated. No biosimilar has yet been approved as an interchangeable product in the United States. However, such an approval would allow substitution at the pharmacy level without consulting the prescriber, eliciting concerns among physicians wanting to track any effects of switching in their patients.

While physicians debate their comfort with biosimilar safety and efficacy, other market factors including price and regional availability are likely to play critical roles in biosimilar uptake. Studies like NOR-SWITCH are available because the cost savings gained by using biosimilars are large enough to encourage policies that require switching in some European countries. However, in the United States, savings from biosimilars are reaped by pharmacy benefit managers and vertically integrated healthcare systems rather than by physicians or patients, making biosimilar use less enticing. In addition, companies have begun to find novel ways of keeping market share for their bio-originators. Most recently, Pfizer took Janssen to court over Janssen’s exclusive contracts with insurance companies and hospitals for the use of Remicade, in turn blocking prescription of Pfizer’s infliximab biosimilar, Inflectra. Biosimilars are also often available earlier in Europe, like AbbVie and Amgen’s recent settlement that will make biosimilar adalimumab available in Europe in 2018 and in the United States in 2023. Lack of a financial incentive combined with limited availability of biosimilars and different healthcare system means that brand erosion for biologics in the United States will be slower than in Europe. DRG is actively monitoring these complex market dynamics with our Biosimilar Advisory Service.

Recent Regulatory Setbacks and Outlook for Jak Inhibitors: While emerging RA therapies, especially Jak inhibitors, upadacitinib and filgotinib, have shown promising efficacy in clinical trials, questions about safety signals seem particularly urgent. The recent surprising FDA CRLs given to Lilly’s Jak inhibitor Olumiant (baricitinib) and to Janssen’s IL-6 inhibitor sirukumab citing concerns about safety have clinical trial leaders taking a closer look at their data for unusual safety signals that may risk approval. Janssen announced that it will not pursue global approval of sirukumab. However, Lilly appears to have high hopes for Olumiant’s approval after its planned NDA resubmission in January 2018 as demonstrated by the company sponsored programming at ACR to educate physicians on Jak inhibitor. Uptake of the Jak inhibitor Olumiant in EU5 countries where it has launched has been swift, suggesting that regulators’ concern about an imbalance of thromboembolic events is less worrying to European physicians. KOLs interviewed by DRG express interest in seeing how Jak inhibitor perform in real world clinical settings. However, it seems that in an increasingly crowded RA market, attention to safety signals is becoming more important for regulatory agencies especially when evaluating second, third, and fourth in-class agents with little differentiation in efficacy to their first-in-class counterparts. Our insights into expectations of recently launched and emerging agents in RA are available in our Rheumatoid Arthritis Disease Landscape & Forecast.

Citations:

1.     Jørgensen KK et al. (2017) Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. Jun 10;389(10086):2304-2316. doi: 10.1016/S0140-6736(17)30068-5.

2.     Glintborg B et al. (2017) A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry. Ann Rheum Dis. Aug;76(8):1426-1431. doi: 10.1136/annrheumdis-2016-210742.

3.     Tweehuysen L et al. (2017) Subjective Complaints as the Main Reason for Biosimilar Discontinuation After Open-Label Transition From Reference Infliximab to Biosimilar Infliximab. Arthritis Rheumatol. Oct 18. doi: 10.1002/art.40324.