Overview

QPI-1002 (teprasiran, I5NP) is a small interfering RNA (siRNA) therapeutic drug designed to reduce the incidence and severity of Acute Kidney Injury (AKI) and Major Adverse Kidney Events (MAKE) following cardiac surgery. It is also meant to reduce the incidence and severity of Delayed Graft Function (DGF) in kidney transplant patients. QPI-1002 works by silencing the p53 gene. It has been granted Orphan Drug and Fast Track Designations by the US Food and Drug Administration (FDA) and Orphan Drug Designation by the European Medicines Agency (EMA) for Delayed Graft Function.

Drug Product

QPI-1002 is a synthetic, chemically-stabilized, double-stranded siRNA designed to temporarily inhibit the expression of the cell death-inducing gene p53 by activating the RNA interference (RNAi) pathway. The compound is designed to allow high and specific RNAi activity while attenuating off-target and immunostimulatory effects.

Mechanism of Action and Non-clinical Studies

The p53 protein is activated by a variety of stresses, such as DNA damage, hypoxia, and oxidative stress. Once activated, it induces cell cycle arrest, cell senescence, or programmed cell death. The type of p53-induced damage depends on the severity of the stressful stimulus: cell death requires more substantial p53 activation compared to that necessary for cell cycle arrest. p53 is a known tumor suppressor gene; however, when activated in normal cells, it may lead to cell death and tissue failure, as seen following chemotherapy or radiotherapy, or in the context of Ischemia-Reperfusion Injury (IRI).
QPI-1002 is being developed based on a proprietary concept involving the temporary and reversible inhibition of p53 in normal cells as a therapy aimed to protect tissue, first described by Quark and collaborators at the University of Illinois, Chicago in 1999 (Komarov et al.1999, Science 10:285). When administered systemically, QPI-1002 specifically concentrates in the renal proximal tubular epithelial cells, the main cellular substrate of kidney IRI and the site of p53 activation. Following severe oxidative stress caused by IRI, QPI-1002 temporarily reduces the expression of p53, mitigating programmed cell death and allowing for repair of cellular damage, thereby preserving the integrity and function of the affected kidney tissue.

Intravenous administration of a p53-targeted siRNA significantly reduced AKI in several nonclinical models, including transient renal vessel pedicle clamp, partial aortic clamp, cisplatin-induced AKI, and warm and cold ischemia kidney transplant models (Molitoris et al, J Am Soc Nephrol. 2009; 20(8):1754–1764; Imamura et al, Cell Transplant. 2010; 19(12):1659-70).

Furthermore, QPI-1002 exhibited a favorable safety profile in non-clinical toxicology studies.

Acute Kidney Injury (AKI) in Cardiac Surgery

AKI is defined as an abrupt decrease in kidney function, regardless of the source of injury, which manifests in increased serum creatinine, or by decreased urine production, or both. Even mild, reversible AKI has important clinical consequences [KDIGO 2012 AKI Guidelines]. AKI is associated with poor long-term outcomes: a two-fold increase in mortality; a three- to four-fold increase in adverse kidney events leading to Chronic Kidney Disease (CKD) or End-Stage Renal Disease (ESRD) requiring dialysis; and a two-fold increase in cardiovascular events such as stroke or myocardial infarction [See et al., 2018; James et al., 2020].

AKI is a serious clinical condition which leads to complications in approximately 5% of hospital admissions and in up to 30% of admissions to intensive care units. In patients undergoing major cardiac surgery, AKI develops within hours to days following surgery as a result of ischemic conditions caused by reduced local blood flow to the kidneys during surgery and its restoration thereafter (reperfusion), leading to oxidative stress and IRI. More than 300,000 cardiac surgeries are performed in the U.S. annually with 40% or more of all cardiac surgery patients developing AKI. It is estimated that over $10 Billion are spent on AKI-related medical issues [Englberger et al., 2010; Hobson et al., 2009; Hobson et al., 2014 and Arora et al., 2012]. The 30-day mortality rate following the onset of post-surgical AKI is greater than 50% [Cardiorenal Med 2013; 3:178-199]. The prognosis among patients requiring dialysis due to AKI after cardiac surgery is poor, with an increased mortality risk exceeding 60% [Annals of Thoracic Surgery 93.1 (2012): 337–347].

The mitigation of AKI post cardiac surgery is an unmet medical need, with no specific treatment or prophylaxis available. Results of QRK209, a multinational, randomized, double-blind, placebo-controlled Phase 2 trial in subjects at high risk of AKI after cardiac surgery indicate that QPI-1002 has the potential to mitigate this devastating condition.

Delayed Graft Function in Kidney Transplant Patients

Kidney transplant is the best available long-term treatment solution for end-stage renal disease (ESRD) patients. While there are over 100,000 patients on the U.S. kidney transplant list, only less than 25% of waitlist patients undergo transplant due to a severe shortage of procured kidneys [Wey et al., 2017]. In July 2019, the US president has signed an Executive Order aiming to double the number of available kidneys for transplant by 2030.

DGF, defined as the need for dialysis within the first week after transplant, is one of the most common complications of deceased-donor kidney transplant. DGF appears to be primarily related to IRI [FDA Guidance for Industry: DGF, 2019] resulting from ischemia during organ procurement from the donor, preservation and initial steps of transplant surgery, and reperfusion following vascular reconnection in the recipient. IRI can lead to acute renal tubular epithelial cell dysfunction and cell death.

DGF is associated with poorer short-term and long-term outcomes: reduced graft function, and an increased need for dialysis; increased risk of acute rejection and a decreased graft survival; reduction in Quality-Adjusted Life Years (QALYs) [Yarlagadda et al., 2009; Incerti et al., 2018] and increased mortality. DGF is associated with a significant economic burden in both the short term and the long term due to extended hospital stays and costly patient management. It is an unmet medical need, with dialysis remaining the best available treatment.

Due to a severe shortage of kidneys for transplant, using marginal (e.g., with longer graft cold storage) and older kidneys is important for meeting growing organ demand. However, the risk for DGF is higher in these organs. Currently there are no FDA-approved therapies to mitigate DGF. Increasing kidney utilization remains an unmet medical need that, if addressed by therapeutic interventions such as QPI-1002, could potentially contribute to reducing the kidney transplant waitlist.

Clinical Studies

QPI-1002 was the first siRNA to be administered intravenously to humans and is being evaluated in multiple clinical trials across different clinical settings. The table below is a summary of these trials.

Indication Phase # of Subjects Key Assessments Status
AKI and (MAKE)
following cardiac surgery
Phase 1
(QRK002)
N=16 Safety, tolerability and pharmacokinetics Completed
Phase 2 (QRK209) N=341 Safety, DMPK, efficacy Completed
Phase 3 (QRK309) N=1,043 Safety, efficacy Ongoing
DGF
following deceased donor kidney transplant
Phase 1
(QRK006a)
N=40 Safety, tolerability and
Pharmacokinetics
Completed
Phase 2 (QRK006b) N=327 Safety, efficacy Completed
Phase 3 (QRK306) N=594 Safety, DMPK, efficacy Completed

 

During clinical trials the following results were reported for QPI-1002:

AKI/MAKE following cardiac surgery:

  • Reduction in the incidence of MAKE composite in the 90 days following cardiac surgery [29% relative risk reduction (RRR) vs. placebo, p=0.0235] in higher-risk patients
  • Reduction in the incidence of AKI in the 5 days following cardiac surgery [28% RRR vs. placebo, p=0.012]
  • Reduction in the severity [p=0.0065] and duration [p=0.0113] of AKI
  • Favorable trend for increased dialysis free survival and overall survival at one year vs. placebo
  • Well tolerated with a favorable safety profile as compared to placebo.

DGF after kidney transplant:

  • Reduction in DGF incidence [34-47% RRR vs. placebo, p<0.016] in high risk allografts
  • Reduction in DGF severity [51-64% RRR vs. placebo, p<0.03] in high risk allografts
  • Favorable trend for reduction in acute graft rejection at 6 months vs. placebo
  • Well tolerated with favorable safety profile as compared to placebo.

To date, over 600 subjects from completed clinical trials and over 500 subjects from the ongoing clinical trial have been exposed to the intended therapeutic dose of QPI-1002. No dose-limiting toxicities were reported for the compound in any of the clinical studies. The safety profile of QPI-1002 appears to be in line with expectations.

What’s Next for QPI-1002

The ongoing multinational, randomized, double-blind, placebo-controlled, Phase 3 QRK309 trial for prevention of AKI and MAKE90 in patients undergoing cardiac surgery has completed the recruitment of 1,043 patients; top-line data are expected in Q1/2021. Subject to study results, Quark is preparing for an NDA submission for the AKI indication.

A confirmatory, multinational, randomized, double-blind, placebo-controlled, Phase 3 QRK316 trial in ~150 kidney transplant patients for reduction in DGF incidence and severity has been designed based on FDA feedback. Subject to successful completion, the study is aimed to support NDA submission for the DGF indication.