Inclusion Criteria:
1. Diagnosis of probable or definite (>55%) IIM and subgroup classification as
dermatomyositis according to the 2017 EULAR/ACR classification criteria for idiopathic
inflammatory myopathies.
2. Age > 25 years and < 72 years at time of signing informed consent Refractory disease:
subject with previous failure (or intolerance) to glucocorticoids and at least two
non-glucocorticoid immunosuppressive therapies (including mycophenolate mofetil or
mycophenolic acid, cyclophosphamide, azathioprine, methotrexate, calcineurin
inhibitors, tofacitinib or other JAK inhibitors, rituximab, or IVIG) administered for
at least 12 weeks within 24 months prior to screening.
.Moderate-to-severe dermatomyositis as per EITHER: muscle weakness, defined as Manual
Muscle Testing (MMT-8) score <142/150; or cutaneous disease as per Cutaneous
Dermatomyositis Assessment and Severity Index-activity subscore (CDASI-a)>=19.
PLUS at least 2 other abnormal IMACS Core Set Measures (CSMs) from the following:
- - Patient global VAS≥2 cm.
- - Physician's global VAS ≥2 cm.
- - Global extramuscular activity score ≥2 cm.
- - Elevation of at least one of the muscle enzymes (CK, AST, ALT, aldolase, LDH) >1.5
times upper limit of normal.
2.For patients enrolling on the MMT-8 criterion, muscle disease must be active, as
deemed by one of the following:
- - Creatine kinase, aldolase, LDH, AST, or ALT (if deemed due to muscle inflammation by
investigator) ≥2×ULN.
- - MRI evidence of active myositis within last 3 months.
- - EMG evidence of active myositis within last 3 months.
Other
inclusion criteria:
Subject must sign a written ICF prior to any screening
procedures.
1. Subject must be ≥25 and ≦72 years of age.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 3. Adequate organ function as per table below. Haematology Haemoglobin: ≥10.0 g/dl
(without prior red blood cell transfusion within 7 days before the laboratory test)a
Platelets: ≥100,000/ μL (without transfusion support within 7 days before the
laboratory test).
Absolute Lymphocyte Count (ALC):≥700/μL Absolute Neutrophil Count (ANC) 1,500/μL
(prior growth factor support is permitted but must be without support in the 7 days
prior to the laboratory test) Hepatic AST and ALT: ≤2.5×upper limit of normal (ULN)
unless deemed by the investigator to be secondary to DM.
Total bilirubin ≤1.5×ULN; except in subjects with congenital bilirubinaemia, such as
Gilbert syndrome (in which case direct bilirubin ≤1.5×ULN is required) Renal
Creatinine clearance Calculated creatinine clearance ≥45 mL/min/1.73 m2 (measured by
Cockcroft-Gault equation) Pulmonary Grade≤1 dyspnoea Oxygen saturation measured by
pulse oximetry ≥92% on room air a .For subjects who meet the inclusion criteria at
screening, transfusion of red blood cells is permitted after screening as needed to
maintain a haemoglobin level ≥8.0 g/dL.
4. Must be up to date on all recommended vaccinations, including against COVID-19/ SARS
CoV-2, per Centers for Disease Control and Prevention or institutional guidelines for
immune-compromised individuals.
5. Women of childbearing potential must have a negative pregnancy test at screening using
a highly sensitive serum pregnancy test (β-human chorionic gonadotropin [β-hCG]).
Women of childbearing potential are defined as a sexually mature woman who has not
undergone a hysterectomy or tubal ligation or who has not been naturally
postmenopausal for at least 24 consecutive months.
6. Female subjects of childbearing potential who have a fertile male sexual partner must
agree to use a highly effective method of contraception (failure rate of <1% per year
when used consistently and correctly) from the time of signing the ICF until 1 year
after the KYV-101 infusion. Examples of highly effective method of contraception
include:
- - Established use of hormonal methods of contraception associated with inhibition
of ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the
subject or male subject's female partner plans to remain on the same treatment
throughout the entire study and has been using that hormonal contraceptive for an
adequate period of time to ensure effectiveness.
- - Correctly placed copper containing- intrauterine device or intrauterine
hormone-replacing system.
- - Male sterilization with absence of sperm in the post-vasectomy ejaculate.
- - Female sterilization (bilateral tubal ligation/bilateral salpingectomy or
bilateral tubal occlusive procedure (provided that occlusion has been confirmed).
- - Sexual abstinence, defined as completely and persistently refraining from all
heterosexual intercourse (including during the entire period of risk associated
with the study treatments) may obviate the need for contraception ONLY if this is
the preferred and usual lifestyle of the subject.
7. Male subjects, if not surgically sterilized, must agree to use highly effective method
of contraception and not donate sperm from the time of signing the ICF until 1 year
after the KYV-101 infusion.
8. For females: a negative pregnancy test at screening and prior to lymphodepletion
chemotherapy.
9. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively,
until at least 1 year after receiving a KYV-101 infusion.
EXCLUSION CRITERIA:
DM-related exclusion criteria. 1. Evidence of any of the following:
- - Severe muscle damage as per one of the following criteria:
1.
Myositis Global Damage Index (MDI) ≥5.
2. Severe proximal muscle atrophy of upper or lower extremity on MRI.
3. Severe proximal muscle atrophy of upper or lower extremity on clinical
examination.
4. Wheelchair-bound at home.
5. MMT-8 of ≤80.
- - MDA5-positive rapidly progressing interstitial lung disease (subjects with stable
ILD not requiring supplemental oxygen are eligible).
- - Findings of muscular inflammation or myopathy other than the indication, such as
polymyositis (PM), immune mediated necrotizing myopathy (IMNM), inclusion body
myositis (IBM), cancer-associated myositis (myositis diagnosed within 2 years of
cancer), drug-induced myopathy, amyloid myopathy, muscular dystrophy, metabolic
myopathies, or myositis in the context of significant overlap with another
systemic autoimmune rheumatologic disease (overlap myositis), except with
Sjogren's syndrome.
- - Generalized, severe musculoskeletal or neuro-muscular conditions other than DM
that prevent a sufficient assessment of the patient by the investigator.
2. Subject with any of the following:
- - Patients with ILD associated with any of the following oRequiring O2 therapy
and/or FVC ≤45% of predicted or DLCO ≤40% of predicted at screening oEvidence of
PH as defined as estimated RVSP or ≥45 mmHg or right atrial or ventricular
enlargement or dilatation, unless subsequent RHC shows no PH.
oPAH on right heart catheterization requiring PAH specific treatment.
•Current gangrene of a digit. Other
exclusion criteria:
1. Prior treatment with cellular immunotherapy (eg, CAR T) or gene therapy product
directed at any target.
2. History of allogeneic or autologous stem cell transplant.
3. Systemic autoimmune disease, other than DM, requiring systemic immunosuppressive
therapies. 4. Plan to receive live, attenuated vaccine after signing ICF (inactive vaccines, like
the flu vaccine, are allowed). Unable to washout or interrupt autoimmune disease
therapy prior to apheresis as specified in Table .
5. Positive hepatitis B surface antigen (HBsAg) and hepatitis C serology confirmed by
polymerase chain reaction (PCR) (except hepatitis C cured with pharmacotherapy);
subjects who are HBsAg negative and hepatitis B core antibody (HBc) positive with no
detectable DNA will be allowed into the study but will require regular monitoring of
hepatitis B virus (HBV) DNA.
6. Positive serology for human immunodeficiency virus (HIV).
7. Positive screening test for SARS-Cov-2.
8. Primary immunodeficiency.
9. History of splenectomy.
10. History of stroke, seizure, dementia, Parkinson's disease, coordination movement
disorder, cerebellar diseases, psychosis, paresis, aphasia, and any other neurologic
disorder investigator considers would increase the risk for the subject.
11. Impaired cardiac function or clinically significant cardiac disease including:
1. Unstable angina or myocardial infarction or coronary artery bypass graft (CABG)
within 6 months prior to apheresis.
2. New York Heart Association (NYHA) stage III or IV congestive heart failure.
3. History of clinically significant cardiac arrhythmia (eg, ventricular
tachycardia), complete left bundle branch block, high-grade atrioventricular (AV)
block.
4. History of severe nonischaemic cardiomyopathy.
5. Left ventricular ejection fraction (LVEF) <45% as assessed by echocardiogram
(ECHO)
12. Previous or concurrent malignancy with the following exceptions:
1. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing
is required prior to screening).
2. In situ carcinoma of the cervix or breast, treated curatively and without
evidence of recurrence for at least 3 years prior to screening.
3. A primary malignancy which has been completely resected, or treated, and is in
complete remission for at least 5 years prior to screening.
13. Serious and/or uncontrolled medical condition that, in the investigator's judgment,
would cause unacceptable safety risk, interfere with study procedures or results, or
compromise compliance with the protocol, such as:
1. Active, uncontrolled, viral, bacterial or systemic fungal infection (including
human T cell lymphotropic virus [HTLV], human polyomavirus 2 [JC virus], or
syphilis); or recent history of repeated infections.
2. Requirement of supplemental oxygen to maintain oxygen saturation.
3. Clinical evidence of dementia or altered mental status.
4. A thromboembolic event within 6 months prior to apheresis.
14. Ongoing toxicity from previous therapy that has not resolved to baseline levels or to
Grade 1 or less, except for alopecia, fatigue, nausea, and constipation.
15. Major surgery within 4 weeks prior to apheresis or planned within 4 weeks after
KYV-101 administration. For surgery planned after 4 weeks post KYV-101 administration,
discuss with the sponsor.
16. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to
KYV-101 or its excipients, including dimethyl sulfoxide; or to CYC (or to fludarabine
if relevant), or to tocilizumab.
17. Pregnant or breastfeeding; or plans to become pregnant or breastfeed, or father a
child within 1 year after receiving the KYV-101 infusion.
