High dose fasinumab improves chronic lower back pain, function
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Patients treated with 9 mg of fasinumab every 4 or 8 weeks, instead of 6 mg, experienced improvements in chronic lower back pain and function, according to data published in the Annals of the Rheumatic Diseases.
“Chronic LBP (CLBP) is defined as pain persisting for more than 3 months,” Paula Dakin, MBChB, of Regeneron Pharmaceuticals, in Tarrytown, New York, and colleagues wrote. “Guidelines recommend initial treatment with non-pharmacological interventions, including exercise and multidisciplinary rehabilitation. If these interventions are inadequate or if CLBP persists, guidelines recommend non-steroidal anti-inflammatory drugs (NSAIDs) as first-line pharmacological treatments and duloxetine and tramadol as second-line treatments. Stronger opioids are an option only if patients fail the afore-mentioned treatments and if the potential benefits outweigh the risks.”
“However, long-term use of both NSAIDs and opioids is limited by tolerability issues and adverse effects, such as gastrointestinal bleeding, cardiovascular events, and the potential for abuse and dependence,” they added. “Fasinumab is a fully human monoclonal antibody shown to reduce pain in OA.”
To analyze the efficacy and safety of fasinumab (Regeneron Pharmaceuticals) in moderate-to-severe chronic lower back pain, Dakin and colleagues conducted a phase 2/3, double-blind, placebo-controlled study of patients aged 35 years and older with an inadequate response, or intolerance to, NSAIDs and opioids. Participants were randomized to receive either 6 mg or 9 mg of subcutaneous fasinumab every 4 weeks, or 9 mg of intravenous fasinumab every 8 weeks, or a placebo.
The primary endpoint was the change in average daily low back pain intensity (LBPI) numeric rating score from baseline to week 16. Important secondary efficacy variables included Roland-Morris Disability Questionnaire (RMDQ) and Patient Global Assessment (PGA). The researchers reported results based on a modified intent-to-treat analysis of 563 participants out of the 800 they had initially planned to include. Enrolment was ended early due to emerging signs of joint risk in other osteoarthritis studies at similar doses.
According to the researchers, there were significant placebo-adjusted LBPI reductions among participants in both 9 mg fasinumab groups at week 16, with a least squares mean of –0.7 (P < .05), but not the 6mg group, at –0.3 (P = .39). In addition, RMDQ and PGA improvements to week 16 were greatest for the 9mg fasinumab group. Patients with peripheral OA demonstrated numerically greater efficacy through 16 weeks, compared with those without.
Treatment-emergent adverse events occurred in 65.6% participants in the combined fasinumab groups, and in 67.1% of those who received a placebo. Meanwhile, adverse events impacting the joint — mostly rapid progressive OA type 1 — were more frequent in the combined fasinumab groups, with 19 events across 16 patients compared with one event in one patient for the placebo group. All except one of these events occurred in patients with peripheral OA.
“Despite dosing being prematurely terminated, all fasinumab doses provided improvements versus placebo in measures of pain (average daily LBPI NRS score), function (RMDQ) and overall patient assessment (PGA) over the first 8 weeks of the study,” Dakin and colleagues wrote. “Significant pain improvement was maintained over 16 weeks for both fasinumab 9mg groups, but not for 6mg. Further studies will be needed to determine whether the robust efficacy shown at week 8 is sustained for longer durations at lower doses.”
“Although the treatment benefit in this study was numerically greater in the pOA subgroup, the rates of AA in these patients were substantially higher,” they added. “This study, therefore, validated concerns about the use of fasinumab in CLBP subjects with concomitant OA, whose benefit–risk at the highest doses was unacceptable. For patients without pOA, low rates of AA were observed at these high doses, though treatment effect was more modest. In these patients, since their back pain may be dominated by mechanisms other than OA, fasinumab may be less likely to provide benefit.”
Perspective
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Mark D. Harris, MD, FACR
In this phase 2/3 trial, parenteral treatment with fasinumab, at higher doses of 9 mg SC every 4 weeks or 9 mg IV every 8 weeks, was shown to improve pain and function in patients with chronic low back pain (CLBP) at 16 weeks. Patients with moderate to severe CLBP with inadequate relief or intolerance to acetaminophen, oral NSAIDs and at least 1 opioid were randomized after discontinuation of all pain medications for 7 days and enrolled to high-dose fasinumab 9 mg SC every 4 weeks, 9 mg IV every 8 weeks, low-dose 6 mg SC every 4 weeks vs. placebo.
The primary endpoint of daily low back pain intensity (LBPI) at 16 weeks was met by both 9 mg dose groups (P<0.05) but not the 6 mg group. Treatment benefit was also higher in patients with documented peripheral osteoarthritis (pOA).
A significant limitation in this study was an FDA hold and early termination of dosing following a case of rapidly progressive osteoarthritis (RPOA). Therefore, results and adverse events (AEs) are based on a smaller cohort with 35%-56% receiving planned drug doses.
Concern has been raised with previous NGF studies of a drug-specific AE profile including neurosensory symptoms, peripheral neuropathies and — the most concerning — rapidly progressive and destructive osteoarthritis leading to joint arthroplasty. The current study did include AEs of special interest such as sympathetic nervous system dysfunction and adjudicated arthropathies (AA) to include RPOA.
Patients treated with fasinumab had higher rates of AA with 20 joints involved in the treatment group and one joint in the placebo arm. Of the 20 joints with AAs, 19 were in patients with concomitant pOA.
In this study, fasinumab has efficacy for CLBP at high dose compared to placebo. Clinicians would welcome a long-term study with an active comparator group with common therapies for CLBP such as analgesics and physical therapy. This study also validates a safety concern for AA with fasinumab in patients with pre-existing osteoarthritis.
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