| Eligibility |
Inclusion criteria
Idiopathic inflammatory myopathy (including dermatomyositis, antisynthetase syndrome,
immune mediated necrotizing myopathy, and polymyositis)
1. Diagnosis of probable or definite (>55%) idiopathic inflammatory myopathy, including
dermatomyositis, anti-synthetase myopathy, immune-mediated necrotizing myopathy
(including anti-HMGCoR-myopathy, anti-SRP myopathy), polymyositis, according to the
2017 ACR/EULAR Classification Criteria for idiopathic inflammatory myopathies
(Lundberg, Tjarnlund et al. 2017).
2. Disease severity and minimal core set measure criteria: MMT-8 score <136/150, with at
least 2 other abnormal core set measures (CSMs) from the following:
- Patient global VAS=3 on a 1-10 scale (Appendix 3).
- Physician's global VAS =3 on a 1-10 scale (Appendix 4).
- Global extramuscular activity score =2 cm (Appendix 5).
- Elevation of at least one of the muscle enzymes (CK, AST, ALT, aldolase, LDH)
>1.5 times upper limit of normal (Appendix 6)..
- HAQ-DI=0.25 (Appendix 7).
3. Active disease as per one of the following:
- Creatine kinase =4×ULN.
- Active rashes of dermatomyositis such that CDASI-activity =6 (Appendix 8).
- Evidence on MRI of active myositis within last 6 months.
- Evidence on EMG of active myositis within last 6 months.
- Muscle biopsy evidence of active myositis within last 6 months
4. Positive, at screening or by documented medical history, for one myositis-specific or
myositis-associated autoantibody per pre specified list (Table 3), except for patients
with DM who need not have a positive test for a myositis-specific antibody.
Table 3. Pre specified List of Autoantibodies
Myositis-specific: Target Antigen • Anti-ARS: ..
- Anti-Jo-1: Histidyl-tRNA synthetase
- Anti-HA/YRS: Tyrosyl-tRNA synthetase
- Anti-Zo: Phenylalanyl-tRNA synthetase
- Anti-EJ: Glycyl-tRNA synthetase
- Anti-PL-7: Threonyl-tRNA synthetase
- Anti-OJ: Isoleucyl-tRNA synthetase
- Anti-KS: Asparaginyl-tRNA synthetase
- Anti-PL-12: Alanyl-tRNA synthetase
- Anti-Mi-2: Nucleosome remodeling deacetylase complex
- Anti-TIF1 gamma; Transcription intermediary factor 1
- Anti-MDA5: Melanoma differentiation associated protein 5
- Anti-SAE: Small ubiquitin-like modifier activating enzyme
- Anti-NXP2: Nuclear matrix protein 2
- Anti-SRP: Signal recognition particle
- Anti-HMGCR: 3hydroxy-3methylglutaryl CoA reductase
5. Refractory disease: subject with previous failure (or intolerance) to glucocorticoids
and at least two non-glucocorticoids immunosuppressive therapies. An adequate trial of
medication defined as at least 12 weeks of therapy or intolerance/adverse reaction
necessitating discontinuation.
Diffuse cutaneous systemic sclerosis
1. Classified as systemic sclerosis according to the 2013 ACR/EULAR classification
criteria, with a total score of =9.
2. Clinical disease as follows:
- Classified as diffuse cutaneous SSc.
- 6 years or less since first non-Raynaud's sign or symptom.
- Active disease defined as:
- MRSS =16 with, in the prior 6 months, one or more of the following:
- An increase in MRSS of =3 units
- Involvement of 1 new body area with =2 mRSS units
- 2 new body areas with =1 mRSS unit. OR
- Progressive ILD meeting all of the following criteria
* Inadequate response or intolerance to at least one treatment, including
cyclophosphamide, methotrextate, MMF/mycophenolic acid, nintedanib,
rituximab, or tocilizumab.
AND one of the following:
- Evidence of progression on HRCT OR
- FVC<80% or DLCO<80% or evidence of FVC decline of 10% (absolute decline)/FVC decline
of 5% to 9% and DLCO 15%
SLE-related nephritis
1. Clinical diagnosis of SLE consistent with the 2019 European League Against Rheumatism
(EULAR)/American College of Rheumatology (ACR) classification criteria.
2. Active, biopsy-proven, proliferative LN Class III or IV according to the revised
ISN/RPS criteria (Krassanairawiwong, 2021: DOI: 10.1007/s11255-020-02732-3).
• Overlapping membranous changes are allowed.
- Biopsy must be within 12 months prior to screening or during screening.
- Further, the following subjects will be excluded:
o Significant chronicity defined as: > 50% glomeruli with global sclerosis
o 50% interstitial fibrosis on renal biopsy
o 2018 revised International Society of Nephrology (ISN)/Renal Pathology Society
(RPS) mNIH chronicity index (CI) =5.
3. Inadequate response (Urine Protein =1.5 g/24 hours - or equivalent value by spot uPCR
but not >7 g/24 hours or equivalent value by spot uPCR) after at least 6 months of
treatment with two or more conventional therapies including, but not limited to,
belimumab, a calcineurin inhibitor, CYC, mycophenolate mofetil/mycophenolic acid,
obinutuzumab, or rituximab.
4. Active disease after treatment with CYC-based therapy ANCA-associated vasculitis 1.
Diagnosis of GPA or MPA according to the 2022 ACR/EULAR Classification Criteria.
2. Positive serum PR3-ANCA or MPO-ANCA at screening or by documented medical history.
3. Disease activity/course as follows:
- BVAS/WG =3 within prior 60 days (not including the BVAS-WG items of "fever" or
"purpura") (Appendix 9):
- Subjects who have had failure to achieve sustained remission with glucocorticoids
and either cyclophosphamide or rituximab given for at least 4 months, OR
- Intolerance or contraindication to alternative treatments OR
- Refractory disease defined as:
- Subjects with a history of repeated (>2) relapses of AAV despite treatment with
immunosuppressive agents OR
- Subjects requiring prolonged and/or repeated courses of unacceptable doses (as
per investigator judgment) of glucocorticoids to maintain adequate control.
Other Inclusion Criteria Subject must sign a written ICF prior to any screening procedures.
1. Subject must be =18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 2.
3. Adequate organ function as per table below.
Hematology
- Hemoglobin =8.5 g/dl without any transfusion support a
- Platelets =100,000/uL (without transfusion support within 7 days before the
laboratory test).
- Absolute Lymphocyte Count (ALC) =800/uL (with detectable circulating B cells: >5
cells/mL)
- Absolute Neutrophil Count (ANC) Within Normal Limits (WNL)
Hepatic - AST and ALT =1.5×upper limit of normal (ULN)
- Total bilirubin Within Normal Limits (WNL) ; except in subjects with congenital
bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin =1.5×ULN is
required)
Renal - Creatinine clearance Estimated glomerular filtration rate =45 mL/min/1.73 m2
(measured by CKD-EPI Creatinine Equation)
Cardiac - Left Ventricular Ejection Fraction (LVEF) = 40% confirmed by ECHO/MUGA
a For subjects who meet the inclusion criteria at screening, transfusion of red blood
cells is permitted after screening as needed to maintain a hemoglobin level =8.0 g/dL.
1. Women of childbearing potential must have a negative pregnancy test at screening using
a highly sensitive serum pregnancy test (ß-human chorionic gonadotropin [ß-hCG]) at
screening and prior to lymphodepletion chemotherapy.
2. Female subjects of childbearing potential who have a fertile male sexual partner must
agree to use highly effective methods of contraception (failure rate of <1% per year
when used consistently and correctly) specifically 2 forms of contraception, one of
which must be a barrier method, 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.
3. Male subjects, if not surgically sterilized, must agree to use highly effective method
of contraception from the time of signing the ICF until 1 year after the KYV-101
infusion.
4. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively,
from time of signing the ICF until at least 1 year after receiving a KYV-101 infusion.
Exclusion Criteria
Autoimmune Disease-Related Exclusion Criteria
Idiopathic inflammatory myopathy
1. a. Evidence of any of the following:
- Severe muscle damage as per one of the following criteria:
o Myositis Global Damage Index (MDI) =5.
o Severe proximal muscle atrophy of upper or lower extremity on MRI.
o Severe proximal muscle atrophy of upper or lower extremity on clinical
examination.
o Wheelchair-bound at home.
o MMT-8 of =80.
- MDA5-positive rapidly progressing disease (subjects with stable ILD not requiring
supplemental oxygen are eligible).
- Findings of muscular inflammation or myopathy other than the indication, such as
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 Sjögren's syndrome.
- Patients with ILD requiring O2 therapy and/or FVC =45% of predicted.
- Generalized, severe musculoskeletal or neuro-muscular conditions other than IIM
that prevent a sufficient assessment of the patient by the physician.
Diffuse cutaneous systemic sclerosis 1.b. Subject with any of the following:
- Patients with ILD with any of the following o Requiring O2 therapy and/or FVC
=45% of predicted or DLCO =40% of predicted at screening
- Evidence of PAH as defined as estimated RVSP or =45 mmHg or right atrial or
ventricular enlargement or dilatation, unless subsequent RHC shows no PAH.
- PAH on right heart catheterization requiring PAH specific treatment.
- Active bleeding related to gastric antral vascular ectasia (GAVE) in past 6
months.
- Gastrointestinal dysmotility requiring total parenteral nutrition (TPN).
- Renal crisis within 1 year prior to enrollment.
- Pericardial tamponade within 6 months prior to enrollment.
- Active infection of a digital ulcer within 3 months prior to enrollment.
- Current gangrene of a digit
SLE-related nephritis 1.c. Subject with any of the following:
• Evidence of rapidly progressive glomerulonephritis (defined as a doubling of serum
creatinine within 3 months prior to enrollment).
• History of or currently active severe CNS lupus, including cerebritis,
cerebrovascular accident (CVA), and seizures. Presence of active neuropsychiatric
lupus as assessed by a neurologist and a rheumatologist (at time of screening or
during screen period).
• Patients with volume overload inadequately controlled by a stable dose of diuretics
ANCA-associated vasculitis 1.d. Subject with any of the following acute manifestations
of ANCA-associated vasculitis: • Alveolar hemorrhage requiring pulmonary ventilation
support. • Respiratory failure
• Spinal cord lesion
• Stroke Abbreviations: CNS=central nervous system; CVA=cerebral vascular accident;
DLCO=diffusing capacity of lung for carbon monoxide; FVC=forced vital capacity;
ILD=interstitial lung disease; MDI=Myositis Damage Index; MRI=magnetic resonance
imaging; PAH=pulmonary arterial hypertension; RHC=right heart catheterization;
RSVP=right ventricular systolic pressure
Other Exclusion Criteria
1. Prior treatment with cellular immunotherapy (eg, CAR T) or gene therapy product
directed at any target.
2. 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.
3. Positive serology for human immunodeficiency virus (HIV).
4. Primary immunodeficiency.
5. History of other autoimmune disorders other than the target disease requiring
immunosuppressve therapies.
6. 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.
7. Subjects who have central nervous system manifestations of the target disease
condition i.e., Idiopathic inflammatory myopathy, Diffuse cutaneous systemic
sclerosis, SLE, ANCA-associated vasculitis.
8. Impaired cardiac function or clinically-significant cardiac disease including:
a. Unstable angina or myocardial infarction or coronary artery bypass graft (CABG)
within 6 months prior to leukapheresis.
b. New York Heart Association (NYHA) stage III or IV congestive heart failure. c.
History of clinically significant cardiac arrhythmia (eg, ventricular tachycardia),
complete left bundle branch block, high-grade atrioventricular (AV) block.
d. History of severe ischemic or nonischemic cardiomyopathy. e. Left ventricular
ejection fraction (LVEF) <45% as assessed by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan (performed =8 weeks of leukapheresis).
9. 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.
10. 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. Thromboembolic event within 6 months prior to enrollment
11. 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.
12. Major surgery planned within 4 weeks prior to leukapheresis or planned within 4 weeks
after KYV-101 administration. For surgery planned after 4 weeks post KYV-101
administration, discuss with the sponsor investigator.
13. Contraindications or life-threatening allergies, hypersensitivity, or intolerance to
KYV-101 or its excipients, including dimethyl sulfoxide; or to cyclophosphamide or
fludarabine, or to tocilizumab.
14. Pregnant or breastfeeding; or plans to become pregnant or breastfeed, or father a
child within 1 year after receiving the KYV-101 infusion.
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