Rheumatology Drug Updates: Biosimilars Seek Regulatory Approval in the U.S., Europe; Methotrexate Underused

Image Credit: ajt/shutterstock.com

Biosimilars Receive Positive News

On Nov. 19, 2015, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorization for SB4, an etanercept biosimilar product that will be called Benepali.¹ If approved, Benepali can be used to treat rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis and plaque psoriasis. At present, no biosimilars of etanercept or subcutaneous anti-TNF biosimilars are available in the European market. If approved, Benepali will meet both of these criteria.

On Nov. 25, 2015, Amgen submitted an application for marketing approval to the U.S. Food and Drug Administration (FDA) for ABP 501, its adalimumab biosimilar.² The submission includes analytical, clinical and pharmacokinetic data. Phase 3 safety and comparative efficacy studies were performed for both moderate to severe plaque psoriasis and moderate to severe RA. The study results showed clinical equivalence to adalimumab, with safety and immunogenicity comparable with adalimumab. On Jan. 5, 2016, the FDA accepted this application for review.

Worldwide, Humira (adalimumab) sales were almost $12.5 billion in 2014. Humira patents expire in December 2016 in the U.S. and April 2018 in Europe.

Methotrexate Underused in U.S. for RA Patients

A recent analysis of U.S. methotrexate (MTX) use for RA was evaluated using Symphony Health Solutions’ anonymized patient-level claims data.³ Using ICD-9 codes, the researchers identified 35,640 RA patients who started oral MTX treatment in 2009. The study followed these patients to 2014. The data included switches from oral to subcutaneous MTX and/or biologics, timing of treatment changes and oral MTX or subcutaneous MTX dosing switches/addition, time or end of follow-up.

Forty-four percent of patients continued oral MTX alone through the end of the follow-up period (n=15,599). Forty-nine percent added or switched to a biologic agent (n=17,528). The median time before the addition of a biologic was 170 days, and 42% added a biologic within 90 days of oral MTX initiation. Only 7% switched from oral to subcutaneous MTX (within 534 days); 14% switched to oral MTX (within 90 days).

Overall, 71% of patients who switched from oral to subcutaneous MTX stayed on this treatment for about three years. Patients who added a biologic agent switched to a biologic after about 289 days. The mean time to change to a biologic agent was significantly longer (823 days, P<0.0001) for patients treated with subcutaneous MTX compared with those who received only oral MTX (170 days). This study showed that more than 40% of RA patients who initiated oral MTX treatment switched to or had a biologic added within 90 days after a median dose of 15 mg per week.

MTX was frequently underdosed, given for an inadequate length of time and rarely switched to the subcutaneous form before biologic therapy initiation. The study’s authors note that switching to subcutaneous MTX prevents the need for or significantly extends the time to starting a biologic. Optimizing MTX dosing could lead to better RA control and significant cost savings.

Sarilumab Effective for RA

Sarilumab is a human monoclonal antibody directed against the IL-6 receptor. In the TARGET RCT trial, sarilumab, in combination with non-biologic disease-modifying anti-rheumatic drugs (DMARDs), demonstrated efficacy in patients with active rheumatoid arthritis (RA).⁴ This was an intent-to-treat population (n=546). Patients were randomized in a 1:1:1 ratio to receive placebo, 150 mg sarilumab every two weeks or 200 mg sarilumab every two weeks with background DMARDs. Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), AM stiffness, Pain VAS, Work Productivity Survey, Rheumatoid Arthritis Impact of Disease and Short Form-36 (SF-36) were the patient-reported outcomes assessed.

Patients were evaluated at baseline and Weeks 2, 4, 12 and 24. Baseline evaluation showed all patients had a significant disease burden. For sarilumab-treated patients, statistically significant improvements (P<0.025) were seen compared with placebo-treated patients for FACIT-F, AM stiffness, pain, Work Productivity Survey and Rheumatoid Arthritis Impact of Disease. The Physical Component Summary Measure of the SF-36 also significantly improved, with no decline in the SF-36 Mental Component Summary Measure. Significant improvements were seen in the majority of the SF-36 domain scores for sarilumab-treated patients.

Serious adverse events and treatment-emergent adverse events occurred more commonly in sarilumab-treated patients than in placebo-treated patients. Laboratory findings were consistent with IL-6 blockade and from observations reported from the prior MOBILITY study. From the RA patient perspective, ability to participate in family and leisure activities, fatigue, morning stiffness, pain and being able to work were important outcomes to assess treatment effectiveness. The achievement of these outcomes was demonstrated in this study.

Pregabalin Fails in Clinical Trial

In a recent Phase 3 study, pregabalin (Lyrica) missed its primary efficacy endpoint for mean pain reduction from baseline compared with placebo in adults with chronic post-traumatic peripheral neuropathic pain.⁵ This 15-week study evaluated pregabalin treatment using daily pain diaries kept by patients to report their pain scores. No new safety signals were identified. The most common adverse events were dizziness, fatigue, nausea and somnolence.

At present, no biosimilars of etanercept or subcutaneous anti-TNF biosimilars are available in the European market.

Ibuprofen in a Patch

Working in conjunction with the polymer technology company, Medherant, researchers at the University of Warwick in England have developed a patch that delivers a consistent dosage of ibuprofen transdermally.⁶ The patch, a transparent adhesive, delivers a prolonged, transdermal, high dosage of ibuprofen over 12 hours. This product does a better job of controlling the dosage than other topical ibuprofen products—none of which are available in the U.S., but are available abroad. The patch is cosmetically appealing and transparent, and has a strong adhesive that remains in place throughout its use. It’s also comfortable and easy to remove.

Michele B. Kaufman, PharmD, CGP, RPh, is a freelance medical writer based in New York City and a pharmacist at New York Presbyterian Lower Manhattan Hospital.

References

1. Pro Pharma Communications International. EMA recommends approval of etanercept biosimilar. GaBI Online. 2015 Nov 27.
2. Pro Pharma Communications International. Amgen submits biosimilar adalimumab application to FDA. GaBI Online. 2015 Nov 27.
3. O’Dell JR, Rohr M, Cohen SB, Thorne JC, Mikuls TR. Underuse of methotrexate (MTX) in the treatment of rheumatoid arthritis (RA) in the United States (US): Results of a comprehensive pharmaceutical claims analysis. Arthritis Rheumatol. 2015;67(suppl 10).
4. Strand V, Kosinski M, Graham N, et al. Impact of sarilumab on fatigue, pain, morning stiffness, productivity and health related quality of life (HRQoL) in patients with active rheumatoid arthritis who were inadequate responders or intolerant of anti-TNF-α therapy: Results from a phase 3 study (RCT). Arthritis Rheumatol. 2015;67(suppl 10).
5. Pfizer Inc. News release: Pfizer’s Lyrica fails Phase III study in post-traumatic neuropathic pain. First Word Pharma. 2015 Nov 25.
6. University of Warwick. News release: Researchers create world’s first ibuprofen patch—delivering pain relief directly through skin. 2015 Dec 8.