Angion ANG-3777 prior data, multitargeted MOA well-placed to tackle DGF
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Angion’s ANG-3777 prior data, multitargeted MOA well-placed to tackle delayed graft function but faces uphill task in complex patient population

By Manasi Vaidya 11 May 2021 (Last Updated May 11th, 2021 16:10)

Angion Biomedica’s bid to treat delayed graft function (DGF) following kidney transplantation is strong with clinical signals and mechanistic potential.

Angion’s ANG-3777 prior data, multitargeted MOA well-placed to tackle delayed graft function but faces uphill task in complex patient population
Past Phase III attempts in this space, including Alexion Pharmaceuticals’ complement inhibitor Soliris, have aimed to prevent DGF and failed. Credits: Hospital man/Shutterstock.com.

Angion Biomedica’s bid to treat delayed graft function (DGF) following kidney transplantation is strong with clinical signals and mechanistic potential. However, patient heterogeneity makes predicting clinical success a challenge, experts said.

The Phase II data indicating the drug’s impact on achieving a standard urine output after kidney transplantation connect well with the ongoing Phase III primary outcome measuring kidney function. In the Phase III trial, the primary endpoint is measured at one year after the kidney transplant. While measuring efficacy over a longer period after kidney transplantation is clinically relevant, other factors can influence a patient’s well-being in the interim period, said one expert.

There is no FDA-approved therapy to treat DGF. Past Phase III attempts in this space, including Alexion Pharmaceuticals’ complement inhibitor Soliris (eculizumab), have aimed to prevent DGF and failed. However, ANG-3777 aims to treat DGF after it occurs, an approach experts found to be particularly rational.

The causes for ischemia reperfusion injury leading to DGF are varied in the kidney transplantation setting, and the state of the donor kidney plays a significant role. Different triggers for injury make it difficult to predict success with one therapeutic approach, and biomarkers to identify patient subsets are lacking. These caveats, combined with the history of past failures in the space, make it challenging to assess which therapy could show a clinically significant difference in a randomised study, experts said.

Results from the 253-patient, Phase III study are expected by YE21, as per the company’s 4Q20 results.

ANG-3777 is a hepatocyte growth factor (HGF) mimetic. It activates the HGF/c-MET pathway and is also being studied in Covid-19-associated pneumonia and cardiac-associated acute kidney injury. One analyst is confident about the company and views the Phase III DGF results as one of the catalysts earmarked for 2021. Angion Biomedica had an IPO in February this year and its market cap is $419.86m.

Phase II data sound though caveats for patient population

The Phase II results were clinically significant even thought it was a small study, said ANG-3777 investigator Dr Jonathan Bromberg, professor of Surgery and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore. A nephrology expert agreed, adding an improvement in estimated glomerular filtration rate (eGFR), which is a measure of kidney function, was also observed. At days 14 and 28, and at six and 12 months, an eGFR was higher in the ANG-3777 arm compared to the placebo arm (Bromberg, J., et al., Transplantation, 2021 Feb 1, 105(2), 443–450). Moreover, in the 28-patient, Phase II study, 83.3% of patients treated with ANG-3777 met the primary endpoint of 1,200cc urine for 24 hours by 28 days post-transplantation versus 50% on placebo (p=0.09). While urine output is not directly correlated to kidney function, it is sufficiently connected to note if the former it not high enough, the eGFR will not be high, said Bromberg.

The Phase III trial’s primary endpoint is measuring kidney function via eGFR rate at 365 days post-transplantation. The trend of looking at kidney function trajectory over one year instead of initial kidney function at a few weeks after transplantation is a recent one, said Bromberg.

With longer-term outcomes, other host factors can play a role in influencing efficacy measurement, said Dr Yasir Qazi, associate professor of Clinical Medicine, University of Southern California, Keck School of Medicine, Los Angeles. However, if the resolution of renal function is immediate, those kidneys also tend to have fewer complications, he added. Still, while prolonged DGF is linked to a high risk of rejection, it is still unclear whether rejection rates are lower in allografts due to faster recovered kidney function, being much faster or for some other reason, he added. The post-transplantation setting is challenging because other influencing  events can occur due to medication noncompliance or idiopathic organ rejection, none of which have anything to do with DGF, said Bromberg.

The Phase II trial captured data indicated an initial benefit extended to one year after transplantation, Angion CEO Jay Venkatesan said. He agreed several factors can influence the result in a smaller study, but noted due to the Phase III trial’s size, any random events would be balanced on both arms so they do not meaningfully change the result.

Nonetheless, given the complex physiology of DGF, it is important to look at all factors like urine output and creatinine levels, said Qazi. If a kidney has a significant cold ischemia time but is from a young donor, there is a good chance the eGFR will be satisfactory post-transplantation, said Qazi. The time between the chilling of a tissue, organ or body part after its blood supply has been reduced or cut off and the time it is warmed by having its blood supply restored is defined as cold ischemia time, as per the National Cancer Institute.

Patient heterogeneity a complication

The mechanism leading to acute kidney injury (AKI) is critical to the eventual therapy outcome, said Qazi. However, the risk of developing AKI is also dynamic, and even in an enriched population of patients with AKI, the mechanism leading to injury in a particular patient is unknown, said a transplantation expert. The trial is enrolling patients with renal failure requiring haemodialysis or peritoneal dialysis initiated at least three months prior to transplantation and a donor organ cold ischemia time of less than 30 hours. Qazi made the distinction between a single injury and multiple, simultaneous injuries involving many pathways seen in DGF, which makes it further challenging to investigate a single treatment.

AKI following transplantation depends on the donor’s biological factors, including manner of death, comorbidities, perioperative factors and warm/cold ischemia time, said Qazi. As such, targeting one therapeutic target or molecular mechanism of ischemia reperfusion injury may not work in all patients, the transplantation expert added. Qazi did not dismiss the potential of a single therapy addressing DGF successfully, but noted the multiplicity of the pathways and the potential of a predominant pathway in a particular individual makes it challenging. Since about two-thirds of patients will not get DGF regardless of an intervention, it is harder to show a benefit with a preventive approach in the remaining patients, in comparison to an approach to treat it, said Venkatesan.

However, ANG-3777 works via a growth factor that may make cells resist injury or heal more rapidly after an injury, said Bromberg. One of the most recent approaches to fail in DGF is Soliris, but full results explaining why the complement inhibitor did not show adequate efficacy have not been published.  In a 21 December 2016 press release, Alexion stated the Phase II/III DGF study did not meet its primary endpoint of incidence of DGF. Allowing the cells to heal and recover from injury with ANG-3777 is a different way of approaching DGF than past efforts, said Bromberg. ANG-3777’s target is rational for therapeutic intervention because c-MET is expressed for three to seven days, starting at 24 hours after injury, which allows the drug to augment the natural HGF, said Venkatesan.

The drug’s preclinical MOA is convincing and is meant to attenuate the AKI once it happens, said the transplantation expert. In a TGF-beta-induced acute lung injury model, ANG-3777 was shown to increase survival compared to placebo, as per a November 2020 company presentation. The c-MET axis has pleiotropic effects, so ANG-3777 is proangiogeneic, promitogenic and downregulates TGF-beta so it is a multifaceted approach addressing several elements of organ injury, unlike other past attempts, said Venkatesan.

While the HGF mimetic approach is mechanistically rational, experts cited challenges with extrapolating too much information from preclinical models establishing this approach in this indication. Replicating the stability of a lab setting is challenging because the clinical scenario in DGF is very noisy, said the transplantation expert. In humans, the injury may occur through various mechanisms or not occur at all, and that may not be related to the target a therapy is attacking, he added. Bromberg agreed that in vitro models are overly simplistic and have not always translated well into human trials. Also, in human donors,  kidneys have already aged 40–50 years, while mouse models are only 8–12 weeks old, said Bromberg.

The field needs to develop better biomarkers to identify the pathophysiologies of the disease to correctly subclassify the disease pathophysiology of AKI, Qazi said. This may also help sift out a signal in a subset of patients in ongoing or future trials, said the transplantation expert.

Manasi Vaidya is a Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.