Xiaflex STRIDE Phase III Win Opens First-Mover Window, But Durability and Payer Gaps Threaten Conversion

Keenova's Xiaflex Achieves Phase III Success in Plantar Fibromatosis

Keenova Therapeutics announced positive Phase III results for Xiaflex (collagenase clostridium histolyticum) in the STRIDE study (NCT06151197) for plantar fibromatosis, a rare foot disease. The double-blind, randomized, placebo-controlled trial, involving 436 patients, met its primary endpoint with Xiaflex demonstrating a statistically significant, patient-reported improvement in pain compared to placebo. The drug also showed improvements in foot functionality, disease severity, and treatment satisfaction, with a favorable safety profile. Keenova plans to submit an application to the US Food and Drug Administration (FDA) in Q4 2026, aiming for Xiaflex to become the first approved therapy for this condition.

• The Phase III STRIDE study successfully met its primary endpoint, showing that Xiaflex treatment led to a statistically significant, patient-reported improvement in pain for individuals with plantar fibromatosis compared to placebo. This outcome is crucial for patients currently relying on symptom relief and off-label treatments.
• Beyond pain reduction, Xiaflex also demonstrated significant improvements across several secondary measures, including foot functionality (difficulty and activity limitation), disease severity, treatment satisfaction, and the characteristics of fibrous nodules. The drug was well-tolerated, with most adverse events being mild-to-moderate and no severe treatment-linked AEs reported.
• Following this success, Keenova Therapeutics intends to submit an FDA application for Xiaflex in plantar fibromatosis in Q4 2026. If approved, this would mark Xiaflex as the first FDA-approved therapy for this rare disease, further expanding its clinical legacy which includes prior approvals for Dupuytren's disease (2010) and Peyronie's disease (2013). The drug generated $134m in Q1 2026 net sales.

Current Treatment Challenges for Plantar Fibromatosis Patients

Plantar fibromatosis presents a significant therapeutic challenge, with no established clinical guidelines in the United States and limited real-world evidence to inform treatment decisions. Both conservative and surgical strategies carry meaningful limitations, and the condition frequently persists or recurs despite intervention.

• High surgical recurrence rates across all procedure types: Surgery is considered the mainstay of treatment when conservative measures fail, yet failure rates have been reported as high as 100% depending on the type of fasciectomy performed. In a 1997 study, recurrence was documented across all surgical approaches — local excision (40%; 4/10 feet), wide excision (33%; 1/3 feet), and subtotal fasciectomy with or without skin grafting (50%; 2/4 feet) — with all postoperative recurrences emerging within 14 months of surgery (mean 6.9 months).

• Compounded recurrence risk in patients with prior surgical history: Among patients presenting with recurrent lesions — all of whom had previously undergone local excision at outside institutions — further recurrence rates remained substantial. Local or wide excision yielded a 75% recurrence rate (3/4 feet), while subtotal fasciectomy was comparatively more effective at 23.5% (4/17 feet), though still imperfect.

• Identifiable risk factors that amplify recurrence probability: Multiple nodules, bilateral lesions, and a positive family history have been associated with increased recurrence risk, compounding the clinical difficulty of achieving durable surgical outcomes even with wide fascial resection.

• Conservative treatments provide symptom management but not cure: The majority of patients (91.13%) receive conservative treatment — including injectable corticosteroids (59.19%), oral corticosteroids (44.68%), and physical/occupational therapy (40.81%) — yet these modalities manage symptoms without eradicating disease. Accommodative orthotics, verapamil, extracorporeal shock wave therapy, tamoxifen, and collagenase have all been described, but supporting evidence derives predominantly from small-scale trials.

• Post-surgical reliance on conservative management signals persistent disease burden: Among patients who underwent surgery, 92.86% subsequently received conservative treatments, suggesting ongoing symptom burden or disease recurrence following surgical intervention and underscoring the inadequacy of current approaches to achieve lasting resolution.

• Emerging modalities remain investigational: Radiotherapy has shown promising early results as a treatment for plantar fibromas, but its role has not yet been codified into formal guidelines, leaving clinicians without standardized protocols to guide sequencing or escalation of therapy.

Key Design and Endpoints of the STRIDE Study for Xiaflex

The available evidence base for plantar fibromatosis consists primarily of retrospective studies and systematic reviews rather than prospective randomized controlled trials, reflecting the rarity of the condition and the absence of an approved pharmacological intervention to date. The studies summarized below vary in design rigor but collectively inform current understanding of surgical and conservative treatment outcomes.

• 2024 Retrospective Case Series (Wide Resection): Level IV evidence evaluating 12 patients assessed 2–13 years following wide resection (mean follow-up 7.8 years). The primary endpoint was recurrence rate assessed via clinical examination and MRI; secondary endpoints included the Foot Functional Index (FFI) and American Orthopaedic Foot and Ankle Society (AOFAS) score. Recurrence was observed in 2 patients (17%); median FFI was 1 (range 0–66) and median AOFAS score was 95 (range 44–100). A systematic review component encompassed 6 studies comprising 109 feet (92 patients).

• 2020 Systematic Review: A PubMed, Google Scholar, and Cochrane literature search using terms including "plantar," "fibromatosis," "Ledderhose," "Dupuytren," and "foot" identified 25 citations encompassing 233 patients. Conservative treatment outcomes were captured across 5 studies (35 patients); operative outcomes were reported in 178 patients (92 male, 86 female) across 196 feet. Endpoints were success rate and functional outcome evaluation.

• 2020 ESWT Retrospective Cohort Study (Level III): Evaluated 26 patients (30 feet) with plantar fibromatosis, of whom 10 feet received extracorporeal shockwave therapy (ESWT); a plantar fasciitis comparator cohort of 42 feet was included. Eligibility required a "Poor" or "Fair" Roles-Maudsley Score (RMS) with symptoms persisting >6 months. Primary outcomes were the Numerical Rating Scale (NRS) and RMS, with ultrasonographic changes as a supplementary measure. Treatment success was defined as >50% NRS reduction and achievement of a "Good" or "Excellent" RMS grade. Short-term success (one week post-ESWT) was 70.0%, rising to 80% at long-term follow-up (mean 34.0 months).

• 2010 Retrospective Study (Three-Decade Series): Assessed 27 patients undergoing 40 operations across 33 feet over three decades. The primary endpoint was recurrence rate stratified by procedure type. Overall recurrence was 60%; total plantar fasciectomy yielded a 25% recurrence rate versus 100% for local resection alone.

• 1999 Retrospective Clinical Evaluation: Analyzed 11 patients (13 feet) undergoing 24 operations including local excision, wide excision, and complete plantar fasciectomy. Recurrence rates by procedure were: 0/2 for primary fasciectomy, 3/6 for revised fasciectomy, 7/9 for wide excision, and 6/7 for local excision.

• 1996 Consecutive Case Series: Enrolled 12 patients (5 primary, 7 revision procedures) with mean follow-up of 47 months (range 22–66 months) for the primary group and 40 months (range 21–78 months) for the revision group. Outcomes were rated as satisfactory in 4/5 primary operations (one recurrence) and 5/7 revision operations (no recurrences).

Xiaflex's Expanding Legacy Beyond Plantar Fibromatosis

Xiaflex (collagenase Clostridium histolyticum, CCH) has demonstrated clinical utility well beyond plantar fibromatosis, with the most extensively studied indication being Peyronie's disease (PD) — a fibrotic condition of the tunica albuginea resulting in penile curvature and deformity that impairs sexual function. CCH holds the distinction of being the first and only FDA-approved non-surgical treatment for PD, with its efficacy and safety profile established through rigorous clinical investigation.

• Phase III Randomised Controlled Trials (IMPRESS I & II): The pivotal evidence base for CCH in PD was built through two large phase III RCTs, which evaluated changes in penile curvature angle and Peyronie's Disease Questionnaire (PDQ) domain scores as primary and secondary outcome measures, confirming that CCH is both safe and effective in this indication.

• Propensity-Score Matched Comparative Study: A prospective cohort study (April 2017–April 2018) enrolled 161 consecutive PD patients treated with CCH via a shortened protocol combined with a vacuum device. Using 1:1 propensity-score matching (adjusted for age, penile curvature, and IIEF-15 scores at baseline), 50 patients were allocated to either CCH plus sildenafil 25 mg twice daily (Group A, n=25) or CCH monotherapy (Group B, n=25). Mean baseline penile curvature was 47.0° (SD 21.88); post-treatment, mean curvature reduction was 25.6° (SD 9.05) in Group A versus 25.6° (SD 9.7) in Group B (P <.01).

• Meta-Analysis of CCH with Adjunctive Mechanical Therapies: A meta-analysis assessed CCH combined with penile traction or vacuum pump devices versus CCH monotherapy in stable PD. Combination therapy yielded an additional reduction of only 0.3° in penile curvature (95% CI: −3.97 to 4.49, I² = 0%) and an increase of 0.5 cm in penile length (95% CI: −0.32 to 1.4, I² = 70%) compared with monotherapy alone.

• Systematic Review Across Disease Phases: A systematic review and meta-analysis incorporating 13 studies in active PD and 10 in stable PD (1,962 total participants) evaluated available combination treatment modalities. The analysis concluded that adjunctive mechanical therapies added to CCH do not produce meaningful incremental improvements in symptoms beyond CCH monotherapy.

• Dupuytren's Disease (Dupuytren's Contracture): CCH is also an established intervention for Dupuytren's disease, studied in RCTs against both placebo and percutaneous needle aponeurotomy (PNA). A 10-year efficacy review at Veterans Affairs hospitals (247 collagenase injections) reported a mean contracture reduction of 29.40°; however, 50 of 155 contractures initially classified as resolved (32.2%) subsequently recurred. Comparative data indicate that open fasciectomy is associated with significantly greater deformity correction, higher resolution rates, and a 74.2% reduction in the likelihood of recurrence relative to collagenase injection.

Xiaflex's STRIDE Success: A New Era for Plantar Fibromatosis

The recent announcement from Keenova Therapeutics regarding positive Phase III results for Xiaflex (collagenase clostridium histolyticum) in plantar fibromatosis represents a significant advancement for patients suffering from this rare and often painful condition. Plantar fibromatosis, or Ledderhose disease, is a challenging disorder characterized by the formation of collagen-rich nodules in the foot, leading to pain and functional impairment. Historically, treatment options have been limited, with conservative measures offering inconsistent relief and surgical interventions frequently associated with high recurrence rates and complications.

Xiaflex's success in the STRIDE study, demonstrating statistically significant improvements in pain, functionality, and disease severity, positions it to become the first approved therapy for plantar fibromatosis. This is a pivotal moment, as it not only addresses a substantial unmet medical need but also further validates the therapeutic utility of collagenase in breaking down excessive collagen deposits. The drug has already established a strong track record in other fibrotic conditions like Dupuytren's contracture and Peyronie's disease, where it has become a gold standard for non-surgical management. This expansion into plantar fibromatosis underscores the potential of targeted enzymatic therapies across a spectrum of collagen-driven pathologies.

However, as with any novel treatment, certain considerations will be important for its long-term success and integration into clinical practice. While the immediate safety profile appears favorable, the known local adverse events associated with collagenase injections, such as bruising and swelling, will need careful management and patient education. Furthermore, the long-term recurrence rates for plantar fibromatosis following Xiaflex treatment will be a key area of interest, given the historical challenges with recurrence in this disease and in other collagenase-treated conditions. The economic implications and generalizability of these findings across diverse patient populations and healthcare settings will also warrant ongoing evaluation. Ultimately, this development offers a promising new avenue for patients, potentially transforming the treatment landscape for plantar fibromatosis and reinforcing the strategic value of collagenase-based therapies.