Allogeneic Mitochondria (PN-101) Transplantation for Refractory Polymyositis or Dermatomyositis

• ClinicalTrials.gov Identifier: NCT04976140
• Recruitment Status: Enrolling by invitation
• First Posted: July 26, 2021
• Last Update Posted: June 13, 2022
• Sponsor: Paean Biotechnology Inc.
• Information provided by (Responsible Party): Paean Biotechnology Inc.

Study Description

Brief Summary:

To determine the maximum tolerated dose (MTD) based on the safety and tolerability after single-dose administration of PN-101 in patients with refractory polymyositis or dermatomyositis. To explore the efficacy after single-dose administration of PN-101 in patients with refractory polymyositis or dermatomyositis.

Condition or disease	Intervention/treatment	Phase
Polymyositis; Dermatomyositis	Biological: PN-101	Phase 1; Phase 2

Detailed Description:

This Phase 1/2a clinical trial involves patients diagnosed with refractory polymyositis or dermatomyositis.

The initial safety assessment is conducted, including development of DLT in subjects up to Week 2 after the investigational product administration.

[DLT assessment criteria and method]

• Low dose or intermediate dose level

  1. No DLT developing in the initially enrolled 3 subjects (0/3): Increase the dose to the next dose group
  2. DLT developing 1 of 3 subjects (1/3): Enroll 3 additional subjects at the same dose group and then assess DLT, and ① DLT developing in 1 out of total 6 subjects (1/3+0/3; 1/6): Increase the dose to the next dose group ② DLT developing in ≥ 2 out of total 6 subjects (≥ 2/6): In case of the low dose level, the trial is discontinued without MTD determination. In case of the intermediate dose level, MTD is assessed at the low dose which is a one lower dose level

• High dose level

  1. No DLT developing in the initially enrolled 3 subjects (0/3): Declare as the MTD
  2. DLT developing 1 of 3 subjects (1/3): Enroll 3 additional subjects at the same dose group and then assess DLT, and ① DLT developing in 1 out of total 6 subjects (1/3+0/3; 1/6): Declare as the MTD ② DLT developing in ≥ 2 out of total 6 subjects (≥ 2/6): Assess MTD at the intermediate dose which is the one lower dose level

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 18 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Open, Dose-escalation, Multi-center, Phase 1/2a Trial to Evaluate the Safety, Tolerability and to Explore the Efficacy of PN-101 in Patients With Refractory Polymyositis or Dermatomyositis
• Actual Study Start Date: December 15, 2021
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: April 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Low dose group; The investigational product is intravenously administered according to the planned dose.	Biological: PN-101; PN-101: Mitochondria isolated from Allogeneic Umbilical Cord-derived Mesenchymal Stem Cells. 3 or 6 subjects are enrolled in each dose group in line with the traditional 3+3 rule-based method, and the investigator intravenously administers a single-dose of the investigational product according to the planned dose.
Experimental: Intermediate dose group; The investigational product is intravenously administered according to the planned dose.	Biological: PN-101; PN-101: Mitochondria isolated from Allogeneic Umbilical Cord-derived Mesenchymal Stem Cells. 3 or 6 subjects are enrolled in each dose group in line with the traditional 3+3 rule-based method, and the investigator intravenously administers a single-dose of the investigational product according to the planned dose.
Experimental: High dose group; The investigational product is intravenously administered according to the planned dose.	Biological: PN-101; PN-101: Mitochondria isolated from Allogeneic Umbilical Cord-derived Mesenchymal Stem Cells. 3 or 6 subjects are enrolled in each dose group in line with the traditional 3+3 rule-based method, and the investigator intravenously administers a single-dose of the investigational product according to the planned dose.

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity(DLT) [ Time Frame: 2 weeks after IP administration ]

   Assessment of DLT for each dose group up to 2 weeks after the IP administration.

   Severity will be graded according to CTCAE, Version 5.0.

2. International Myositis And Clinical Studies group-Total Improvement Score(IMACS-TIS) [ Time Frame: 12 weeks after the IP administration ]
   Assessment of IMACS-TIS at Week 12 after the IP administration. Total Improvement Score (TIS) based on absolute percentage change is assessed scale 0 to 100. Higher score indicates greater improvement.

Secondary Outcome Measures :

1. International Myositis And Clinical Studies group-Total Improvement Score(IMACS-TIS) [ Time Frame: 4 weeks after the IP administration ]
   Assessment of IMACS-TIS at week 4 after the IP administration. Total Improvement Score (TIS) based on absolute percentage change is assessed scale 0 to 100. Higher score indicates greater improvement.
2. International Myositis And Clinical Studies group-Total Improvement Score(IMACS-TIS) [ Time Frame: 8 weeks after the IP administration ]
   Assessment of IMACS-TIS at week 8 after the IP administration. Total Improvement Score (TIS) based on absolute percentage change is assessed scale 0 to 100. Higher score indicates greater improvement.
3. Response rate of IMACS-TIS [ Time Frame: 12 weeks after the IP administration ]
   Proportion of subjects with the IMACS-TIS ≥ 20 at week 12 after the IP administration.
4. Changes of Core Set Activity Measures(CSAM) [ Time Frame: Visit 2(Day 1), Visit 5(4 weeks), Visit 6(8 weeks), Visit 7(12 weeks) ]
   Changes in CSAM for the IMACS assessed at week 4, week 8 and week 12 after the IP administration from the baseline (Visit 2).
5. Changes of Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) [ Time Frame: Visit 2(Day 1), Visit 5(4 weeks), Visit 6(8 weeks), Visit 7(12 weeks) ]
   Changes in CDASI assessed at week 4, week 8 and week 12 after the IP administration from the baseline (Visit 2) for dermatomyositis only.
6. Changes of Peak Pruritus Numeral Rating Scale(PPNRS) [ Time Frame: Visit 2(Day 1), Visit 5(4 weeks), Visit 6(8 weeks), Visit 7(12 weeks) ]
   Changes in PPNRS assessed at week 4, week 8 and week 12 after the IP administration from the baseline (Visit 2) for dermatomyositis only. The intensity of pruritis is assessed on a patient reported scale 0 to 10.

Eligibility Criteria

• Ages Eligible for Study: 19 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult aged 19 years or more

2. A subject who is diagnosed with polymyositis or dermatomyositis and satisfies all of the followings

   • Clinical profile: Slowly progressing clinical profile with symmetrical and apparent muscular weakness confirmed at the proximal muscle (in case of dermatomyositis, clinical findings related with characteristic skin symptoms*)

     * Gottron's papules or sign, erythema purpura, poikiloderma, calcinosis cutis, etc.

   • Serum test: Serum creatine kinase (CK) elevated (CK ≥ 1.3 × upper limit of normal (ULN)) or serum myositis-specific antibodies (MSA) positive
   • Electromyography (EMG): Presence of a finding that indicates myopathy

3. Baseline (prior to the investigational product administration) manual muscle testing-8 (MMT-8) result < 125/150 (bilaterally), and at least 2 of the following International Myositis and Clinical Studies Group (IMACS) core set results

   • Physician global disease activity [visual analogue scale (VAS)] ≥ 2 cm
   • Patient global disease activity [VAS] ≥ 2 cm
   • Health assessment questionnaire (HAQ) disability assessment ≥ 0.25
   • 1 or more items with the serum muscle enzyme > 1.3 × ULN
   • Global extramuscular disease activity [VAS] > 1 cm
4. A subject with the drug treatment history of polymyositis or dermatomyositis for ≥ 8 weeks, who cannot receive the conventional treatment due to being refractory or for a side effect and adverse event, and has received glucocorticosteroids at an intermediate dose (prednisone 0.5 mg/kg/day or equivalent) or higher for at least 4 weeks alone or in combination
5. A subject who fully understands the trial and provided voluntary written consent to take part in the trial

Exclusion Criteria:

1. A subject with clear muscular damage, with the VAS-based myositis damage index (MDI) of ≥ 5 at screening

2. A subject with the following medical history or surgical history

   • A surgical operation history within 12 weeks of screening
   • Malignant tumor within 5 years of screening (excluding a subject who passed 3 years or more from complete recovery of cervical cancer or skin squamous cell carcinoma)
3. A patient with severe respiratory muscular weakening or interstitial pulmonary disease (a patient who has no moderate or severe dyspnea and has stable interstitial pneumonia may participate)

4. A patient with the following comorbidity at screening

   • Acute viral infection or severe infection
   • Active hepatitis B (e.g.: HBsAg positive and HBV DNA detected) or hepatitis C (e.g.: Anti-HCV positive and HCV RNA [qualitatively] detective)
   • Human Immunodeficiency virus (HIV) positive
   • Findings of muscular inflammation or myopathy other than the indication (inclusion body myositis (IBM), drug-induced myopathy, amyloid myopathy, myotonic dystrophy, etc.)
   • Autoimmune disease such as rheumatoid arthritis (RA), systemic lupus erythematosus, psoriatic arthritis, etc. (however, in case of the overlap syndrome, a subject may participate if diseases other than inflammatory myositis are stable and myositis is thought to be due to inflammatory myositis.)
   • Findings of cardiac disorder such as moderate or severe heart failure (New York Heart Association Class III/IV) or QT corrected interval prolonged
   • Serious disease that may affect this study, at the discretion of the investigator (neurological disorder, cardiovascular disorder, uncontrolled blood pressure or diabetes, etc.)

5. Hematological, renal and hepatic dysfunction based on the following laboratory findings at screening

   • Glomerular filtration rate (GFR)* < 45 mL/min

     *eGFR (mL/min/1.73m^2) = 175 × (serum creatinine concentration (mg/dL))^-1.154 × (age)^-0.203 × (0.742 in female) [modification of diet in renal disease (MDRD) formula]

   • Hemoglobin < 10 g/dL
   • White blood cell (WBC) count < 3.0×10^9/L
   • Absolute neutrophil count (ANC) < 1.5×10^9/L (1500/mm^3)
   • Platelet count < 100×10^9/L
   • AST and ALT > 2.5 × ULN (except for the elevation due to muscle enzyme at the discretion of the investigator)
   • Alkaline phosphatase (ALP) > 2.5 × ULN
   • Total bilirubin > 1.5 × ULN (> 3 × ULN, in case of Gilbert's syndrome)
   • Thyroid stimulating hormone level exceeding the normal range (however, if the level exceeds the normal range due to the study indication at the discretion of the investigator, the subjects are allowed to enroll.)
6. A subject with a difficulty in the efficacy assessment including the muscular strength assessment during the trial
7. A subject who is determined to require prohibited concomitant treatment during the trial

8. Pregnant woman and lactating mother or woman of childbearing potential and man who is planning to have a child or not willing to practice acceptable contraception* during the trial

   *Hormonal contraception, intrauterine device or intrauterine system implant, double barrier method (use of both male condom and occlusive cap (contraceptive diaphragm or cervical cap) along with spermicide), surgical sterilization procedure/operation (vasectomy, tubal ligation, etc.)

9. Participation in other clinical trial and administration of an investigational product or application of an investigational device within 4 weeks or half-life x 5 (whichever is longer) prior to screening
10. A subject who is otherwise ineligible for this trial, at the discretion of the investigator

Contacts and Locations

Locations

Korea, Republic of

Seoul National University Hospital

Seoul, Korea, Republic of, 03080

Soonchunhyang University Seoul Hospital

Seoul, Korea, Republic of, 04401

Hanyang University Seoul Hospital

Seoul, Korea, Republic of, 04763

Sponsors and Collaborators

Paean Biotechnology Inc.

Investigators

• Principal Investigator: Eunyoung Lee, MD; Seoul National University College of Medicine
• Principal Investigator: Daehyun Yoo, MD; Hanyang University College of Medicine
• Principal Investigator: Hyunsook Kim, MD; Soonchunhyang University College of Medicine

More Information

• Responsible Party: Paean Biotechnology Inc.
• ClinicalTrials.gov Identifier: NCT04976140
• Other Study ID Numbers: PN-101-101
• First Posted: July 26, 2021
• Last Update Posted: June 13, 2022
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Paean Biotechnology Inc.:

mitochondria

Additional relevant MeSH terms:

Dermatomyositis; Polymyositis; Myositis; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Connective Tissue Diseases; Skin Diseases