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Experimental Monoclonal Antibody Shows Promise in Huntington's Disease

​A monoclonal antibody designed to target the first stop of the immune system's complement pathway–C1q—could alter the course of Huntington's disease (HD) in some patients, according to preliminary findings from a phase 2 safety study presented in April at the AAN Annual Meeting.

Rajeev Kumar, MD, medical director of the Rocky Mountain Movement Disorders Center in Colorado, said that there is aberrant deposition of complement protein at the synapse in HD, and that lowering levels of C1q complement reduces neuroinflammation that in turn may lessen motor symptoms and slow progression of the disease.                   

Twenty-three of 28 patients completed the phase 2, open-label, multicenter study. Ninety percent of the patients had early manifest HD and were still independent with mild symptoms. The other 10 percent were beginning to experience the first symptoms, a so-called premanifest stage. 

Lowering C1q could put people at risk for infections, and all patients received vaccinations to common encapsulated bacteria, according to the researchers. The patients were premedicated with an antihistamine, but virtually all of them experienced a rash because of pseudo-allergy during the first loading infusion, which was delivered over a 23-hour period to completely knock down the C1q complement. All were treated with a steroid or antihistamine once the rash developed. It resolved during the infusion or by the next day. Three patients experienced more serious side effects, including hemolytic anemia, a lupus-like presentation, and lung inflammation during the course of maintenance infusion therapy.

“Targeting complement is one of the ways we attack abnormal proteins and cells," said Dr. Kumar, who treats people with Huntington's disease. “This monoclonal antibody, ANX005, is not easy to deliver."

After the loading infection, participants returned every two weeks for a three-hour infusion. The infusion therapy lasted for 24 weeks, followed by 12 weeks of follow-up when no drug was received. Blood was collected throughout the trial, and lumbar punctures to collect cerebrospinal fluid was done at baseline and weeks six, 12, 24, and 36. 

C1q was completely depleted in the serum and in the CSF after the loading infusion as measured at week six. It remained absent until the end of the treatment phase. When the treatment stopped, complement returned to where it was before the first infusion. 

The researchers collected biomarker data—neurofilament light and YKL-40—and found that neurofilament light, a marker of brain injury, remained stable throughout the course of the study while YKL-40 was reduced, suggesting reduced activity of activated microglia. YKL-40 is a glycoprotein produced by inflammatory, cancer, and stem cells.

They also looked for any clinical changes. Looking at the entire group, they didn't find differences in the Unified Huntington's Disease Rating Scale (UHDRS) compared with measurements taken in control population data collected in the TRACK-HD study. The UHDRS is used to assess motor function, cognitive function, behavioral abnormalities, and functional capacity.

But at the end of the study, they decided to see if there might be a difference in those who had high complement ratio of C4A/C4 at baseline. That ratio would suggest a higher level of neuroinflammation, and the monoclonal antibody might work better because it targets the C1q inflammatory pathway, Dr. Kumar explained. They identified a median setpoint and separated the group into those with a high C4A/C4 ratio and a low ratio.

Those with a high ratio showed improvement compared those with a low ratio on the UHDRS measures, suggesting that the drug may have reduced motor symptoms and slowed progression, Dr. Kumar said. The total motor score was improved (p<0.01) while some cognitive measures also trended toward significance (p=0.055.)  The patients with the low ratio were more like the historical controls from the TRACK-HD data. Other neuroinflammatory markers were also reduced at week 24 in those who showed improvement.

The group is now designing a phase 3 clinical trial that may exclude patients with a high baseline ANA[EF1] [EF2] , as they may be at risk for the more serious side effects observed in the study. The researchers are still trying to decide whether they should exclude patients with low baseline complement ratio of C4A/C4, who may be less likely to benefit.

“These are still early days," said Samuel Frank, MD, associate professor of neurology at Harvard Medical School and director of the HDSA Center of Excellence at Beth Israel Deaconess Medical Center.

“They are taking a broader approach targeting downstream events rather than targeting the HD genetic mutation. This is a safety-based study, and 100 percent had an infusion reaction," which did resolve within a day of the loading infusion. “Infusion therapy every two weeks is a huge ask," Dr. Frank added. “This is a short exposure for a disease that lasts for decades."

Dr. Kumar disclosed that his institution has received fees from his consulting for US World Meds, Abbvie, Teva Pharmaceuticals, Annexon, Roche, Acorda Therapeutics, and Cerevel Therapeutics. He has served on a speakers bureau for Supernus, Teva, Acorda Therapeutics, and Kyowa Kirin. Dr. Kumar has received fees for serving on the scientific advisory or data safety monitoring boards for Impel Pharma and as an officer or member of the board of directors for Research Catalyst LLC, in which he has stock. He also has stock in CenExel. His full disclosures are listed here.

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