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Discussing the Potential of 3K3A-APC as an ALS Treatment

Kent Pryor, PhD, the CEO of ZZ Biotech, provided insight into a phase 2 trial that will evaluate the safety and efficacy of the investigational treatment in 16 patients with amyotrophic lateral sclerosis.

ZZ Biotech recently announced that the first patients with amyotrophic lateral sclerosis (ALS) had been dosed in a phase 2 clinical trial (NCT05039268) of its investigational treatment, 3K3A-APC, a genetically engineered variant of human active protein C (APC). Conduced at Macquarie University in Sydney, Australia, the trial will enroll 16 patients, then divided into 2 cohorts to receive 5 doses of either 15-mg or 30-mg 3K3A-APC, given intravenously 12 hours apart. 

The treatment has previously been studied in the completed phase 2 RHAPSODY trial (NCT02222714), which included patients with acute ischemic stroke. Data from the study suggest 3K3A-APC demonstrated beneficial cytoprotective activity on different cells in the brain, highlighting its potential to benefit patients with ALS. Following positive results from RHAPSODY, 3K3A-APC received fast track designation from the FDA for stroke in 2020.

To learn more about the treatment, its mechanism of action, and the phase 2 trial, NeurologyLive® sat down with Kent Pryor, PhD, CEO of ZZ Biotech. Pryor shared his perspective on the treatment, calling attention to the work of lead investigator for the trial, Dominic Rowe, MD, PhD, professor of neurology, Macquarie University Centre for Motor Neuron Disease Research, and his development of a “novel method” to be applied in the study. 

NeurologyLive®: Can you provide an overview of the trial’s design and main end points?

Kent Pryor, PhD: ZZ Biotech just started an ALS clinical trial. We're looking at 16 patients, and we're going to have 8 patients at a low dose and 8 patients at a higher dose, with 5 doses every 12 hours for 2-and-a-half days. The primary end point in the study is going to be safety, but the other coprimary end point we’re looking at is the drug’s ability to attenuate microglial activation in the motor cortex by using PET scanning. 

We have secondary end points where we're looking at the MRI and doing studies to determine whether we can affect the blood brain barrier. We're also doing extensive biometric measurements of serum, plasma, urine, and CSF [cerebrospinal fluid]. What we’re really looking to see is, can 3K3A-APC attenuate the altered cytokine and metabolic profiles that are always present in ALS patients?

Are any end points or measures unique in any way?

We're looking at a lot of different things that are pretty common to look at in ALS, but 1 of the particularly unique aspects of this trial is our principal investigator of the clinical trial, Professor Dominic Rowe [MD, PhD], has developed a novel method to determine whether monocyte activation in peripheral blood can act as a surrogate marker of microglial activation state in the brain in ALS patients.

What do you think the potential is for 3K3A-APC if successful in this early phase testing? Does anything separate it from prior approaches in ALS?

There are basically 2 broad categories of approaching ALS clinical research right now. One is going after genetic forms of the disease—looking at a particular slice of patients and going after it that way. But what 3K3A-APC does, it addresses the underlying pathologies of the disease, pretty much regardless of the genetic aspects of the disease. The action on the PAR1 and PAR3 receptors leads to a host of downstream beneficial effects. There's microglial overactivation, there's cytoprotection, there's anti-inflammation—these are all things that help deal with the damaged brain in ALS, to help reduce ongoing damage and try and preserve the brain tissue that's there. 

Hopefully, 3K3A-APC would be able to both protect motor neurons directly and attenuate microglial cells—so protect cells and decrease the source of ongoing damage for those cells, and again, it should be independent of the genetic basis of the disease.

Does the therapy's mechanism of action or administration route lend itself to how it might be used in the clinic?

The drug is an active serine protease—‘APC’ stands for activated protein C. So, 3K3A-APC is a 3 amino acid variant of a naturally occurring human protein. Because it is a protein, it is folded in a certain way, the drug is going to be provided by an infusion. It is actively transported across the blood brain barrier, so we do get good levels in the brain from peripheral activity.

At this point, we still need to figure out the optimal chronic dosing regimen for the drug. In this particular clinical trial, we're using the dosing regimen that we've already established in our phase 1 study, and in our phase 2 stroke clinical trial that’s been completed. But that dosing regimen, as I mentioned, is 1 dose every 12 hours, for 5 total doses. That's really designed, in this study, just to give us an idea of whether we're able to move these different biomarkers and impact the ALS disease state. That's not the dosing regimen we expect for the chronic clinical use.

Transcript edited for clarity.

REFERENCE
1. ZZ Biotech announces first patients doses in phase 2 clinical trial of 3K3A-APC for treatment of amyotrophic lateral sclerosis. News release. ZZ Biotech. December 2, 2021. Accessed December 10, 2021. https://www.biospace.com/article/releases/zz-biotech-announces-first-patients-dosed-in-phase-2-clinical-trial-of-3k3a-apc-for-treatment-of-amyotrophic-lateral-sclerosis-als-/
2. ZZ Biotech announces FDA fast track designation for stroke program. News release. ZZ Biotech. June 12, 2020. Accessed December 10, 2021. https://www.b3cnewswire.com/202006122080/zz-biotech-announces-fda-fast-track-designation-for-stroke-program.html