A Phase 3, Randomized, Double-blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of QPI-1002 for Prevention of Delayed Graft Function in Recipients of a Donation After Brain Death Older Donor Kidney Transplant

See protocol p23 - 36

1.1 Drug Product and Proposed Indication
QPI-1002 is a nuclease-resistant, synthetic double-stranded RNA oligonucleotide
designed to temporarily inhibit the expression of the pro-apoptotic gene, p53,
via activation of the RNA interference (RNAi) pathway. QPI-1002 has been
evaluated in a large Phase1/2 study:
*Controlled, Randomized Prospective, Double-Blind, Multicenter Phase1/2,
Dose-Escalation Study of the Safety, PK, and Clinical Activity of I5NP for
Prophylaxis of Delayed Graft Function in Patients Undergoing Decreased Donor
Kidney Transplantation* (QRK006).
QPI-1002 is being developed for reduction in the incidence and severity of
delayed graft function (DGF) in patients receiving renal transplants.

1.2 Nonclinical Studies
QPI-1002 is rapidly cleared from the plasma and accumulates to appreciable
levels only in the kidney. Following IV administration of QPI-1002, the
majority of the drug is cleared rapidly from the plasma by kidney filtration
and a small proportion is reabsorbed by the proximal tubules, with the rest
being excreted in the urine. Two-photon microscopy studies indicate that
QPI-1002 uptake by the kidney occurs mostly through re-absorption of QPI-1002
from the glomerular filtrate. The results of the nonclinical toxicology program
indicated that there are no significant issues that would preclude evaluation
of IV administration of QPI-1002 in humans. The nonclinical studies are
described in the Investigator*s Brochure.

1.3 Background of Disease:
Role of p53 and Donor Age The etiology of DGF appears to be primarily related
to ischemia-reperfusion (IR) injury.
Renal tubular epithelial cell dysfunction and apoptotic cell death are the
hallmarks of this process.[8] The expression of p53 is upregulated within 24
hours of injury in the rat IR model of acute kidney injury.[9] Activation of
the pro-apoptotic p53 protein was found to be a reliable marker for cellular
damage in human renal biopsies.[10] Increased p53 protein was also identified
in *zero hour* human kidney biopsies from deceased donors whose recipients had
DGF post-transplant.
No significant increase of p53 in living donors or deceased donor transplant
recipients without DGF was found.[11]
Following ischemic injury, proximal tubular cells (PTC) die in a p53-dependent
manner[12] or enter a p53-dependent G2 type of cell cycle arrest, do not
proliferate effectively, and begin secreting pro-fibrotic factors. This favors
fibroblast proliferation and fibrosis rather than regenerative type of wound
healing.[13] These early pro-fibrotic events following acute renal injury
appear to contribute to late outcomes such as chronic allograft nephropathy, as
demonstrated in animal models and human histological studies.[13-15] The
rationale for temporary therapeutic inhibition of p53 activity for amelioration
of DGF following kidney transplantation is thus two-fold. First, by blocking
p53-dependent apoptosis, it may afford
PTC the opportunity to repair their cellular damage and avoid massive cell
death in response to the injury, thus preserving the organ integrity and
functionality.[16] Secondly, blocking p53-dependent prolonged G2 arrest may
favor regenerative rather than fibrotic type of renal wound healing. In
accordance with this concept, preclinical renal transplant models with an
analogue of QPI-1002 have demonstrated efficacy in reducing injury.[17] In
kidney transplant patients, the rationale for the temporary inhibition of p53
expression by QPI-1002 is that it affords kidney cells time to repair cellular
damage and therefore avoid induction of apoptosis. Cells that are too damaged,
or that have accumulated deleterious mutations, are later eradicated when the
effects of QPI-1002 have subsided and p53 expression levels return to
normal.[18] In rat kidneys, p53 expression levels returned to normal between
2-3 days after intravenous administration of a rat analogue of QPI-1002.
Another clinically relevant attribute observed in the preclinical studies was
that treatment with siRNA targeting p53 could be administered up to 4 hours
after the ischemic reperfusion injury.
Recent preclinical data also indicate that p53 activation in
ischemia-reperfusion injury is greater in older kidneys[19,20] (Figure 1-1).
Thus, treatment of recipients of older kidneys with a p53 inhibitor is expected
to yield a greater beneficial effect than in recipients of younger donor organs.
Donor organ age has a direct impact on outcomes in renal transplantation. Due
to the growing disparity between the numbers of candidates awaiting
transplantation and available donor organs, the use of kidneys from older
donors, such as extended criteria donors (ECD) have been used.[21] Patients who
receive ECD kidneys exhibit higher rates of DGF, experience longer lengths of
stay during the transplant hospitalization, and are also readmitted more
frequently thereafter than those receiving grafts from standard criteria donors
(SCDs).[22] In a recent review of the United Network of Organ Sharing (UNOS)
database, the incidence of DGF in ECD kidneys was 36% compared to 24% for
non-ECD kidneys.[23] Concerns over risk of DGF development in older kidney
grafts affects medical decision-making and contributes to higher organ discard
rates. Donor age has been suggested to be the most potent donor risk factor and
a surrogate measure of kidney quality for physiologic reasons, including
increased comorbidities and greater vulnerability to ischemic injury.[24]
Published data show a direct correlation between increasing kidney donor age
and organ discard rates.[25]

1.4 Background of Disease: DGF Severity
In a recent review, eighteen different clinical definitions of DGF were
identified in literature published since 2000, reflective of a lack of
consensus within the transplant community regarding this condition.[2] Ten
different methods to diagnose or identify DGF were also noted, including
several different approaches to the assessment of the rate of recovery of renal
function following reperfusion of the allograft.[24,26] Efforts to assess acute
kidney injury and function are confounded by a number of clinical variables,
including the timing of pre-transplant dialysis in relation to transplant
surgery, and intra- and post-operative management of the patient. The endpoints
used in DGF studies can be grouped into two categories: those based upon the
need for dialysis and those based upon the rate of recovery of renal function
following transplantation. Non-dialysis definitions of DGF that have been
proposed include:
1) DGF defined as present if serum creatinine levels increased, remained
unchanged, or decreased less than 10% per day for three consecutive days in the
first week after transplantation[3]; 2) a 24 hr urinary creatinine excretion <
1000 mg during the first postoperative day[4]; 3) a length of time of > 6 days
needed to achieve a level of renal function corresponding to a creatinine
clearance > 10 mL/min[27]; and 4) in patients not receiving dialysis, a serum
creatinine reduction ratio on Day 2 versus Day 1 (SCRR2) < 30% (nondialysis
DGF, nd-DGF).[28] DGF is most commonly defined as the need for dialysis within
the first seven days after transplantation, as used by the UNOS, which has been
shown to be associated with poorer graft function and survival.[2]
While the simple dichotomy of an incidence of dialysis-based endpoints such as
the UNOS endpoint has had predominant use in clinical trials, it is unable to
discriminate between clinically important aspects of DGF, such as the
difference between a short course of dialysis to support a patient during DGF
versus a long course. Recently, data have been presented that support a more
discriminating functional endpoint that is less subjective and less variable
than the decision to dialyze a patient in the first week post-transplant,
allowing prediction of outcomes based on the amount of post-transplant
dialysis. This endpoint, known as DGF severity, is defined as the number of
dialysis sessions required immediately posttransplant.[29-32] Schnuelle et al.,
evaluated 300 consecutive DBD transplants performed at a single center in
Germany from 1998 to 2005.[32] It was observed that there was a significant
relationship between both duration of dialysis in days and duration measured as
dialysis session counts and graft survival.
Marek et al., evaluated outcomes of three groups based on need for dialysis: 1)
less than 7 days (n = 52); 2) 7-14 days (n = 13; and 3) > 14 days (n = 18).
Creatinine clearance was significantly different among the three groups at 30
days (42.5, 33.8, and 20 mL/min, respectively, p < 0.001) and at 1 year (56.7,
49.2, and 37.3 mL/min, respectively, p = 0.031). A multivariate regression
analysis identified time needed on dialysis as a significant predictors of
creatinine clearance at 1 year.[31] Buchanan et al., analyzed data from the
U.S. Renal Data System (USRDS).[30] Graft survival rates varied significantly
based on post-transplant dialysis utilization with the worst outcomes occurring
in those with DGF and requiring dialysis beyond the first week posttransplant.
Akkina et al., analyzed the incidence and clinical correlates of DGF (defined
as need for dialysis in the first week after transplant) and long-term outcomes
from 5072 adult kidney only transplants performed at 2 centers from
1984-2006.[29] The severity of DGF, as defined by the number of dialysis
treatments, was associated with graft failure. Short DGF (1*2 dialysis
treatments) was associated with a 27% higher risk of graft failure. Prolonged
DGF (* 3 dialysis treatments) was associated with an increased risk of graft
failure (51%). Schneulle et al., also showed that DGF requiring > 2 dialysis
treatments (N = 78) was associated with worsened graft survival compared to
both immediate function (N = 189) and DGF requiring only 1*2 dialysis
treatments (N = 43). These studies indicate that small increments in
post-transplant dialysis are associated with worsening clinical outcomes.[32]
The relationship between DGF risk score and severity of DGF was evaluated based
on data from the QRK006 Phase 2 study (placebo group) (Squiers et al., AJT
2015).[33] This relationship was quantified using the negative binomial model.
Using the DGF risk prediction model[34] based on the UNOS registry, association
of DGF risk and long-term graft failure, the relative impact of the severity of
DGF on long-term graft failure can be inferred. A change in dialysis sessions
per subject from 0.5 to 1.5 (range: 0.9 to 2.8), increased the risk of graft
failure and reduced 3 year graft survival by 9%. With a further increase in the
number of dialysis sessions to 6.6 sessions per subject (range: 3.5 to > 10 per
subject) a 16% decrease in graft survival at 3 years post-transplant was
observed compared with 0.5 dialysis sessions per subject.
This analysis, along with the other published studies[29-32] supports that not
just having DGF, but each additional dialysis session during early
post-transplant period, is clinically meaningful and is associated with poorer
outcomes following transplantation. The impact of each individual dialysis is
not unexpected as each dialysis carries a risk of transient ischemia, inducing
further damage to the kidneys, which have a variable degree of existing damage
and is also reflective of the degree of injury of the deceased donor organ.
Such analyses indicate that each additional dialysis session increases disease
burden, leading to poor graft survival, a clinically meaningful outcome for the
transplant patient and health care providers.
The mean number of dialysis sessions for patients treated with placebo in the
QRK006 Part B study was 2.3 sessions when including all patients (assigning a
value of 0 to patients who did not develop DGF) and 4.6 when only including
patients who experienced DGF. Reducing these values by 40% (the percent
decrease used to power the study) would reduce the number of dialysis sessions
by approximately 0.92 when including all patients by 1.84 dialysis sessions
when only including patients who experienced DGF. Both of these reductions are
well within the range predicted by the literature and by the DGF risk
prediction model to be important in predicting long-term outcome. Even lesser
reductions in the range of 30% would be expected to yield clinically
significant improvements on long-term outcome.

1. To determine the efficacy of QPI-1002 to reduce the incidence and severity
of delayed graft function in comparison to placebo in recipients of a donation
after brain death (DBD) older donor kidney.
2. To assess the safety and tolerability of QPI-1002 in comparison to placebo
when administered to recipients of a DBD donor kidney.

This is a Phase 3 randomized, placebo-controlled, double-blind, multi-center
trial stratified by donor age (45-59 years vs * 60 years) and by region to
evaluate the reduction in incidence and severity of delayed graft function with
kidney allografts from DBD donors who were at least 45 years of age.

This is a single dose treatment protocol. Subjects who meet all eligibility
criteria will be randomized 1:1 within 48 hours prior to transplant surgery to
receive a blinded single infusion of either QPI-1002 (10mg/kg) or placebo.

See IB - 5.5 Evaluation of the Benefit-Risk Ratio
Unblinded review by the Sponsor and DSMB of the Phase 1 safety data for
QPI-1002 (AEs, ECGs, laboratory data) did not indicate the presence of any dose
related toxicity. From the Phase 2 study in DGF (N = 332), based on the
evaluation of safety in the QPI-1002 and Placebo treatment groups, the
cumulative frequencies and types of adverse events reported were those expected
among patients with ESRD undergoing deceased donor renal transplantation.
Events such as anemia, complications of kidney transplant and hyperkalemia are
expected during the perioperative period, in particular, with transplantation
of ECD kidneys and those SCD kidneys with prolonged cold ischemia times, where
DGF or slower recovery of graft function is more common.
The overall frequency and severity distribution of AEs was similar in both
treatment arms, and nearly all events (99.6%) were assessed by investigators as
not related, or unlikely to be related, to study drug.
As was observed for adverse events, the observed patterns of abnormal safety
laboratory results was typical of an adult ESRD population. This was seen in
terms of the generally moderate degree of reduction in blood hemoglobin levels,
the transient increase in WBC count as an acute phase reactant during the early
postoperative period, and the observed electrolyte and metabolic disturbances
and pre-transplant elevations in serum amylase and/or lipase. Variable, mild to
moderate, but transient elevations in hepatic transaminase levels were observed
in both treatment groups and did not differ significantly between them. None of
these elevations were associated with de novo elevations in serum total
bilirubin, and there were no cases identified, by individual investigators or
by the Sponsor, that met the Hy*s Law Criteria for potential drug-associated
hepatotoxicity. Indices of pancreatic function, notably serum amylase and
lipase levels, tended, in some cases, to increase perioperatively for reasons
that remain unclear. However, the elevations were always transient and the
magnitude, as reflected by changes in mean and median blood levels, was similar
in the QPI-1002- and Placebo treatment groups.
In both treatment arms, the cumulative rates of acute rejection at 6 months
post-transplant* 15.6% and 15.9% in the QPI-1002 and Placebo groups,
respectively, were consistent with published rates of rejection of high risk
kidney transplants.[72]
On the basis of the single SAE reported as related (Myocardial Infarction) in
QRK006 Part B, the Sponsor examined the events reported in the cardiac SOC for
evaluation of potential signals, as well as the Embolic and Thrombotic event
SMQ. Both serious and non-serious events at the SOC and SMQ level and PT levels
included in the SOC and SMQ were similar between treatment groups and no safety
signal was identified. Additional review of events corresponding to nonclinical
toxicology findings was performed post hoc.
An equal number (n = 89) of patients in each treatment group reported events
corresponding to the gastrointestinal SOC, with no events of gastric ulceration
reported so there was no clinical events, and no suggestion of a safety signal,
corresponding to the non-clinical reports of erosion/ulcers of the stomach
following QPI-1002 treatment. No adverse events that would correspond to thymic
hemorrhage or lymphoid hyperplasia as seen in the nonclinical toxicology were
reported, and no PTLD was reported in the study.
The overall frequency and type of AEs of special interest including rejection,
serious infections such as those associated with CMV, and BK virus, and
malignancies reported were typical for the population of ESRD patients under
study and did not differ between treatment groups. Over the time period of the
study for which data is available (2008-20012), graft loss or death was
reported in 4.8-6.3% of deceased donor kidneys overall (2012 SRTR) and the 6-
month allograft and patient survival rates were similar to those in the
published literature[72] and did not differ between the treatment groups.
In summary, when administered to ESRD patients undergoing transplantation of
expanded criteria donor kidneys, the single-dose, IV bolus administration of
QPI-1002 demonstrated a safety profile comparable to that of isotonic saline
placebo. There have been no identified or validated safety signals from the
administration of QPI-1002 and thus no defined risks associated with QPI-1002
compared to placebo control in the populations evaluated to date. The benefit *
risk of QPI-1002 is acceptable for further investigation in the reduction in
the incidence and severity of delayed graft function (DGF) among recipients of
kidney transplant from deceased donors, and for the prevention of acute kidney
injury (AKI) in patients undergoing cardiovascular surgery.