EN3835

EN3835 is injectable collagenase clostridium histolyticum (CCH), the same active enzyme mixture Endo already sells as Xiaflex for Dupuytren's contracture and Peyronie's disease, being repositioned for plantar fibromatosis (Ledderhose disease), a benign but painful fibrous nodule disorder of the sole of the foot [1][5]. The Phase 3 pivotal trial NCT06151197 has completed enrollment of 436 patients with pain reduction at Week 12 as the primary endpoint [1]. Topline (the first public disclosure of whether the trial met its primary endpoint) is likely in the Q4 2026 to H1 2027 window given a 12 week primary follow-up plus analysis lag. This is a life-extension play for a franchise that generated $516M in 2024 net sales and helped keep Endo solvent through its Chapter 11 restructuring, now branded under Keenova Therapeutics [4][9].

EN3835 is not a novel molecule. Collagenase clostridium histolyticum has been FDA-approved since 2010 for Dupuytren's contracture (Xiaflex) and since 2013 for Peyronie's disease, and it was briefly marketed as Qwo for cellulite before Endo pulled that indication in 2022 over persistent bruising complaints [5][8]. What is under review here is a new indication, plantar fibromatosis, using the same enzyme in the same injectable format. Published off-label case reports of CCH in Ledderhose used the standard Xiaflex 0.58 mg per cord dose, and Endo has not publicly indicated a different dose in the Phase 3 program [10]. No FDA breakthrough, fast track, orphan, or RMAT designation is on public record for this program. The Phase 3 study (NCT06151197) is listed as completed with n=436, and a long-term durability and retreatment study (NCT05254457, n=145) has also completed, which is the data package a supplemental Biologics License Application (sBLA, a regulatory filing that adds a new approved use to an already approved biologic) typically requires [1][2]. Endo has not publicly guided to a specific sBLA submission date. Sponsorship on ClinicalTrials.gov now reads as "Endo USA Inc., a Keenova Therapeutics Company," the post-bankruptcy corporate identity that emerged when Endo restructured under a new equity holder group in 2024 [4]. Expect a topline release before any regulatory filing, and expect Endo to lean on the well-worn Xiaflex safety database rather than build a fresh one.

Collagen is the rope that holds tissue together. In Ledderhose disease, cells in the plantar fascia (the tough sheet of tissue on the bottom of the foot) lay down thick, disorganized cords of collagen that form palpable nodules. Walking on them hurts. The disease is the foot cousin of Dupuytren's contracture in the hand, driven by similar myofibroblast activity (myofibroblasts are the scar-forming cells that produce excess collagen in both conditions). CCH is a two-enzyme cocktail (AUX-I and AUX-II, both bacterial collagenases from Clostridium histolyticum) that cuts triple-helical collagen at complementary sites [5]. Injected directly into the cord, the enzymes chemically dissolve it over roughly 24 to 72 hours, which is why Xiaflex is dosed as an in-office injection followed by a physical manipulation of the finger the next day. The mechanistic case for Ledderhose is straightforward read-across, and it is not just theoretical. Published off-label case reports and small series show single-injection CCH can dissolve plantar cords with durability out to nearly four years in some patients [10]. The open question is whether that translates into reproducible pain relief in a randomized Phase 3 population, in a weight-bearing tissue that gets reloaded every step.

The pivotal is NCT06151197, a Phase 3, placebo-controlled study that enrolled 436 adults with symptomatic plantar fibromatosis [1]. Primary endpoint is change from baseline to Week 12 in the weekly mean of Average Daily Pain (ADP) on an 11-point numeric rating scale (NRS), a validated patient-reported outcome that FDA generally accepts in painful benign conditions. The Phase 2 dose-finding study (NCT05152173, n=176) used the Foot Function Index pain subscale at Day 57 as its primary, and the pain-NRS switch for Phase 3 aligns with what regulators prefer for labeling claims [3]. Dose and formulation have not been publicly disclosed for the pivotal in detail, but published off-label experience with the marketed Xiaflex 0.58 mg per cord unit suggests the Phase 3 is most likely using the same or a closely related dose [10]. A separate long-term study, NCT05254457, followed 145 patients for safety, retreatment, and durability, which is the package needed to characterize repeat dosing since Ledderhose nodules recur [2]. Endo is also running a Phase 2 in plantar fasciitis with CCH (NCT06169319, n=231), a much larger commercial opportunity than Ledderhose, so read this Phase 3 as the first of potentially two foot indications [6]. Design concerns are modest: 12 weeks is short for a fibrotic disorder, and the placebo effect on subjective foot pain is typically 20 to 30 percent, which sets a real bar for separation.

Our model estimates a 29% chance this drug is eventually approved. It starts from the historical base rate for Phase 3 drugs in this area (about 69%), then adjusts using ten facts about the trial and sponsor. What moves the number most: it is helped by more secondary endpoints than usual; it is held back by the sponsor's thin or weak approval record, weak or limited earlier-phase results, and a randomized design. The other facts land near average for this stage, so they leave the estimate roughly where the base rate put it.

Efficacy risk is the biggest one. The Phase 2 dataset (NCT05152173) has not been fleshed out in the public literature, so the magnitude of pain reduction over placebo is unknown outside Endo [3]. Foot pain is subjective, placebo response in injectable trials is meaningful, and 12 weeks may be too short to capture recurrence. Safety risk is well-characterized but non-trivial. CCH labels for Xiaflex carry warnings for tendon rupture, ligament damage, and injection-site reactions including hematoma and skin tears, and injecting near the plantar fascia sits close to intrinsic foot ligaments and the flexor tendons [5]. The Qwo cellulite withdrawal in 2022 was a commercial rather than safety failure, but it demonstrated that even a well-tolerated CCH indication can flame out if the value proposition to patients and injectors is not compelling [8]. Commercial risk is real. Ledderhose disease is uncommon, with a worldwide prevalence commonly cited around 1.75 to 2.1 per 100,000, implying roughly a few thousand to low tens of thousands of symptomatic US patients at any given time (epidemiology is poorly characterized, so estimates vary widely) [11]. Many patients manage with orthotics or steroid injections. The primary structured non-surgical comparator is low-dose radiotherapy, which is used across Europe and at some US academic centers and showed significant pain reduction versus sham in the LedRad Phase 3 RCT, with published case series reporting roughly 70 percent lesion regression or stabilization rates and a mild toxicity profile [12]. Radiotherapy is cheap, widely reimbursed in Europe, and will be the direct clinical comparator payers ask about, alongside the standard $50 orthotic. Surgery is a reasonable option in refractory cases. Execution risk is lower than average because Endo already runs a Xiaflex specialty distribution network with certified injectors, but the corporate transition to Keenova adds uncertainty on commercial focus and sales infrastructure [4].

Worth watching, moderate signal weight. The specific data point that flips this from filler to a real event is the Phase 3 topline pain-NRS delta versus placebo. Published minimal clinically important differences (MCID) for pain NRS in musculoskeletal indications generally fall in the 1.5 to 2.0 point range on an 11-point scale, and FDA precedent in comparable injectable pain trials has accepted separations in that band when paired with function gains, so a placebo-adjusted separation above roughly 1.5 points would be a clean commercial win and support an sBLA filing. Anything under 1 point makes payer coverage a fight even if the p-value is nominally significant, especially with radiotherapy sitting there as a cheap, established alternative [12]. Check back when NCT06151197 topline hits, likely in the Q4 2026 to H1 2027 window given completed enrollment and the 12 week primary follow-up, and again if Endo announces the sBLA submission [1]. The strategic frame: this is Keenova (post-restructuring Endo) trying to squeeze more indications out of its most durable specialty asset, a franchise that hit $516M in 2024 net sales and remains the single most important product on the balance sheet [9]. If Ledderhose reads out cleanly, the much larger plantar fasciitis Phase 2 (NCT06169319) becomes the real commercial story, because plantar fasciitis affects roughly two million Americans a year and has no approved injectable disease-modifier [6]. Ledderhose is the appetizer. Plantar fasciitis is the entrée. Read this program as the setup trial for the bigger one.