A Three-Part, Multi-Centre, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Sequential Adaptive, Phase II Study to Evaluate the Safety, Tolerability and Efficacy of OPN305, a Humanised Monoclonal Antibody that Blocks Toll-Like Receptor 2, in Renal Transplant Patients at High Risk of Delayed Graft Function

OPN305 is a humanised IgG4 monoclonal antibody (MAb) against Toll-like receptor
2 (TLR2) that has orphan medicinal product designation from the European
Medicines Agency (EMA) for prevention of Delayed Graft Function (DGF) following
solid organ transplantation. A similar designation has been granted by the Food
& Drug Administration in the USA in December 2011. DGF, for this study, is
defined as the post-operative failure of a transplanted kidney that requires
dialysis in the 7 days following transplantation. DGF management increases the
associated health-economic costs.
DGF in the first week following transplantation has been associated with a
higher risk of graft loss at 1 year. OPN305 may reduce the rate of DGF by
reducing the innate immune response following ischaemic-reperfusion (I-R)
injury of the donor graft. The inhibitory effect of the anti-TLR2 antibody
OPN305 on inflammatory signals resulting from I-R injury has been proven in
murine and porcine model studies. Moreover, the anti-inflammatory properties of
OPN305, in combination with immunosuppressive drugs, may contribute directly to
the reduction of allograft loss. Therefore, OPN305 may have promise as a new
treatment for renal allograft recipients as it may reduce post-transplant Acute
Tubular Necrosis (ATN), control inflammation caused by I-R injury in the
transplanted organ and help prevent allograft rejection by an accessory
immunosuppressive effect.
A randomised, double-blind, placebo-controlled, dose-escalating Phase I study
to assess the safety and tolerability of single ascending IV doses of OPN 305
in healthy subjects has been completed, Forty-one male subjects were enrolled
in this study; 29 received one IV dose of OPN305 and 12 received placebo. The
most frequently reported adverse events (AE) in subjects receiving OPN305 were
nasopharyngitis, headache, abdominal pain and dizziness. No dose relationship
was apparent for the incidence of these AEs. There were no severe or fatal AEs
reported.
Two placebo subjects reported 3 serious AEs; one subject experienced a
cerebrovascular accident and carotid artery dissection and another suffered a
ligament rupture.
Pharmacokinetic and pharmacodynamic data have shown:
*Up to 100% TLR2 receptor occupancy for *14 days has been achieved at all
dosages tested
*The ex vivo whole blood assays demonstrated inhibition of IL-6 stimulation
release following ex vivo stimulation by TLR2 agonists after OPN-305
administration
*The pharmacokinetics of OPN305 are proportional to dose
*No neutralising antibodies have been detected

Primary Objectives:

*Phase 0: To determine the receptor occupancy of OPN-305 1.5mg/kg in patients
receiving an ECD, DCD or SCD(CIT>18h) kidney transplantation and to verify the
doses of OPN-305 to be used in Part A of the study.

*Part A: to select the optimal single IV dose of OPN-305 for Part B of the
study in ECD/DCD/SCD(CIT>18h) kidney transplantation patients. The primary
endpoint for this objective is:
o The incidence of DGF on Day 7 defined as the need to initiate dialysis in
the first 7 days post-transplantation (dDGF) in patients receiving an
ECD/DCD/SCD(CIT>18h) kidney transplantation
Secondary endpoints that will contribute to the decision will be:
o Functional DGF, defined as a failure of the serum creatinine to decrease
by at least 10% daily on 3 successive days during the first week post
transplantation (fDGF). This endpoint applies only to patients who do NOT
receive dialysis in the first 7 days post-transplantation. A creatinine
decrease in patients receiving dialysis can be an outcome of dialysis and not
an indicator for the absence of fDGF.
o Receptor occupancy.

*Part B: to extend the evaluation whether the optimal dose of OPN-305 from Part
A can reduce the incidence of DGF
*Parts A and B: to evaluate whether OPN-305 can reduce the incidence of DGF
defined as the initiation of dialysis in the first 7 days following
transplantation (dDGF)

Secondary Objectives (Phase 0)
To determine the pharmacokinetics and safety of a single-dose IV administration
of OPN-305 1.5mg/kg

Secondary Objectives (Part A only)
*To assess the safety and pharmacokinetics of different doses of OPN305 in
patients undergoing ECD/DCD/SCD(CIT>18h) kidney transplantation.

Secondary Objectives (data from Parts A and B Combined)
To assess the effect in patients receiving an ECD, DCD or SCD(CIT>18h) kidney
transplantation of single IV doses of OPN-305 on:
*Graft function
*Composite endpoint
o Graft loss
o Incidence of biopsy-proven kidney allograft rejection (biopsies will be
done on a for-cause basis only)
o Patient death
o Lost to follow-up*Functional DGF (fDGF) in patients who do not receive
dialysis in the first 7 days following transplantation
*Time to biopsy-proven kidney allograft rejection (biopsies will be done on a
for-cause basis only)
*Functional DGF (fDGF) in patients who do not receive dialysis in the first 7
days following transplantation
*Time to first dialysis and DGF duration. DGF Duration is defined as;
o For dDGF, it is the time from the end of the transplantation surgery until
completion of the final dialysis for DGF
o For fDGF, it is the time from transplantation to the time when creatinine
starts to fall by >10% without dialysis
*Incidence of dialysis between Days7 and 30.
*Incidence of primary non-function.
*Blood and urine biomarkers for acute kidney injury (AKI)
*Duration of initial hospitalisation and the duration and reason for subsequent
hospital re-admissions
*Safety
- Incidence of infections by type and actual organism.

This is a three-part, group sequential, adaptive, Phase II study to assess the
safety and to evaluate the clinical effect of single intravenous doses of
OPN305 on renal function in patients scheduled to receive a kidney
transplantation from:

*An extended criteria donor (ECD) (subject to a limit of 50% of all patients in
Parts A and B) defined as:
o Donor *60 years of age
o Donor 50-59 years of age with all three of the following criteria present:
-Death due to cerebrovascular accident
-Pre-existing history of systemic hypertension
-Terminal serum creatinine *1.5mg/dL (132.6µmol/L)

OR
*Donation after circulatory death (DCD) - previously *Donation after Cardiac
Death* and *Non Heart Beating Donors*

OR
*A standard criteria donor (SCD) with a cold ischaemic time (CIT) greater than
18 hours at randomisation in Parts A and B (SCD[CIT>18h])

Note 1: SCD Definition; An SCD donor is;
*Any donor <50 years of age who is not a DCD and has a serum creatinine
<2mg/dL (176.9µmol/L)
*Any donor 50-59 years of age who has none or only one of the following
criteria (hypertension, cerebro-vascular accident [CVA] or creatinine >1.5mg/dL
but < 2mg/dL), i.e.: none or only one of the following;
oAged 50-59 with a creatinine <2mg/dL (176.9µmol/L) who has no history
of hypertension and died for reasons other than a CVA;
OR
oAged 50-59 who died due to a CVA with creatinine <1.5mg/dL (132.6µmol/
L) and no history of hypertension;
OR
oAged 50-59 with a history of hypertension who died for reasons other
than CVA (e.g., brain trauma)and creatinine < 1.5mg/dL (132.6µmol/L)

Note 2: Maximum CIT for all Donor kidney types: The patient should not be
randomised if the CIT time for any kidney is expected to be greater than 30h at
the start of surgery. If the patient is randomised and there are unforeseen
delays at the time of surgery an additional 2 hours CIT will be permitted. If
the CIT at the outset of surgery is more than 32 hours the patient should not
be dosed with OPN-305/placebo. The start time for measurement of CIT is the
time of clamping of the donor kidney.


Prior to the initiation of the double-blind, randomised study an open-label,
single arm, pilot (Phase 0) pharmacokinetic/pharmacodynamic (PK/PD) evaluation
of single-dose intravenous (IV) pharmacokinetic variables over 28 days,
receptor occupancy (RO) over 14 days and safety over 28 days following a
single IV dose of open-label OPN-305 1.5mg/kg in 8 patients was done.

The data generated in Phase 0 were used to select the doses of OPN-305 for Part
A of the double-blind, randomised study: OPN-305 0.5, 1.5 and 5mg/kg IV.

The data from patients in Phase 0 will not be used in the main Phase II study.

Part A:
This will be a single-infusion, dose-confirmation part of the study to
determine the optimal IV dose to be studied further in Part B. The rationale
is to confirm whether there is a difference in dose required should receptor
upregulation require a higher dose for the same occupancy period and to assess
if there is a trend to better efficacy based on the primary endpoint. Three IV
doses of OPN305 will be compared to IV placebo and will be randomised 1:1:1:1.
An independent Data and Safety Monitoring Board (DSMB) will assess safety,
review the PK/PD and efficacy data from Part A, and decide on the optimal dose
to be used in Part B.
Patients who give written informed consent will be screened for eligibility and
randomised to one of the treatment groups. The treatment arms in Part A will be
as follows:
*OPN-305 0.5, 1.5 or 5.0mg/kg
AND
*Matching placebo

There will be 144 patients randomised in Part A; 36 patients in each of the 4
dose groups.
At the end of Part A, the DSMB will decide which active dose to use in Part B
based on a review of safety, PK/PD and efficacy data. In the event that it is
not possible to distinguish between the doses, the lowest effective dose will
be selected. At the end of Part A also, the assumptions for the primary
endpoint will be reassessed and a sample re-estimation, based on conditional
power, may be required. A decision on futility will also be made at this time.

Part B: The single IV dose chosen by the DSMB from Part A will be used in Part
B to further assess the effect of OPN305 on DGF versus placebo in the first 7
post-operative days in patients undergoing ECD/DCD/SCD(CIT>18h) kidney
transplantation. The primary endpoint will be the proportion of patients who
require dialysis during this time. The sample size for the combined optimal
dose in Part A plus Part B is based on a superiority design (OPN305 versus
Placebo). Data from patients in Part A who received the dose of OPN305 used in
Part B as well as the placebo patients from Part A and all of the patients from
Part B will therefore make up the efficacy analysis database for the study.
126 Patients will be randomised in a double-blind manner in Part B; 63 patients
will be randomised to a single IV dose of OPN305 and 63 to placebo. Therefore,
a total of 270 patients will be enrolled into the double-blind parts of the
study (144 in Part A and 126 in Part B).

NA