New study may explain why ALS therapy BIIB078 didn’t work
Drug was discontinued in 2022 due to a lack of clinical benefit
The investigational antisense oligonucleotide (ASO) therapy BIIB078 may have failed in amyotrophic lateral sclerosis (ALS) clinical trials because it wasn’t adequately reversing key disease processes in the brain and spinal cord.
Analyses of body fluids and tissue from participants showed that, while BIIB078 reached key tissues, it couldn’t entirely stop toxic proteins from accumulating and other molecules that contribute to the disease’s progression.
The drug’s development was discontinued in 2022 due to a lack of clinical benefit, but scientists hope the new data will offer insights into developing better ASOs, a class of treatments to which the approved ALS therapy Qalsody (tofersen) and other experimental therapies belong.
“This work is an important step forward to better understanding the biology of ASO therapies in people with neurological diseases,” Jonathan Glass, MD, professor and director of the ALS center at Emory University, and one of the study’s senior authors, said in a university news story. “We expect our new data will be influential in the development of new ASO-directed therapies.” The study, “Molecular impact of antisense oligonucleotide therapy in C9orf72-associated ALS,” was published in Cell.
Mutations in the C9ORF72 gene are the most common genetic cause of ALS and usually involve an abnormal expansion of a short DNA sequence within the gene, meaning the sequence is repeated too many times. This repeat expansion can damage nerve cells in several ways — by reducing levels of the normal C9ORF72 protein, by generating abnormal RNA molecules that disrupt essential cell processes, and by producing small toxic proteins. Together, these effects are believed to drive neurodegeneration.
Developing ASOs for ALS
ASOs can help address the genetic underpinnings of ALS. They contain short strands of genetic material that bind to a gene’s messenger RNA, the template molecule used to produce protein from DNA, and target it for degradation. Qalsody, developed by Biogen and Ionis Pharmaceuticals, treats forms of the disease associated with SOD1 gene mutations.
The two companies were also behind BIIB078, which targeted C9ORF72 to suppress toxic proteins that contribute to ALS-related nerve damage.
A Phase 1 trial (NCT03626012) and its open-label extension study (NCT04288856) tested BIIB078’s safety and tolerability in adults with C9ORF72-associated ALS.
The trial data showed it worked as intended to reduce toxic protein levels in the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord, but participants given BIIB078 at any dose didn’t show signs of clinical improvement relative to a placebo group. CSF disease biomarkers improved, but it wasn’t clear if the investigational therapy actually reached central nervous system (CNS) tissue — that is, the brain and spinal cord — to alter the course of the disease, according to Zachary McEachin, PhD, assistant professor at Emory and the study’s first author.
“We need better ways to know whether a treatment is truly changing the course of ALS,” McEachin said. “Our study addresses some of those questions and shows that CSF biomarkers do not always reflect changes in the CNS.”
Where did BIIB078 fail?
In the recent analysis, the scientists looked again at CSF and postmortem CNS tissue samples from the trial’s participants. The study included eight people with C9ORF72-associated ALS who received BIIB078, and 31 C9ORF72-associated ALS patients who didn’t receive it and 32 people without ALS, who served as controls.
The results showed BIIB078 reached the CNS and was widely distributed in key disease-associated regions, including the spinal cord and the brain’s motor cortex. Still, key ALS disease drivers, including the toxic accumulation of proteins such as TDP-43 and levels of abnormal RNA molecules derived from the repeat expansion, persisted. Widespread protein abnormalities were also still seen in the spinal cord.
Also, the biological responses to the ASO appeared highly variable and didn’t reliably correlate with clinical measures of disease progression. That shows the need to move toward precision and personalized medicine approaches, the scientists said.
Other experiments offered additional insights into how the immune system responds to the ASO, which may influence its effectiveness.
“Overall, this study resolves important knowledge gaps in our understanding of BIIB078 distribution, efficacy, and inflammatory responses in CNS tissue,” wrote the researchers, who said abandoning the therapeutic premise of BIIB078 “may be premature,” despite it clinical failure. These new analyses instead could help design more effective ASOs.
The data offer “new biomarkers of treatment and insights to better design and monitor future clinical trials,” said Nicholas Seyfried, PhD, an Emory professor and a study senior author.
BIIB078 is not the only ASO candidate from Biogen and Ionis that’s been discontinued. The companies previously developed BIIB105 that targeted the ATXN2 gene, but stopped its development due to a lack of clinical efficacy.
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