The De-novo Use of Eculizumab in Presensitized Patients Receiving Cardiac Transplantation

The growing proportion of sensitized cardiac recipients presents an additional challenge to
the transplant practitioner attempting to minimize the occurrence of antibody mediated
rejection (AMR). Patients pre-exposed or "sensitized" to antigen exposing events (i.e.: blood
transfusions, multiple pregnancies, prior organ transplantations, ventricular support
devices) are more likely to both possess preformed and develop de-novo antibodies. Sensitized
patients with panel reactive antibodies > 25% are at risk for increased mortality after heart
transplantation.

A central component of antibody-mediated cell injury is complement activation. The inhibition
of terminal complement activation may be the missing link to decreasing possibly both
complement-mediated AMR and cellular rejection (CR) by inhibiting both the inflammatory
effects of both circulating antibodies and cytokine induced cell death.

Eculizumab is a monoclonal antibody that specifically binds to complement protein C5 with
high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation
of the terminal complement complex C5b-9. By this mechanism, Eculizumab (Soliris®) inhibits
terminal complement mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria
patients.

This study is a non-randomized, open-label, investigator-initiated safety and efficacy trial
investigating the de-novo use of Eculizumab alongside conventional therapy to prevent
antibody mediated rejection. The duration of the study will include an open enrollment period
and at least 12 months of follow-up (post-transplant). The trial will enroll a total of 10
"sensitized" patients with a panel reactive antibody score greater than 70%, who are not
previously or currently enrolled in another ongoing trial. The use of Eculizumab will be
un-blinded to all study and research practitioner participants. A historical cohort of 10
additional patients will also be utilized for comparison.

Inclusion Criteria:

- Patient is ≥ 18 years of age.

- Patient has a panel reactive antibody (PRA) ≥ 70% at any time prior to screening.

- Patient is considered compliant and intends to be available for a minimum follow-up
study period of 1 year.

- Patient must be vaccinated against Neisseria meningitides at least 2 weeks prior to
receiving treatment therapy.

- Voluntary written informed consent must be obtained before performance of any
study-related procedure not considered routine medical care, with the understanding
that consent may be withdrawn by the subject at any time without prejudice to future
medical care.

- Female subject is either post-menopausal or surgically sterilized or willing to use
two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study and for up to 2 months after the last dose of study medication.

Exclusion Criteria:

- Donor or recipient age is < 18 years or > 75 years.

- Cold ischemia time is > 6 hours.

- Current clinical, radiographic, or laboratory evidence of active or latent
tuberculosis (TB), as determined by local standard of care.

- History of active TB within the last 2 years, even if treated.

- History of active TB greater than 2 years ago, unless there is documentation of
adequate treatment according to locally accepted clinical practice.

(Note: Patients at risk of TB reactivation preclude administration of conventional
immunosuppression, as determined by the study investigator and based upon appropriate
evaluation).

- Receipt of desensitization treatment with rituximab less than 2 weeks prior to therapy
and cluster of differentiation antigen 20 (CD20) count >2%.

- Receipt of a live vaccine within 4 weeks prior to study entry.

- Patients with current or recent severe systemic infections within the 2 weeks prior to
transplantation.

- Prior history of splenectomy.