Biogen's SOD1-ALS Therapy Qalsody Gains FDA Accelerated Approval Based on NfL Biomarker Data

On April 25, the U.S. FDA approved Biogen’s antisense oligonucleotide (ASO) therapy Qalsody (tofersen) for the treatment of amyotrophic lateral sclerosis associated with superoxide dismutase 1 mutations (SOD1-ALS) via the accelerated approval pathway.This marks the first time the FDA has approved a drug for the treatment of ALS under the accelerated approval pathway based on a biomarker.

“Today also marks a pivotal moment in ALS research, as we have reached consensus for the first time that neurofilament light chain can serve as a surrogate marker to reasonably predict clinical efficacy in SOD1-ALS,” said Christopher A. Viehbacher, CEO of Biogen.

Therapeutic options for ALS are extremely limited. The most widely used drug, riluzole; the new drug edaravone (Radicava), approved in 2017; and Relyvrio (AMX0035) were all approved based on their benefits in terms of function or survival. However, these drugs have not significantly altered the course of the disease.

Neurofilament light chain (NfL) has garnered widespread attention as a biomarker for neurodegenerative diseases. When nerve cells are damaged, NfL levels rise in the blood and cerebrospinal fluid surrounding the brain and spinal cord. In Biogen’s studies, patients treated with tofersen exhibited a significant reduction in NfL levels compared to those receiving placebo. Biogen utilized this reduction as a surrogate endpoint, which served as a key rationale for the accelerated approval of tofersen and represented an innovative regulatory approach by the FDA for drugs targeting central nervous system (CNS) disorders.

In the field of ALS, the industry has waited 30 years to identify a biomarker capable of predicting therapeutic efficacy and changes in disease progression. Industry stakeholders anticipate that this marks the beginning of an era in which biomarkers and precision medicine drive the development of ALS therapies.

Tofersen was initially discovered by Ionis Pharmaceuticals, and Biogen entered into an agreement in 2018 to license the drug. The drug binds to SOD1 mRNA, leading to its degradation by ribonuclease, thereby reducing the production of SOD1 protein.

The approval for market launch is primarily based on the results from the Phase I clinical trial in healthy volunteers, the Phase I/II multiple ascending dose (MAD) clinical trial, the Phase III VALOR clinical trial, and the open-label extension (OLE) study, which also includes integrated results from the VALOR and OLE studies over the past 12 months.

The results indicate that tofersen can delay and reduce disease progression in motor neuron disease caused by SOD1 gene mutations. Although the primary endpoint of significant clinical improvement at 28 weeks was not met, investigators observed significant improvements in motor and pulmonary function when the trial was extended to 52 weeks.

Despite not meeting the primary endpoint, Biogen Inc. still submitted an accelerated approval application for the drug to the FDA. In February this year, the FDA convened an advisory panel to gather information on tofersen.

On March 22 of this year, Biogen and Ionis jointly announced that the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted 9–0 in unanimous support of considering tofersen for potential accelerated approval. The effect of tofersen on this protein is “reasonably likely” to predict clinical benefit, which is a core requirement for accelerated approval.

The voting results have already revealed the FDA’s stance, making the final approval of tofersen an expected outcome. Last month, FDA officials wrote that their approach to evaluating this class of drugs is guided by the FDA “Formed through interactions with patients and their caregivers, who describe their willingness to accept less certain efficacy in exchange for earlier access to much-needed medications.。”

“It is evident that the FDA is actively supporting the development of CNS drugs, which would certainly not have been approved under conventional review milestones,” said Yan Jiemin, CEO of Yuce Bio, in an exclusive interview with VCBeat New Medicine. “The clinical pharmacologists and statisticians involved in the review process appear to be gradually reaching a consensus. Furthermore, the overall trend in evaluating CNS diseases focuses on prognostic functional outcomes; improvements in biomarkers alone do not constitute true patient benefit. However, over the past two years, the FDA has shown me that they are becoming less ‘stringent.’”

YuCe Bio is a company dedicated to the clinical translation of ultra-sensitive biomarkers,Yan Jiemin believes this is also related to the previous updates to the CNS review legislation. “After all, some hope must be given.”

In 2021, the FDA issued a final guidance entitled “Cancer Drugs for Patients with CNS Metastases,” which details optimal clinical trial designs for evaluating drugs and biological products intended to treat patients with central nervous system (CNS) metastases.

In the guidelines, the FDA considers leptomeningeal disease (LMD) as a condition affecting the entire central nervous system. For patients diagnosed with LMD based on clinical symptoms but lacking imaging data, cerebrospinal fluid biomarker testing should be performed to support the diagnosis of LMD.

“This guideline offers a different approach compared to traditional clinical enrollment protocols. Therefore, in future clinical practice for CNS diagnosis, cerebrospinal fluid or blood biomarkers can serve as specific markers alongside scales and imaging.”

“With tofersen setting a regulatory precedent, the acceptance of biomarkers as clinical endpoints means that biomarkers can serve as a guiding criterion during randomized, double-blind trials and during phased enrollment. This will improve the accuracy and comparability of patient enrollment in clinical trials conducted by pharmaceutical companies and biotech firms. Many Phase III failures or suboptimal Phase II results for CNS drugs have been linked to flaws in clinical trial design and enrollment criteria,” summarized Yan Jiemin, highlighting the value and benefits of this approval for CNS clinical trials.

Nevertheless, the FDA’s efforts remain limited in scope.SOD1-ALS is a rare hereditary form of ALS, with approximately 2% of ALS cases associated with SOD1 gene mutations.

Bao Yanghuan, founder of Pubaisi Biotech, who has years of experience in the CNS field, stated, “Approximately 10% of ALS patients have clearly identified pathogenic gene mutations. SOD1-ALS targets one such mutation, and it is straightforward to use the reduction of mutant SOD1 protein as an evaluation criterion. In other words, SOD1-ALS focuses on a rare disease with a well-defined mutation.” Pubaisi Biotech is committed to integrating data from biomarkers, omics, and imaging to help predict the efficacy of CNS drugs.

Even if the approval of tofersen represents only a modest breakthrough, it has undeniably provided greater encouragement to the industry.

First, it will pave the way for the review and approval of CNS drugs.Under the FDA’s updated approval framework for CNS drugs, an increasing number of central nervous system therapeutics are likely to gain market approval through mechanisms such as Breakthrough Therapy designation and Accelerated Approval pathways.This is good news for companies pursuing first-in-class CNS pipeline strategies.

Secondly,CNS New Drugs Are Evolving from Small-Molecule Targeted Therapies to CGT Drugs“We are gradually witnessing the emergence of cell therapies for central nervous system (CNS) disorders such as Alzheimer’s disease and Parkinson’s disease. Some approaches aim to replace damaged neurons using stem cell therapy, while other companies focus on symptom management. For instance, Auvelity, developed by Axsome, has received FDA Breakthrough Therapy designation for treating agitation associated with Alzheimer’s disease. The therapeutic landscape for CNS disorders is expanding, and if further breakthroughs are achieved at the pathological level, it holds promise for covering the entire continuum of CNS care,” explained Yan Jiemin.

Over the past two years, Chinese biotech companies specializing in the central nervous system (CNS) field have risen to prominence, with enterprises focusing on amyotrophic lateral sclerosis (ALS) gradually coming to the fore. Their R&D efforts have become increasingly diversified, achieving steady progress across improved new drugs, small-molecule chemical drugs, and novel modalities. The approval of tofersen will undoubtedly present them with greater opportunities.

Guangzhou Magpie PharmaceuticalsNitronezine, a Class I innovative chemical drug under development, has initiated Phase II clinical trials in China and Phase I clinical trials in the United States. These studies aim to evaluate the efficacy, safety, and pharmacokinetic (PK) profile of nitronezine tablets in patients with amyotrophic lateral sclerosis (ALS). According to Dr. Wang Yuqiang, General Manager of Xique Pharmaceutical, nitronezine significantly enhances muscle strength, improves disease-induced motor impairments, and effectively delays disease progression in ALS animal models. Its therapeutic efficacy surpasses that of riluzole and edaravone, the only two currently marketed drugs for ALS, highlighting its potential as a next-generation treatment for the disease.

Abisko TherapeuticsABSK021 is an oral, highly specific and selective colony-stimulating factor-1 receptor (CSF-1R) antagonist. It is currently undergoing Phase Ib clinical studies in China and the United States to evaluate its safety, tolerability, and pharmacokinetics in patients with cancer. Preclinical studies have demonstrated that inhibition of CSF-1R can delay disease progression in multiple animal models of amyotrophic lateral sclerosis (ALS). Preliminary clinical data have shown that ABSK021 is well tolerated, exhibits favorable pharmacokinetic properties, and effectively inhibits its target. Previously, Abbisko Therapeutics entered into a collaboration with Shufang Pharmaceuticals.

Nanjing Baixinyu PharmaceuticalFocusing on improved new drugs, we have developed the world’s first sublingual edaravone tablet for the treatment of amyotrophic lateral sclerosis (ALS). Co-developed by Baixinyu and Beijing Tiantan Hospital, this medication addresses key technical challenges associated with oral edaravone, including administration difficulties, low bioavailability, and instability due to susceptibility to oxidation.

In addition to small-molecule chemical drugs, domestic biotech companies are also catching up in new modalities for ALS.

Zhongmei RuikangRAG-17, an independently developed oligonucleotide drug, received Orphan Drug Designation from the U.S. FDA last month. RAG-17 is a double-stranded small interfering RNA (siRNA) targeting the SOD1 gene, designed to treat patients with amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations by reducing SOD1 protein expression. Preclinical efficacy studies conducted in mouse and rat models of ALS demonstrated that treatment with RAG-17 significantly delayed disease onset, extended survival, and improved motor function.

Furthermore, resulting from the transformation of scientific and technological achievements at Tsinghua UniversityShenji Changhua, focusing on central nervous system diseases, leveraging years of in-depth research into the pathogenic mechanisms of ALS and innovative therapeutic targets, we are developing gene therapy drugs for ALS using adeno-associated virus (AAV) vector technology, which has currently entered the preparatory stage for investigator-initiated trials (IIT).

Similarly,NeuOrion PharmaThey have also embarked on the development of new drugs for ALS through AAV gene therapy, and currently, they have announced a three-year collaborative research project on gene therapy for amyotrophic lateral sclerosis (ALS) with the University of Massachusetts Medical School.

Previously, Artery New Medicine interviewed Cai Lei, the former vice president of JD.com, who has been tenaciously battling amyotrophic lateral sclerosis (ALS). He has now become the central figure driving efforts to conquer ALS.

After being diagnosed with amyotrophic lateral sclerosis (ALS) in 2019, Cai Lei resolved to dedicate his career to combating the disease. Within three years, he established a patient-centered ALS data platform reaching more than 10,000 individuals, founded four public welfare funds for ALS, and manages the world’s largest community of ALS patients. To identify life-saving treatments for ALS patients, Cai Lei also built a dedicated research team of 15 members and advanced more than 50 drug candidates in the ALS pipeline.

Regarding the approval of tofersen, Cai Lei told VCBeat New Medicine, “We pay tribute to pharmaceutical companies. After all, they have brought hope for treatment to a small subset (2%) of patients in the field of amyotrophic lateral sclerosis (ALS), which has seen no new drugs for a century.”

He stated that this serves as an encouragement to the community of patients with amyotrophic lateral sclerosis (ALS), but the development of new drugs for ALS still faces a long and arduous journey. “The most challenging issue in ALS currently is that over 90% of cases are sporadic, with no identifiable genetic mutations or clear etiology. We hope that the clinical needs of these patient populations will receive greater support and attention.”