FPI’s raison d’etre is to get effective, international clinical trials on the road (see Part 6 of this series). At ICFTD, FPI’s co-leader, Adam Boxer of the University of California, San Francisco, summarized what trials exist already, and offered a glimpse of the future.

Currently, the field lacks biomarkers for the underlying neuropathology of FTD, so there is no concrete way to know whether tau fibrils or TDP-43 inclusions lurk within the brain of a patient who has no known autosomal-dominant mutation. Hence, present-day FTD trials are limited to carriers of pathogenic C9ORF72, GRN, or MAPT mutations, and to people whose clinical syndromes are known to be tauopathies, such as progressive supranuclear palsy.

Trials for carriers of GRN mutations are the farthest along. At centers that are part of FPI, Alector is conducting Phase 2 and Phase 3 trials evaluating AL001, an anti-sortilin antibody meant to slow progranulin’s degradation. Early trials of AL001 indicated that it restores CSF progranulin levels in mutation carriers. The Phase 3 trial is the first in the field to include presymptomatic mutation carriers. They can enroll if their plasma NfL is elevated, suggesting they are nearing symptom onset. The trial aims for 180 participants total, and also includes symptomatic carriers. It uses the CDR-NACC-FTLD as a clinical primary endpoint, and is slated to run through 2023.

Two companies—Prevail Therapeutics (recently acquired by Eli Lilly & Company) and Passage Bio—are pursuing a gene-therapy approach. Both are hoping to replenish progranulin levels by injecting an adeno-associated virus bearing the progranulin gene directly into the cisterna magna of GRN mutation carriers with FTD. Prevail’s trial of PR006 started in July 2020, while Passage Bio’s trial of PBFT02 is slated to start this month. 

Julio Rojas of the University of California, San Francisco, said the combination of sensitive disease biomarkers (CSF progranulin, plasma NfL, and others) and progranulin-targeted treatment in trials bodes well for this form of familial FTD. “It’s likely we’ll see a treatment for GRN mutation carriers with FTD before we see one for AD,” Rojas said.

Carriers of hexanucleotide expansions in the C9ORF72 gene are also being included within the progranulin umbrella. Owing to the lysosomal dysfunction wrought in both familial forms of the disease, C9ORF72 carriers are included in Alector’s Phase 2 study of AL001.

Other trials are targeting the C9ORF72 mutation specifically. They enroll people with ALS and/or FTD. The furthest along is Ionis/Biogen’s antisense oligonucleotide BIIB078, in Phase 1. The multiple-ascending-dose trial includes 114 people with ALS; results are expected later this year. Participants in the randomized portion of the trial are being enrolled in a two-year, open-label extension. Wave Life Sciences, Cambridge, Massachusetts, is planning to start a Phase 1 trial of its C9-ASO, called WVE-004, in people with ALS and FTD due to C9ORF72 expansion this year (see press release).

Yet another C9-ASO, called afinersen, was designed in Robert Brown’s group at the University of Massachusetts in Worcester. At ICFTD, Boxer showed data from a man with ALS who was treated with afinersen for over a year. During this time, his CSF levels of poly-GP, a dipeptide translated from transcripts of the hexanucleotide expansion, plummeted, and his disease stayed stable during treatment.

The diabetes drug metformin is being tested at the University of Florida, Gainesville, in a Phase 1 clinical trial for C9ORF72 hexanucleotide expansion carriers with ALS or FTD. Besides its better-known effects on glucose levels and insulin sensitivity, metformin has been reported to squelch repeat-associated non-AUG (RAN) translation, the mechanism responsible for translating toxic dipeptides from the C9 repeats (Zu et al., 2020). This open-label study includes 18 participants, and is expected to finish in August 2022.

What about trials for FTLD-tau? So far, most trials have focused on people with clinical syndromes, such as progressive supranuclear palsy, which is known to have underlying tau pathology, but not necessarily a pathogenic tau mutation. Two different anti-tau monoclonal antibodies failed in trials for PSP last year (Jul 2019 news; Dec 2019 news). This prompted cancellation of a “basket trial” that had also included people with non-fluent primary progressive aphasia, corticobasal syndrome, and MAPT mutation carriers with FTD.

Why did these trials fail? A definitive answer is not in, but Boxer noted that CSF studies from the trials indicated that both antibodies, which target tau’s N-terminus, did not rid the brain of all forms of tau pathology. Boxer said the field eagerly awaits results of Biogen’s trial of BIIB080, a tau-targeting ASO in people with mild AD, which could provide proof-of-concept data for primary tauopathies. That Phase 2 trial will finish in May of 2022.

One hurdle to treating primary tauopathies is the lack of fluid biomarkers or PET imaging tracers for many non-AD forms of tau. While some tracers have been found to bind to the 4R-tauopathies PSP and CBD, so far none reliably tag tau in people with bvFTD or PPA, who could have underlying tau or TDP-43 pathology (Jul 2020 news). Once the field develops a marker for either one, people with sporadic FTD will be able to join clinical trials targeting their specific pathology.

MAPT mutations are the rarest cause of familial FTD, i.e., patients with these mutations are scarce. To ensure that trials in this far-flung group of patients are run with the most power possible, the FPI is working to coordinate international platform trials for them, which will test multiple therapies simultaneously against a shared placebo group, Boxer said.—Jessica Shugart


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News Citations

  1. Cohorts Band Together to Get Global FTD Trials Going
  2. AbbVie’s Tau Antibody Flops in Progressive Supranuclear Palsy
  3. Gosuranemab, Biogen’s Anti-Tau Immunotherapy, Does Not Fly for PSP
  4. PET Tracer PI-2620 Detects 4R Tau Deposits

Therapeutics Citations

  1. AL001
  2. PR006
  3. Metformin
  4. BIIB080

Paper Citations

  1. . Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proc Natl Acad Sci U S A. 2020 Aug 4;117(31):18591-18599. Epub 2020 Jul 20 PubMed.

External Citations

  1. July 2020
  2. Passage Bio’s trial of PBFT02
  3. Phase 1
  4. two-year, open-label extension
  5. press release
  6. Phase 1

Further Reading

No Available Further Reading