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24th Annual Pain Medicine Meeting 2025
November 13-15, 2025| JW Marriott Austin, Austin, Texas
2182151
A precision medicine approach to identifying patients with Complex Regional Pain Syndrome Type 1 who may benefit from neridronate
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Scientific Abstracts > Chronic Pain
TITLE: A Precision Medicine Approach to Identifying Patients with Complex Regional Pain Syndrome Type 1 who may Benefit from Neridronate
AUTHORS: Giovanni Adami, MD, PhD; Jeffrey Botbyl, MS; Amarita S Randhawa, PharmD; Gail Cawkwell, MD, PhD; Stephen Bruehl, PhD
BACKGROUND:
• Complex Regional Pain Syndrome Type 1 (CRPS-1) is a rare, chronic, and often disabling condition with no FDA-approved medicines.[1]
• Per the FDA, precision medicine targets the right treatments to the right patients at the right time.[2]
• With this goal in mind, we explored clinical phenotype factors that might identify patients who would respond better to treatment with neridronate, an alkyl-aminobisphosphonate.
• Given that neridronate is believed to have inhibitory effects on activated mononuclear cells that produce inflammatory mediators, we hypothesized that inflammation-relevant clinical features of the warm CRPS-1 subtype (i.e., warmth, redness, edema), all generally present early in disease, might be associated with greater clinical efficacy of neridronate.[3,4]
OBJECTIVE:
• Evaluate neridronate’s efficacy in a subgroup of participants who presented with key features of the warm CRPS-1 subgroup.
METHODS:
• Three phase 3, randomized, double-blind, placebo-controlled trials (KF7013-02 [NCT03530345], NERIAS[5], NAIMES[6]; Table 1) achieved their primary efficacy endpoint.
• These trials evaluated the efficacy and safety of high-dose intravenous (IV) (NERIAS; KF7013-02) or intramuscular (NAIMES) neridronate 400 mg vs placebo for CRPS.
• Following IRB/Ethics Committee approval, participants provided informed consent prior to any trial procedures.
• NERIAS and NAIMES were completed trials and the basis of regulatory filings in Italy; KF7013-02 combined with a second phase 3 trial terminated early due to futility. Despite this, KF7013-02 still achieved its primary endpoint while the second phase 3 trial did not.
• In all three trials, participants diagnosed with CRPS-1 who exhibited features of the warm CRPS subtype in the affected limb at screening or baseline prior to initial dosing (hereafter, collectively referred to as “baseline”) were identified as a subgroup. For comparison, a corresponding subgroup of participants without these features was also identified in each trial, and the two groups were evaluated in this post-hoc analysis.
• Features of the warm subtype included redness, warmth, and/or edema.
• In the KF7013-02 trial, redness and/or warmth in the affected limb were scored as Yes or No by the investigator, and edema was scored as either present (+) or absent (-) by the investigator.
• In NERIAS and NAIMES trials, edema in the affected limb was scored on a 4-point NRS, defined as 0=none, 1=mild, 2=moderate, 3=severe.
• Change from baseline in average pain intensity was analyzed using a linear mixed effects for repeated measures model (MMRM) with fixed effect terms for treatment, visit and the treatment by visit interaction. Baseline was included in the model as a covariate with subject as a random effect.
• Least squares mean changes from baseline (LS mean change) in average pain intensity to the time of each study’s primary endpoint (KF7013-02: LS mean change12week, NERIAS: LS mean change6week, NAIMES: LS mean change4week) and corresponding LS mean differences between neridronate and placebo were estimated from the MMRM model.
• LS mean difference values indicate the placebo adjusted change in average pain from baseline; larger negative numbers indicate greater pain relief with neridronate.
• P-values for testing if the LS mean differences between neridronate and placebo were significantly difference from zero were not adjusted for multiple comparisons.
RESULTS:
• Overall, 206 participants across 3 trials had CRPS-1 at baseline (Table 1).
• Trial KF7013-02
Red and/or warm affected limb subgroup (scored as yes/no):
• The analysis included participants with CRPS-1 and available Week 12 pain intensity scores with (n=12) and without (n=19) physical exam findings of affected limb redness and/or warmth prior to receiving study treatment.
• Treatment with neridronate in participants with a red and/or warm affected limb at baseline showed a greater LS mean difference12week in average pain intensity of -2.11 (95% CI: -3.99, -0.23; nominal p=0.03; Table 2) compared to those without these inflammatory signs at baseline (-1.14; 95% CI: -1.92, -0.36; nominal p=0.004; Table 2).
Edema in the affected limb subgroup (scored as present (+)/absent (−):
• The analysis included participants with CRPS-1 and available Week 12 pain intensity scores with (n=17) and without (n=14) edema prior to receiving study treatment.
• Treatment with neridronate in participants with baseline edema resulted in an LS mean difference12week in average pain intensity of -2.11 (95% CI: -3.32, -0.90; nominal p=0.001; Figure 1), which was greater than that observed in participants without baseline edema (-0.91; 95% CI: -1.99, 0.17; nominal p=0.096; Figure 1).
• NERIAS
Edema in the affected limb subgroup (scored on a 4-point NRS: none, mild, moderate, severe):
• The analysis included participants with CRPS-1 and available Week 6 pain intensity scores with moderate (n=27) and mild (n=26) edema prior to receiving study treatment.
• Treatment with neridronate in participants with moderate edema prior to receiving treatment resulted in a LS mean difference6week in pain intensity of -28.6 (95% CI: -47.1, -10.1; nominal p=0.004; Figure 1), which was notably greater than that observed in participants with mild edema (-15.4; 95% CI: -32.0, 1.22; nominal p=0.068; Figure 1).
• NAIMES
Edema in the affected limb subgroup (scored on a 4-point NRS: none, mild, moderate, severe):
• The analysis included participants with CRPS-1 and available Week 4 pain intensity scores with severe (n=18), moderate (n=25) and mild (n=24) edema prior to receiving study treatment.
• Treatment with neridronate in participants with severe edema at baseline resulted in the greatest LS mean difference4week in pain intensity of -37.6 (95% CI: -61.9, -13.3; nominal p=0.005; Figure 1) vs those with moderate (-24.3 [95%CI: -39.7, -8.79; p=0.003]) and mild edema (-6.71 [95%CI: -31.5, 18.11; p=0.576]).
DISCUSSION:
• This post-hoc analysis reinforces neridronate’s established efficacy in early CRPS-1, highlighting its particular clinical benefit in patients with characteristic features of the warm CRPS-1 subtype.
• Greater improvements in average pain intensity were observed with neridronate treatment vs placebo in subgroups of patients with features of warm CRPS-1 (i.e., redness, warmth, and/or edema in the affected limb) across multiple phase 3 clinical trials.
• This benefit may stem from neridronate’s bone specific immunomodulatory actions, including inhibitor effects on macrophages and gamma-delta T cells, which are particularly relevant in the early, inflammatory phase of CRPS-1.
• Additional research evaluating neridronate’s efficacy and safety in patients with warm CRPS-1 and other relevant precision medicine features, such as a positive triple phase bone scan (given neridronate’s possible bone mechanisms) is warranted.
Limitations:
• Other patient features may also be associated with neridronate response and contribute to a precision medicine approach, ie, neridronate preserves and improves bone architecture, thus increased tracer uptake in the affected limb on triple phase bone scan may also be an important attribute.[7]
• These post-hoc analyses were not pre-specified and should be considered hypothesis-generating rather than confirmatory.
• The sample sizes within subgroups may limit the ability to detect true differences and increase the risk of false negatives.
• Subgroups may differ in other baseline characteristics, introducing bias or confounding effects.
• Findings may not be generalizable beyond the studied subgroups.
KEY TAKEAWAYS:
• In CRPS, given the progressive nature of the disease and its different subtypes, it is important to consider a precision medicine approach that targets the right treatments to the right patients at the right time.
• This post-hoc subgroup analysis suggests neridronate shows meaningful benefit in CRPS-1, particularly in patients with features of the warm CRPS-1 subtype.
• Further research is needed to confirm the efficacy and safety of neridronate in this focused patient population.
REFERENCES:
1. Harden R et al. Pain Med. 2022;23(Suppl 1):S1-S5.
2. Precision Medicine [webpage]. Food and Drug Administration. Available at: https://www.fda.gov/medical-devices/in-vitro-diagnostics/precision-medicine. Accessed Oct 2025.
3. Bruehl S, et al. Pain. 2016;157(8):1674-81.
4. Varenna M, et al. Osteoporos Int. 2025;36:737-740.
5. Varenna M, et al. Rheumatology. 2013 Mar;52(3):534-42.
6. Varenna M, et al. Ther Adv Musculoskelet Dis. 2021 Jun 11;13:1759720X211014020.
7. Varenna M, et al. Calcif Tissue Int. 2024;115(3): 251-259.