First Patients Dosed in Phase 2 Trial of 3K3A-APC in ALS

Kent Pryor, PhD

The first patients with amyotrophic lateral sclerosis (ALS) have been dosed in a phase 2 clinical trial (NCT05039268) evaluating the safety and efficacy of 3K3A-APC, a genetically engineered variant of human active protein C (APC), ZZ Biotech announced.¹ 

The trial will be conducted at Macquarie University in Sydney, Australia, and is anticipated to enroll a total of 16 patients with ALS. Participants will be divided into 2 dose cohorts, receiving 5 doses of 15-mg 3K3A-APC or 30-mg 3K3A-APC, given intravenously 12 hours apart. Primary end points include safety and tolerability of 3K3A-APC and whether the treatment can reduce pathological changes thought to cause ALS. Also evaluated will be biomarkers of microglial and monocyte activation, determining if microglial activation is a pathogenic contributor to the disease. 

The phase 2 RHAPSODY trial (NCT02222714) evaluated the treatment in patients with acute ischemic stroke, with 3K3A-APC receiving fast track designation from the FDA for treatment of stroke in 2020. As the treatment demonstrates beneficial cytoprotective activity on different cells in the brain, it may offer additional benefit to patients with ALS.

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“We have been developing 3K3A-APC for some time now, and we are making great strides in studying it for stroke,” Kent Pryor, PhD, CEO, ZZ Biotech, said in a statement.¹ “The extraordinary generosity of the Firies Climb for Motor Neurone Disease and their donors has allowed us to initiate a clinical program in ALS with 3K3A-APC, another area of great unmet medical need.”

In the RHAPSODY trial, investigators found that all doses were safe and well-tolerated in patients with ischemic stroke. A total of 110 patients were treated between January 2015 and July 2018, and the maximally tolerated dose of 3K3A-APC—540 μg/kg—had an estimated toxicity rate of 7% with no difference in prespecified intracranial hemorrhage (ICH) rates. Exploratory analyses showed 3K3A-APC reduced ICH rates in combined treatment arms from 85.5% to 67.4%, when compared with placebo (P = .046). Total hemorrhage volume was reduced from baseline to an average of 2.1 ml (standard deviation [SD], 5.8) in the placebo group and reduced to 0.8 ml (SD, 2.1) in the 3K3A-APC group.^2,3

“3K3A-APC has shown potent anti-inflammatory effects, along with repairing the blood-brain barrier, both of which are challenges in ALS,” Dominic Rowe, MD, PhD, lead investigator for the trial and professor of neurology, Macquarie University Centre for Motor Neuron Disease Research, said in a statement.¹ “I am extremely excited to test this interesting experimental drug for the first time in ALS patients. Currently, we can’t cure ALS, and we can’t reverse it. But with early diagnosis, and if we can dramatically slow the progression of disease, I firmly believe we can turn this disease around.”

REFERENCES

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 2, 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 2, 2021. https://www.b3cnewswire.com/202006122080/zz-biotech-announces-fda-fast-track-designation-for-stroke-program.html
3. Lyden P, Pryor KE, Coffey CS, et al. Final results of the RHAPSODY trial: A multicenter, phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3L3A-APC, a recombinant variant of human activate protein C, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke. Ann Neurol. 2019;85(1):125-136. doi:10.1002/ana.25383