Clazakizumab in Highly-HLA Sensitized Patients Awaiting Renal Transplant

This is a single center, Phase I/II, open label single-arm exploratory study. The trial will
primarily examine the safety and tolerability of clazakizumab given after consented and
eligible patients begin desensitization therapy to achieve HLAi renal transplantation at
Cedars-Sinai Medical Center. 10 subjects (ages 15 to 75) who are highly-HLA sensitized (HS)
as determined by the cPRA ≥50% and are eligible for desensitization will be evaluated. All
patients will be accrued from the renal transplant program at Cedars-Sinai Medical Center.
Once desensitization begins, anti-HLA antibodies will be assessed which are associated with
ABMR and/or graft loss. HLA antibodies will be detected using solid phase assay systems
currently utilized at the Cedars-Sinai Medical Center HLA Laboratory. These anti-HLA
antibodies may result naturally or from previous pregnancy, transfusions, or prior
transplants. Patients treated with clazakizumab x 6 doses for desensitization will have blood
sampling for HLA antibodies, and other monitoring blood samples as well as immunologic
studies as outlined. If patients receive an HLAi transplant during the study, participants
will receive the standard post-transplant immunosuppressive protocol, and clazakizumab 25 mg
SC Q4W X 6 doses with immune monitoring as indicated.

Immune monitoring in blood samples for Treg, Tfh, Th17 and B-cell subsets as well as IL-6 and
CRP monitoring will be carried out at the Cedars-Sinai Transplant Immunology Laboratory.

Patients identified as study participants will be HS and listed for HLAi renal
transplantation at Cedars-Sinai Medical Center. Cedars-Sinai is a major U.S. desensitization
center and performs ~80 HLAi renal transplants per-year. ~ 100 new HS patients are referred
to Cedars-Sinai each year as potential candidates for desensitization. Eligible patients
entering the study will initially receive PLEX (5-7 sessions) + IVIG and receive clazakizumab
25 mg SC one week post-IVIG. If no safety/tolerability/efficacy issues are observed after the
initial dose, patients will receive 5 additional injections Q4W. If patients receive an HLAi
transplant, clazakizumab will be continued for 6M post- transplant at 25mg SC Q4W for 6 doses
(starting at Day 5 post-transplant). A protocol biopsy will be performed at 6M
post-transplant to assess the allograft for evidence of ABMR, including C4d staining and TG
using Banff 2015 criteria. Patients will continue another 6 doses over 6 months if
improvements are seen after the 6th dose of clazakizumab. Patients who develop evidence of
persistent allograft dysfunction may have non-protocol biopsies for cause. Patients who
receive 12 doses of clazakizumab post-transplant will receive a 12M protocol biopsy. In the
event a patient does not show improvement after receiving 6 doses of clazakizumab, no further
treatment will be given and the patient will return at Day 365 for a final study visit. All
subjects will be evaluated on an intent-to-treat basis. The subject accrual rate will be
limited to no more than 1-2 subjects per month in the initial three months to assure safety
to all subjects. Repeat laboratories will be performed at the completion of clazakizumab
therapy to determine effect on levels and correlation with any potential events.

The subjects will be followed to determine if the use of clazakizumab for desensitization in
this high risk transplant population is safe and without infectious risks. In addition, the
investigators will determine the effects of clazakizumab treatment on HLA antibodies in
efforts to improve access to HLAi transplants for these individuals. The investigators have
previously reported acceptance criteria for HLAi kidney transplants. Renal biopsy assessments
will be performed at 6M (per protocol) and 12M (for those who received 12 doses of therapy).
The investigators will assess the transplanted patients to determine the number who sustain a
viable and functioning kidney allograft as well. All subjects will be evaluated on an
intent-to-treat basis. The subject accrual rate will be limited to no more than 1-2 subjects
per month in the initial three months to assure safety to all subjects.

Inclusion Criteria:

1. Age 15-75 years at the time of screening.

2. HS patients (cPRA≥50%) awaiting DD or LD kidney transplant on the UNOS list.

3. Previous history of pregnancies, blood transfusion and/or renal transplant.

4. Subject/Parent/Guardian must be willing to participate fully with study requirements.

5. Subject/Parent/Guardian must be able to understand and provide informed consent.

6. Pneumococcal vaccinated

7. Negative Tuberculin (ppd) placement result or negative Quantiferon TB gold results

Exclusion Criteria:

1. Multi-organ transplant (e.g. kidney and pancreas)

2. Intolerability to clazakizumab or other IL-6 inhibitor therapies

3. Lactating or pregnant females.

4. Women of child-bearing age and male partners of women of child-bearing age who are not
willing or able to practice FDA-approved forms of contraception during study and for 5
months after last dose.

5. HIV-positive subjects.

6. Subjects who test positive for HBV by HBVeAg/DNA or HCV infection [positive Anti-HCV
(EIA) and confirmatory HCV RIBA].

7. Subjects with latent or active TB. Subjects must have negative Quantiferon TB gold
test result.

8. Recent recipients of any licensed or investigational live attenuated vaccine(s) within
two months of the screening visit

9. A significantly abnormal general serum screening lab result defined as a ANC <2000,
platelet count < 100 X 103/ml, an SGOT or SGPT > 1.5X upper limit normal.

10. Individuals deemed unable to comply with the protocol.

11. Subjects with active CMV or EBV infection as defined by CMV-specific serology (IgG or
IgM) and confirmed by quantitative PCR with or without a compatible illness.

12. Use of investigational agents within 4 weeks of participation.

13. History or active Inflammatory Bowel Disease or Diverticular Disease or
gastrointestinal perforation

14. Recent infection (within past 6 weeks of screening) requiring any antibiotic use
(oral, parenteral or topical).

15. Present or previous (within 5 years) malignancy except for basal cell carcinoma, fully
excised squamous cell carcinoma of the skin or non-recurrent (within 5 years) cervical
carcinoma-in-situ