Dosing Regimen of Eculizumab Added to Conventional Treatment in Positive Crossmatch Deceased Donor Kidney Transplant

A strongly positive crossmatch has long been considered an absolute contraindication to
kidney transplantation and most patients with anti-HLA antibody never were able to receive a
kidney transplant. Over the past decade, significant progress has been made in overcoming
early antibody-mediated renal allograft injury. Despite our best efforts, transplantation in
these patients is still complicated by a high rate of acute humoral rejection.

While we have successfully transplanted more than 250 patients with DSA using living donors,
applying these protocols to recipients of deceased donors has been problematic. This
primarily is due to the fact that in contrast to living donation, the timing of a deceased
donor kidney transplant cannot be planned. This leads to inadequate time to perform the
multiple pretransplant plasmapheresis treatments needed to achieve a safe level of DSA at
transplant. Thus, there is a major unmet need to develop therapy that will allow for the
successful transplantation of deceased donor kidneys in recipients who have DSA.

- At the time of deceased donor kidney transplantation, patients will undergo one
plasmapheresis prior to surgery.

- Patients will be given 1200 mg of eculizumab intravenously over 30 minutes, 1 hour prior
to surgery.

- Patients will be given 900 mg of eculizumab on Day 1 post-transplant.

- Patients will then be given 900 mg of eculizumab weekly through 4 weeks post-transplant

- At week 4, patients will be assessed for DSA. Patients with total DSA normalized values
<5000 will stop eculizumab treatment. Patients with total DSA normalized values >5000
will continue eculizumab treatment every 14 days from week 5 through week 9. The dose
will be increased to 1200 mg and dosing will now be every 2 weeks instead of weekly.
Similar "discontinuation assessments" will be performed at week 9, 26, 39 and 52.

Inclusion Criteria:

- 18 years of age

- Has end stage renal disease (ESRD) and is to receive a kidney transplant from a
deceased donor (DD) to whom he/she has a positive T or B cell crossmatch >200 at the
time of transplant and DSA demonstrated by solid phase assays.

- Willing to comply with the protocol

- Females of child-bearing potential must have a negative pregnancy test (serum β-HCG)
and sexually active females must agree to use a reliable and medically approved method
of contraception

- Willing and able to give written informed consent

- Vaccinated against Neisseria meningitides (quadrivalent vaccine), Pneumococcus and H.
influenzae at least two weeks prior to beginning desensitization

Exclusion Criteria:

- Unstable cardiovascular condition

- Previous splenectomy

- Active bacterial or other infection which is clinically significant in the opinion of
the investigator

- Known or suspected hereditary complement deficiency

- Participation in any other investigational drug study or was exposed to an
investigational drug or device within 30 days of randomization

- Pregnant, breast-feeding, or intending to conceive during the course of the study,
including a one month follow-up period after drug discontinuation

- Known hypersensitivity to the treatment drug or any of its excipients

- History of illicit drug use or alcohol abuse within the previous year

- History of meningococcal disease

- Medical condition that, in the opinion of the investigator, might interfere with the
patient's participation in the study, pose an added risk for the patient, or confound
the assessment of the patient (e.g. severe cardiovascular or pulmonary disease)