Fulranumab for treatment of diabetic peripheral neuropathic pain

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SCIENCE
Fulranumab for treatment of diabetic peripheral neuropathic pain
Key Take-Away: 

Fulranumab treatment resulted in dose-dependent efficacy and generally very well tolerated.

Approximately 16% of patients with diabetes have diabetic peripheral neuropathic pain (DPNP), but it is estimated that 2 of 5 such cases do not receive any treatment for the pain. DPNP affects quality of life and represents an ongoing management challenge for patients and physicians. Many pharmacotherapies available for DPNP, includes antidepressants, anticonvulsants and opioids but their effect size is limited. 

ABSTRACT: 
Background: 

Approximately 16% of patients with diabetes have diabetic peripheral neuropathic pain (DPNP), but it is estimated that 2 of 5 such cases do not receive any treatment for the pain. DPNP affects quality of life and represents an ongoing management challenge for patients and physicians. Many pharmacotherapies available for DPNP, includes antidepressants, anticonvulsants and opioids but their effect size is limited.

Nerve growth factor (NGF) contributes to persistent pain in animal models and its inhibition has potential role to normalize neuronal hyperactivity and sustained clinical pain relief. Fulranumab is a fully human recombinant immunoglobulin G2 monoclonal antibody that has a specific capacity to neutralize the biological actions of human NGF. It has shown efficacy in treating moderate to severe knee and hip osteoarthritis pain.

Rationale behind research

  1. DPNP affects quality of life and it is an ongoing management challenge for patients and physicians

  2. Many pharmacotherapies are available for DPNP, including antidepressants, anticonvulsants and opioids but the effect size of these treatments is limited

Objective

To evaluate the efficacy and safety of Fulranumab compared with placebo, in patients with moderate to severe DPNP that was not adequately controlled by standard pain therapies.

Methods: 

 

Study outcomes

  • Primary outcome: Mean of the daily evening assessment of average pain intensity over the last 24 hours for the last 7 days of DB efficacy phase minus the mean from the 7 day baseline period.

  • Secondary outcomes:
  • 7-day mean of daily evening assessment of pain at its worst in the last 24 hours to the end of week 12

  • Monthly Brief Pain Inventory–Short Form 22 subscale scores

  • Monthly Neuropathic Pain Symptom Inventory (NPSI) 23 total and subscale scores

  • Monthly Patient Global Impression of Change score and exploratory responder analysis included ≥30% or ≥50% improvement in NRS pain intensity from baseline to the end of week 12

  • Safety assessments included treatment-emergent adverse events (TEAEs)

  • Time-points
    • Efficacy: Baseline, 4, 8, and 12 weeks
Results: 

  • Primary outcome:

  • The mean reduction of average daily pain at week 12 compared with baseline, showed a positive dose-response relationship (p = 0.014, 1-sided); the pair-wise comparison between the 10-mg group and placebo was significant (unadjusted p = 0.040, 2-sided).

  • Secondary outcome:

  • An exploratory responder analysis revealed that a greater proportion of patients in the 10-mg group reported ≥30% reduction in the average DPNP intensity compared with placebo at week 12 (p =5 0.006).

  • Although not significant, the improvement from baseline to the end of week 12 in worst pain intensity, NPSI total score and several subscales and most Brief Pain Inventory–Short Form subscales increased with increasing doses consistent with the primary efficacy trend.

  • During combined efficacy and safety extension phases, top 3 treatment-emergent adverse events in combined fulranumab group: arthralgia (11%), edema peripheral (11%), and diarrhea (9%). No cases of joint replacement or death reported.

Conclusion: 

Despite early study termination, fulranumab treatment resulted in dose-dependent efficacy and was generally well tolerated, with the 10-mg dose demonstrating significant improvement over placebo. Long-term trials involving more patients are needed to fully characterize the efficacy, safety, and tolerability of this potentially new class of analgesic drug for treatment of DPNP.

The magnitude of the pain reduction in the 10-mg group could be considered as clinically meaningful pain relief. Consistent with the primary efficacy dose-response relationship, although not statistically significant, most secondary efficacy outcomes showed similar trends. These findings (need to be verified in an appropriately sized future study) may help to inform future research on whether patients with certain baseline phenotypes are likely to be more treatment responsive. However, because of the limited sample size due to the clinical hold, we cannot conclude there is no risk. All future trials will incorporate prospective joint surveillance.

Neurology. 2014 Aug 12; 83(7):628-37
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