Therapeutics

BIIB078

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Overview

Name: BIIB078
Synonyms: BIIB-078, IONIS-C9Rx
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Discontinued)
Company: Biogen, IONIS Pharmaceuticals

Background

BIIB078 is an antisense oligonucleotide targeting the chromosome 9 open reading frame 72 (C9ORF72) gene mRNA. It is being developed for ALS caused by hexanucleotide repeat expansions in C9ORF72 (van Blitterswijk et al, 2012). These expansions are the most common genetic cause of ALS, accounting for about 34 percent of all familial ALS and 12 percent of all ALS cases. The ASO mediates degradation of expansion-containing mRNAs. Both C9ORF72 RNA and the dipeptide proteins produced from the hexanucleotide repeats are believed to be toxic to motor neurons, hence the rationale is that reducing them will be beneficial.

In preclinical work with patient-derived cell lines, C9ORF72 ASOs mitigated RNA toxicity (Donnelly et al., 2013; Sareen et al., 2013; Lagier-Tourenne et al., 2013). In mice expressing the C9ORF72 expansion, a single, intraventricular dose of an ASO targeting the hexanucleotide repeats reduced toxic RNA and dipeptide aggregates, and attenuated behavioral and cognitive deficits (Jiang et al., 2016).

Biogen is developing BIIB078 in collaboration with Ionis Pharmaceuticals.

Findings

In September 2018, Biogen began a first-in-human Phase 1 in adults who have ALS with C90ORF72 expansions. Participants had to have a slow vital capacity above 50 percent of predicted normal and could use riluzole or edaravone, both approved for ALS. The study enrolled 106 participants in six ascending-dose cohorts and placebo, delivered by intrathecal injection five times over an eight-month span. The primary endpoints were adverse events; secondary outcomes included pharmacokinetics, clinical measures of function and muscle strength, and CSF levels of dipeptide proteins and phosphorylated neurofilament heavy chain, a biomarker of motor neuron death. An open-label safety extension offered monthly dosing for two years.

The placebo-controlled portion of the trial ended in November 2021. In March 2022, the companies announced top-line results, according to which the drug was well-tolerated but showed no difference from placebo on clinical endpoints at doses up to 60 mg. The 90 mg dose group trended toward greater decline across secondary endpoints. Based on these results, the companies ended the program, including the ongoing open-label extension (press release). Trial results were published after peer review (van den Berg et al., 2024).

For details on BIIB078 trials, see clinicaltrials.gov.

Last Updated: 10 Sep 2024

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References

Paper Citations

  1. van den Berg LH, Rothstein JD, Shaw PJ, Babu S, Benatar M, Bucelli RC, Genge A, Glass JD, Hardiman O, Libri V, Mobach T, Oskarsson B, Pattee GL, Ravits J, Shaw CE, Weber M, Zinman L, Jafar-Nejad P, Rigo F, Lin L, Ferguson TA, Gotter AL, Graham D, Monine M, Inra J, Sinks S, Eraly S, Garafalo S, Fradette S. Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study. Lancet Neurol. 2024 Sep;23(9):901-912. Epub 2024 Jul 23 PubMed.
  2. van Blitterswijk M, Dejesus-Hernandez M, Rademakers R. How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders?. Curr Opin Neurol. 2012 Dec;25(6):689-700. PubMed.
  3. Donnelly CJ, Zhang PW, Pham JT, Heusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, Maragakis N, Tienari PJ, Petrucelli L, Traynor BJ, Wang J, Rigo F, Bennett CF, Blackshaw S, Sattler R, Rothstein JD. RNA Toxicity from the ALS/FTD C9ORF72 Expansion Is Mitigated by Antisense Intervention. Neuron. 2013 Oct 16;80(2):415-28. PubMed.
  4. Sareen D, O'Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M, Bell S, Carmona S, Ornelas L, Sahabian A, Gendron T, Petrucelli L, Baughn M, Ravits J, Harms MB, Rigo F, Bennett CF, Otis TS, Svendsen CN, Baloh RH. Targeting RNA Foci in iPSC-Derived Motor Neurons from ALS Patients with a C9ORF72 Repeat Expansion. Sci Transl Med. 2013 Oct 23;5(208):208ra149. PubMed.
  5. Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR, Jiang J, Watt AT, Chun S, Katz M, Qiu J, Sun Y, Ling SC, Zhu Q, Polymenidou M, Drenner K, Artates JW, McAlonis-Downes M, Markmiller S, Hutt KR, Pizzo DP, Cady J, Harms MB, Baloh RH, Vandenberg SR, Yeo GW, Fu XD, Bennett CF, Cleveland DW, Ravits J. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4530-9. Epub 2013 Oct 29 PubMed.
  6. Jiang J, Zhu Q, Gendron TF, Saberi S, McAlonis-Downes M, Seelman A, Stauffer JE, Jafar-Nejad P, Drenner K, Schulte D, Chun S, Sun S, Ling SC, Myers B, Engelhardt J, Katz M, Baughn M, Platoshyn O, Marsala M, Watt A, Heyser CJ, Ard MC, De Muynck L, Daughrity LM, Swing DA, Tessarollo L, Jung CJ, Delpoux A, Utzschneider DT, Hedrick SM, de Jong PJ, Edbauer D, Van Damme P, Petrucelli L, Shaw CE, Bennett CF, Da Cruz S, Ravits J, Rigo F, Cleveland DW, Lagier-Tourenne C. Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs. Neuron. 2016 May 4;90(3):535-50. Epub 2016 Apr 21 PubMed.

External Citations

  1. press release
  2. clinicaltrials.gov

Further Reading

Papers

  1. McCampbell A, Cole T, Wegener AJ, Tomassy GS, Setnicka A, Farley BJ, Schoch KM, Hoye ML, Shabsovich M, Sun L, Luo Y, Zhang M, Thankamony S, Salzman DW, Cudkowicz M, Graham DL, Bennett CF, Kordasiewicz HB, Swayze EE, Miller TM, Comfort N, Wang B, Amacker J. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest. 2018 Aug 1;128(8):3558-3567. Epub 2018 Jul 16 PubMed.