International Alliance of ALS/MND Associations

C9orf72 Therapies and Trials

Background

The C9orf72 gene provides instructions for making a protein that is abundant in motor neurons. Faults in the C9orf72 gene, most commonly an enlargement of a specific part of the gene (hexanucleotide G4C2 repeat expansion), were first linked to ALS/MND in 2011 (Renton et al, 2011; DeJesus-Hernandez et al., 2011) and have since been found to account for about 40% of familial ALS/MND cases and a small percentage of sporadic ALS/MND cases. People with a faulty C9orf72 gene are at an increased risk of developing frontotemporal dementia (FTD), with around half of people presenting with C9orf72-ALS/MND later developing FTD. Of those diagnosed initially with C9orf72-FTD, around 15% then go on to develop ALS/MND (Devenney et al, 2014).

The faulty C9orf72 gene causes cells to make toxic RNA, which is the intermediate between DNA and proteins, and this RNA traps important proteins and stops them working properly. It also produces toxic dipeptide repeat proteins (DPRs) and causes loss of normal function of the C9orf72 protein. These mechanisms create a toxic environment that damages the motor neurons (Gendron et al, 2013).

Multiple therapeutic strategies have been tested clinically for C9orf72, most commonly antisense oligonucleotides (ASOs), which directly interfere with the faulty instructions for making a protein. Unfortunately, none of the therapies tested to date have resulted in an approved treatment specifically targeted to C9orf72-ALS/MND.

Previous Trials

ASO Trials

Targeting the faulty RNA reduces the amount of faulty protein that is made, without affecting the production of healthy C9orf72 protein.

A phase 1 trial of an ASO called BIIB078, designed by Biogen Inc. and Ionis Pharmaceuticals Inc, was conducted between 2018 and 2022. The drug was designed to remove C9orf72-RNA containing the repeated expansion linked to MND, in order to reduce the amount of faulty protein made. The trial enrolled 106 people with C9orf72-MND and tested escalating doses of BIIB078 against placebo at a ratio of 3:1 (active drug: placebo). It was administered via intrathecal injection (via lumbar puncture) up to eight times over a treatment period of 12 or 24 weeks in escalating doses up to 90 mg.

In 2022, topline results from the trial showed that although the drug was well-tolerated and reduced the production of faulty protein (poly(GP)), there was no clinical benefit. In fact, people on the highest dose of the drug showed a poorer outcome, compared to those on placebo. Clinical development of the drug was then discontinued, and full trial results were published in September 2024 (Van den Berg et al, 2024). 

In May 2023, Wave Life Sciences Ltd announced the results of their phase 1b/2a trial of a drug called WVE-004. This drug was also an ASO specifically targeting the faulty C9orf72-RNA, thereby enabling normal C9orf72 protein production. The study tested the active drug in 26 people with C9orf72-MND/ALS and compared to 7 placebo controls and included patients with C9-ALS/FTD. As was seen with BIIB078, WVE-004 was found to be safe and well-tolerated and lowered levels of poly(GP). However, WVE-004 was not shown to have any clinical benefit for people living with MND or FTD. No significant difference was observed by ALSFRS-R between those who took WVE-004 and those who took the placebo. Wave Life Sciences have now discontinued development of WVE-004, and the full results from the trial are pending publication.

Both ASO trials raised potential concern as they caused increased levels of a biomarker linked to neuronal damage, neurofilament light chain, when delivered at higher doses, potentially indicating that the drugs were more harmful than no treatment.

Indirect Targeting of Downstream Pathways

There have also been trials indirectly targeting C9orf72 through other pathways known to be disrupted in C9orf72 ALS/MND.

  1. AIT-101 (also known as apilimod) is a repurposed drug that inhibits a protein called PIKfyve. In pre-clinical testing, AIT-101 prolonged survival of motor neurons grown in the lab from patients with C9orf72-MND (Shi et al, 2018). A small phase 2a trial began in December 2021 to assess the safety and activity of AIT-101 in 15 patients with C9orf72-ALS/MND. Trial participants were given 12 weeks of 250 mg/day active drug or placebo, followed by 12-week and 36-week open-label extension. In April 2023, the company announced that the drug was found to be safe and well-tolerated, and also showed promising target engagement and reduction of poly(GP) levels. The results of the trial are published here. The company state that future trials will consider inclusion of a broader population of participants, not just those with a faulty C9orf72 gene, but further development of the drug is on hold pending additional funding.
  2. TPN-101 is a drug that targets a protein called LINE-1 and reduces the amount of it that is made. Increased LINE-1 activity is linked ALS/MND as is believed to contribute to neuronal dysfunction and ultimately neuronal death. In people with ALS/MND and/or FTD associated with a faulty C9orf72 gene, the activity of LINE-1 is even higher due to poor suppression of the protein. Because of this, a Phase 2 trial of TPN-101 was conducted and included 42 people with C9-ALS and/or FTD, to see whether reducing LINE-1 activity was clinically beneficial. Participants were randomly prescribed either 400 mg of TPN-101 or placebo for 24-weeks, followed by a 24-week open-label extension (OLE). Top-line results, released in July 2024, showed that TPN-101 was safe and slowed the progression of the disease, as well as lowering levels of disease markers in the blood. In May 2025, it was announced that TPN-101 was selected to be tested in the HEALEY ALS Platform Trial by the Therapy Evaluation Committee, although there has not been an update on the status of this since the announcement.
  3. Latozinemab (AL001), developed by GSK and Alector, is a monoclonal antibody that targets the lysosomal pathway, which is affected in people with a faulty C9orf72 gene. Top-line results of a trial including people with C9orf72-FTD, were published in September 2023. The drug blocks and reduces the action of the sortilin receptor, which is involved in the removal of an important protein called progranulin (PGRN). By blocking sortilin, PGRN levels increase, indirectly improving lysosomal and immune pathways downstream of faulty C9orf72. The study included 16 people with FTD associated with faulty C9orf72, or a fault in a different gene. The drug was delivered intravenously every 4 weeks and was generally safe and well-tolerated but showed no significant slowing of disease progression for people with C9orf72-FTD. Note that this study did not specifically look at people with C9orf72-MND/ALS. A subsequent larger phase 3 trial looking at another form of FTD showed no effect of disease progression and the company is not taking Latozinemab forward.

Ongoing Trials Involving C9orf72 with ALS/MND patients

  1. A drug called acamprosate is being tested in a phase 1 trial started in February 2026 funded by the National Institute of Neurological Disorders and Stroke (NINDS). The trial recruited 30 people with ALS/MND with a confirmed C9orf72 gene fault and is now fully enrolled. The study will assess the safety and tolerability of acamprosate, and exploratory endpoints will include the effect of the drug on ALS/MND disease progression. A repurposing screening analysis identified acamprosate, licensed as an oral medication to manage alcohol use disorder, as a potential therapeutic for C9orf72 carriers. Acamprosate restores the balance between excitation and inhibition in the brain by normalizing the overactive glutamate system (NMDA receptors) and boosting the inhibitory GABA system. Experiments using motor neurons derived from C9orf72 patients that were grown in a dish showed the potential for the drug to improve the survival of the cells, either alone or in combination with Riluzole. The phase 1 trial is expected to be completed in 2027.
  2. There is currently also a small phase 2 single centre trial sponsored by the University of Florida, which is assessing the effect of metformin in around 16 people with C9orf72 ALS/FTD. This trial began in 2020 and is no longer recruiting, with results expected in 2026. It is an open-label trial, which means it is not being compared to a placebo group. In models of MND, metformin was able to reduce the number of toxic proteins that are made due to the C9orf72 gene change. Metformin works by blocking a key pathway (protein kinase R pathway) that is essential to the production of these toxic proteins. Note that metformin is also currently being tested in all forms of ALS/MND as part of the Experts-ALS platform in the UK, with the first interim analysis expected in July 2026 (Study Progress).

Clinical Trial Networks for FTD

There have previously been, and continue to be, multiple international observational studies currently running to help us to learn more about FTD and people with C9orf72-FTD are invited to join these networks. Below are some examples of these currently active networks:

  1. ALLFTD is an ongoing observational study recruiting those with diagnosed FTD or a family history of FTD (ALLFTD). The goal of the study is to prepare for treatment trials for FTD, by building a cohort of FTD patients across centres who can be available for treatment trials when they are developed. Participants attend annual assessments at a study clinic in the US or Canada, and are assessed through interviews, physical examination, cognitive testing, biofluid testing and often brain imaging. All clinical data collected in the study is being used to try to identify best clinical measurements and biomarkers for tracking the progression of FTD, and for predicting disease onset in those who have an FTD-linked gene change but not yet showing symptoms of FTD. Clinical data is available for researchers in order to drive collaboration and the search for a cure for FTD.
  2. The Genetic Frontotemporal dementia Initiative (GENFI) is a group of research centres across Europe and Canada with expertise in familial frontotemporal dementia (FTD) and is co-ordinated by Professor Jonathan Rohrer at University College London. This is another observational study, similar to ALLFTD, that aims to understand more about genetic FTD, including in those with mutations in C9orf72 genes. The study investigates both people with FTD and those with a known risk of developing the disease due to a change in one of the known risk genes linked to FTD, in order to understand the earliest changes that occur in the development of the disease. The GENFI aims to develop markers which help to identify FTD as early as possible and markers that help to monitor the progression of the disease.
  3. The FTD Prevention Initiative (FPI) brings together genetic FTD groups from across the globe, including members of GENFI and ALLFTD, as well as other initiatives. The FPI consists of researchers, families with FTD, charities, and patient engagement/advocacy groups who are all party to this global effort of promoting clinical trials and finding therapeutics for FTD.

Ongoing Trials Relevant to C9orf72

There is an ongoing phase 1/2 clinical trial looking at a drug called PBFT02 in people with FTD linked to either a faulty C9orf72 gene or faulty granulin gene, which is another gene linked to FTD. The drug is a gene therapy, delivered as a single dose directly into the base of the brain, delivering the granulin gene, which makes the progranulin protein, an important protein for neuronal health. Interim results from the trial, released in April 2026, stated stabilisation of plasma neurofilament light chain levels and reduced brain atrophy. The trial has completed enrolment and has an estimated completion date of 2028.

In June 2024, a multi-stakeholder workshop was conducted to unify efforts to design a prevention trial for the population at elevated genetic risk for the phenotypic spectrum of C9orf72 disease. Workshop participants included community members from C9orf72 families, ALS and FTD physicians and researchers, as well as those with clinical trial, regulatory, and biopharma expertise. The workshop included discussions about the need for biomarkers that detect disease before symptoms occur, improved trial outcome measures and eligibility criteria, amongst other important factors in trial design. Recommendations from the workshop have been summarised and published.

Summary

The failure of two separate trials testing ASOs against C9orf72 repeat expansion RNAs perhaps suggests that other strategies may be more beneficial for targeting C9orf72 ALS/MND and/or C9orf72-FTD. These include removal of faulty C9orf72 at the DNA level rather than RNA level, targeting of the antisense RNA in addition to the sense RNA, and targeting of downstream pathways disrupted due to the faulty protein. Lots has been learnt from the previous trials, which have shown that it is possible to deliver drugs targeting faulty C9orf72 into the central nervous system, and that this is able to lower the amount of faulty protein that is made.

We await the outcome of ongoing trials and studies to see if alternate strategies may deliver more promising outcomes for those living with C9ORF72-MND/ALS

International Alliance of ALS/MND Associations
April 2026

Disclaimer: Consult with a healthcare professional to determine if you could potentially participate in a C9orf72 clinical trial. Always disclose your medical history, including any drugs, natural supplements, or herbal medicines currently being used.

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