A PHASE 3, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY, SAFETY, AND TOLERABILITY OF EN3835 VS PLACEBO IN THE TREATMENT OF PLANTAR FIBROMATOSIS

The purpose of this double-blind, placebo-control Phase 3 study is to assess the

efficacy, safety, and tolerability of EN3835 vs placebo. To date, there is no available therapy that treats

the pathophysiology of plantar fibromatosis and as such, disease progression cannot be prevented.

There is no precedent for drug development in plantar fibromatosis. The overall design of this study is

aligned with the design of Study EN3835-222, the previous Phase 2 study of EN3835 in treatment of

plantar fibromatosis. A placebo-controlled, double-blind, parallel-arm study design was chosen in

accordance with the FDA Guidance for Industry, E10 Choice of Control Group and Related Issues in

Clinical Trials. No active control was used because there are no generally accepted pharmacologic

treatments for plantar fibromatosis. Given the body of immunogenicity safety data available from

previously conducted clinical studies supporting the approved indications of EN3835, and

immunogenicity data from participants with plantar fibromatosis (ie, Studies EN3835-105 and

EN3835-222), further immunogenicity sample collection/analyses are not planned in EN3835-309 PFI.

Age and Sex

1. Be an ambulatory male or female ≥18 years of age. Disease Characteristics

2. Have a diagnosis of plantar fibromatosis AND at least 1 “Hard” or “Firm Throughout” palpable fibrous nodule on clinical examination and measurable by caliper.

3. Have unilateral plantar fibromatosis with ≤ 2 nodules in the foot to be treated.

4. Have current foot pain due to plantar fibromatosis. Type of Participant

5. Be willing and able to comply with all protocol required visits, procedures, and assessments.

6. Be able to read and understand the patient reported assessments in English, Spanish, or the local language of the respective participating country and is adequately informed and understand the nature and risks of the study.

7. Agree not to use opioids (eg, codeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone) during the study period and has not used opioids 30 days before the Screening Visit.

8. Agree not to use drugs (eg, marijuana, cocaine) and/or use of prescription drugs for the purposes of inducing psychoactive effects during the study and has not used these products in the 30 days prior to the Screening Visit.

9. Agree not to use prohibited medication, throughout the study, and not use any medication to treat pain due to plantar fibromatosis except as permitted per the protocol. 10. If female, be of non-childbearing potential (history of hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or postmenopausal with no history of menstrual flow in the 12 months prior to the Screening Visit); or, if of childbearing potential, be non-pregnant, non-lactating and agree to use effective contraception when with a male partner for the duration of the study and for 28 days after any active treatment period. Acceptable forms of contraception include hormonal measures (oral contraceptive pills, contraceptive patch, contraceptive ring, injections), intrauterine devices, double barrier method (condom plus diaphragm, condom or diaphragm plus spermicidal gel or foam, surgical sterilization of the male partner), and abstinence. Informed Consent 11. Be capable of providing consent, are adequately informed, and understand the nature and risks of the study.

Key Exclusion Criteria:

A participant is ineligible for study participation if the participant meets any of the following criteria:

Medical Conditions

1. Has the presence of non-plantar fibromatosis-related nodules on the affected foot (eg, neurofibroma, rhabdomyosarcoma, liposarcoma, neurilemmomas, rheumatoid nodules, desmoid tumors, or malignant soft tissue lesions of the foot or ankle).

2. Has any musculoskeletal, neuromuscular, neurosensory, other neurological or related disorder that affects the participant’s use of his or her foot and/or would impair his/her completion of study assessments as determined by the investigator.

3. Has any significant medical history or examination findings related to the participant’s plantar nodule(s), which in the investigator’s opinion, would make the participant unsuitable for study intervention administration or required assessments and evaluations.

4. Has any nodule > 40. 0 mm.

5. Has a known systemic allergy to collagenase or any excipient of EN3835 or placebo.

6. History of intolerance or hypersensitivity to acetaminophen/paracetamol or any of its excipients or existence of a medical condition for which the use of acetaminophen/paracetamol is contraindicated (refer to product labeling).

7. Has a known bleeding disorder which would make the participant unsuitable for enrollment in the study (see Exclusion Criterion #15).

8. Has a clinically significant laboratory abnormality or any laboratory test results meeting any of

The following criteria:

• alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN)

• total bilirubin (TBL) ≥ 2 × ULN (> 35% direct bilirubin)

• aspartate aminotransferase (AST) ≥ 3 × ULN

• international normalized ratio (INR) >1.5

1. Has concurrent diseases that might interfere with the conduct of the study, confound the interpretation of the study results, endanger the participant’s well-being (eg, evidence or history of malignancy other than excised basal-cell carcinoma), or any significant hematological, endocrine, cardiovascular, respiratory, renal, hepatic, or gastrointestinal disease. If there is a history of such disease but the condition has been stable (defined as not requiring significant change in therapy or hospitalization for worsening disease) for more than 1 year and is judged by the investigator not to interfere with participation in the study, the participant may be included, with the documented approval of the medical monitor. 10. Any other significant medical condition(s), which in the investigator’s opinion would make the participant unsuitable for enrollment in the study. 11. Is pregnant or plans to become pregnant. 12. Is breastfeeding or is providing or plans to provide breast milk in any manner during the study. Prior/Concomitant Therapy 13. Has received any surgical or non-surgical treatment(s) (eg, steroid injection, transdermal/ intralesional verapamil, radiation therapy, extracorporeal shock wave therapy) on the foot or nodule(s) to be treated within 3 months before administration of study intervention. 14. Has received any collagenase treatment (eg, Santyl® ointment, XIAFLEX, EN3835, or CCH) within 30 days prior to Day 1. 15. Is currently receiving, has received (within 7 days of the first treatment of study intervention), or plans to receive any anticoagulant or antiplatelet medication (except for ≤ 150 mg aspirin daily) that would increase the risk of bleeding during the study. Prior/Concurrent Clinical Study Experience 16. Participation in other studies involving an investigational drug within 30 days before treatment with study intervention and/or concurrent study participation. 17. Has previously participated in clinical studies of EN3835 in plantar fibromatosis or plantar fasciitis. Other Considerations 18. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) Title 45, Part 46, Section 46.111(b) and other local and national regulations, including but not limited to, employees (temporary, part-time, full-time, etc) or a family member of the research staff conducting the study, or of the sponsor, or of the contract research organization, or of the IRB.