C9

Pictured: shRNA sense and antisense sequences/iStock, Love Employee The recent FDA approval of Biogen’s Qalsody for superoxide dismutase 1 (SOD1)–ALS highlighted the potential for antisense oligonucleotides in central nervous system diseases. But the recent failure of Wave Life Sciences’ WVE-004 in C9orf72–ALS also showed their limitations. Antisense oligonucleotides (ASOs) are short oligonucleotides that can modify gene expression and mRNA splicing. As of 2021, the FDA had approved 14 oligonucleotide therapeutics, with rare genetic diseases, retinal diseases and neuromuscular diseases dominating the list. Biogen, which licensed Qalsody from Ionis Pharmaceuticals in 2018, is currently studying the therapy in pre-symptomatic adults with SOD1 mutation. When neurons degenerate and die, they release neurofilament light chain (NfL). The participants in Biogen’s ATLAS trial will begin treatment when a spike in NfL is evident, Brett Monia, CEO of Ionis, told BioSpace. Brett Monia Monia said he believes Qalsody could prevent the disease process from ever starting in these individuals and drew parallels between Qalsody and Spinraza, the first drug approved for a neurodegenerative disease developed on Ionis’s ASO platform. Spinraza was approved in December 2016 as the first disease-modifying therapy for spinal muscular atrophy (SMA) caused by mutations in the survival motor neuron 1 (SMN1) gene. In the NURTURE study, it demonstrated long term efficacy in pre-symptomatic infants with a mutation in the SMN1 gene. “The majority of those children today are living normal lives,” Monia said. “We’d never know that they have SMA. That's a motor neuron, neurodegenerative disease like ALS, so we don't have data in SOD1-ALS patients, but there’s reason to believe.” Challenges Persist Still, challenges persist as all targets are different. In Phase Ib/IIa trial results announced May 24, Wave’s WVE-004 failed to show any clinical benefit after 24 weeks in 35 people with C9orf72 (C9)-associated ALS or frontotemporal dementia (FTD). Mutations in the C9orf72 gene cause the accumulation of G4C2 RNA, which produce poly(GP) proteins. While studies have shown poly(GP) to be an effective biomarker in C9-ALS, Wave reported that reductions in this protein did not correlate to clinical success. Paul Bolno “Unfortunately, the biological impact of knocking down the target RNA did not translate to clinical benefit,” Paul Bolno, president and CEO at Wave, told BioSpace. “The lack of any corresponding clinical benefit illustrates the complexity of the disease and, unfortunately, that other biological factors may be at play.” Bolno said a key consideration in drug development for any neuromuscular or neurodegenerative disease is the availability of biomarkers correlated to functional outcomes. “Progress in these diseases has been limited across modalities, not just in the oligonucleotide field, and biomarkers that can tell you if you have a high probability of changing the disease trajectory and which can be incorporated early in drug discovery and development will help accelerate research and de-risk investments in this area.” Before Wave struck out against C9orf72 (C9)-ALS, Ionis and Biogen abandoned their ASO, BIIB078, in March 2022 after failing to show clinical benefit in a Phase I trial. C9-ALS may be caused by a toxic gain of function, a toxic loss of function cause, or a combination of both, Monia said. BIIB078 was designed to target the toxic gain of function, “which is exactly what it did. It blocked production of the presumed toxic peptides that were hypothesized to be a cause of the disease. We proved that hypothesis wrong.” Ben Boros, M.D., Ph.D. candidate in Tim Miller’s lab at Washington University School of Medicine, called C9-ALS a messy disease. “The C9 part of ALS is only a recent discovery in the last decade, and SOD1–[ALS] is sitting on decades of research. I think that might be one contributing factor,” he told BioSpace. Ben Boros Delivery is a primary challenge across RNA therapeutics—ASOs are no different. Monia said last decade has been pivotal in moving the research forward. “We're making great strides in tackling the blood-brain barrier [in] CNS diseases,” he said. Ionis’ 12 clinical-stage drugs are all delivered intrathecally. The earliest ones were delivered monthly, but Monia said further optimization of the company’s platform has allowed it to move to biannual dosing and he believes annual dosing is possible. “But [intrathecal delivery] is still an invasive procedure,” he said. “We think that we can tackle the blood-brain barrier through medicinal chemistry such that in the future, we’ll be able to tackle CNS diseases with a subcutaneous or intravenous injection.” Advantage: ASOs Boros said the main advantage of ASOs over other therapies for CNS diseases is their ability to get into the system—and their safety compared to antisense strategies that require additional packaging in viruses. “Fortunately, for some reason, ASOs are readily taken up if you administer them through a lumbar puncture, and they distribute very well,” he said. “The most amazing thing is that [ASOs] are not that toxic. They don't hurt people quite as much as some of these other gene therapy strategies.” Bolno said that oligonucleotides can be delivered to neurons and reach targeted RNA transcripts with a high degree of specificity. “Oligonucleotides also offer the opportunity to address the root genetic cause of diseases, which may slow, stop or even reverse disease progression.” As for the future, Bolno said he sees significant opportunities for oligonucleotides in brain diseases, “especially if we look beyond ASOs to new modalities like RNA editing, which can restore or repair proteins by correcting RNA transcripts or upregulating protein expression.” Both Monia and Boros highlighted Huntington’s disease and Alzheimer’s disease as areas they believe ASOs can make a difference. Ionis has a Phase II program partnered with Biogen targeting tau in AD. Monia said the approval of Qalsody gives him even greater confidence in their future success. Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.

Pictured: shRNA sense and antisense sequences Love Employee/Getty Images/iStockphoto The recent approval of Biogen’s Qalsody in SOD1–ALS highlighted the potential of ASOs in CNS diseases, while recent failures make it clear there is still work to be done. Pictured: shRNA sense and antisense sequences/ iStock , Love Employee The recent FDA approval of Biogen’s Qalsody for superoxide dismutase 1 (SOD1)–ALS highlighted the potential for antisense oligonucleotides in central nervous system diseases. But the recent failure of Wave Life Sciences ’ WVE-004 in C9orf72–ALS also showed their limitations. Antisense oligonucleotides (ASOs) are short oligonucleotides that can modify gene expression and mRNA splicing. As of 2021, the FDA had approved 14 oligonucleotide therapeutics, with rare genetic diseases, retinal diseases and neuromuscular diseases dominating the list. Biogen, which licensed Qalsody from Ionis Pharmaceuticals in 2018, is currently studying the therapy in pre-symptomatic adults with SOD1 mutation. When neurons degenerate and die, they release neurofilament light chain (NfL). The participants in Biogen’s ATLAS trial will begin treatment when a spike in NfL is evident, Brett Monia, CEO of Ionis, told BioSpace . Brett Monia Ken West Monia said he believes Qalsody could prevent the disease process from ever starting in these individuals and drew parallels between Qalsody and Spinraza, the first drug approved for a neurodegenerative disease developed on Ionis’s ASO platform. Spinraza was approved in December 2016 as the first disease-modifying therapy for spinal muscular atrophy (SMA) caused by mutations in the survival motor neuron 1 (SMN1) gene. In the NURTURE study , it demonstrated long term efficacy in pre-symptomatic infants with a mutation in the SMN1 gene. “The majority of those children today are living normal lives,” Monia said. “We’d never know that they have SMA. That’s a motor neuron, neurodegenerative disease like ALS, so we don’t have data in SOD1-ALS patients, but there’s reason to believe.” Challenges Persist Still, challenges persist as all targets are different. In Phase Ib/IIa trial results announced May 24, Wave’s WVE-004 failed to show any clinical benefit after 24 weeks in 35 people with C9orf72 (C9)-associated ALS or frontotemporal dementia (FTD). Mutations in the C9orf72 gene cause the accumulation of G4C2 RNA, which produce poly(GP) proteins. While studies have shown poly(GP) to be an effective biomarker in C9-ALS, Wave reported that reductions in this protein did not correlate to clinical success. Paul Bolno “Unfortunately, the biological impact of knocking down the target RNA did not translate to clinical benefit,” Paul Bolno, president and CEO at Wave, told BioSpace . “The lack of any corresponding clinical benefit illustrates the complexity of the disease and, unfortunately, that other biological factors may be at play.” Bolno said a key consideration in drug development for any neuromuscular or neurodegenerative disease is the availability of biomarkers correlated to functional outcomes. “Progress in these diseases has been limited across modalities, not just in the oligonucleotide field, and biomarkers that can tell you if you have a high probability of changing the disease trajectory and which can be incorporated early in drug discovery and development will help accelerate research and de-risk investments in this area.” Before Wave struck out against C9orf72 (C9)-ALS, Ionis and Biogen abandoned their ASO, BIIB078, in March 2022 after failing to show clinical benefit in a Phase I trial. C9-ALS may be caused by a toxic gain of function, a toxic loss of function cause, or a combination of both, Monia said. BIIB078 was designed to target the toxic gain of function, “which is exactly what it did. It blocked production of the presumed toxic peptides that were hypothesized to be a cause of the disease. We proved that hypothesis wrong.” Ben Boros, M.D., Ph.D. candidate in Tim Miller’s lab at Washington University School of Medicine, called C9-ALS a messy disease. “The C9 part of ALS is only a recent discovery in the last decade, and SOD1–[ALS] is sitting on decades of research. I think that might be one contributing factor,” he told BioSpace . Ben Boros Delivery is a primary challenge across RNA therapeutics —ASOs are no different. Monia said last decade has been pivotal in moving the research forward. “We’re making great strides in tackling the blood-brain barrier [in] CNS diseases,” he said. Ionis’ 12 clinical-stage drugs are all delivered intrathecally. The earliest ones were delivered monthly, but Monia said further optimization of the company’s platform has allowed it to move to biannual dosing and he believes annual dosing is possible. “But [intrathecal delivery] is still an invasive procedure,” he said. “We think that we can tackle the blood-brain barrier through medicinal chemistry such that in the future, we’ll be able to tackle CNS diseases with a subcutaneous or intravenous injection.” Advantage: ASOs Boros said the main advantage of ASOs over other therapies for CNS diseases is their ability to get into the system—and their safety compared to antisense strategies that require additional packaging in viruses. “Fortunately, for some reason, ASOs are readily taken up if you administer them through a lumbar puncture, and they distribute very well,” he said. “The most amazing thing is that [ASOs] are not that toxic. They don’t hurt people quite as much as some of these other gene therapy strategies.” Bolno said that oligonucleotides can be delivered to neurons and reach targeted RNA transcripts with a high degree of specificity. “Oligonucleotides also offer the opportunity to address the root genetic cause of diseases, which may slow, stop or even reverse disease progression.” As for the future, Bolno said he sees significant opportunities for oligonucleotides in brain diseases, “especially if we look beyond ASOs to new modalities like RNA editing, which can restore or repair proteins by correcting RNA transcripts or upregulating protein expression.” Both Monia and Boros highlighted Huntington’s disease and Alzheimer’s disease as areas they believe ASOs can make a difference. Ionis has a Phase II program partnered with Biogen targeting tau in AD. Monia said the approval of Qalsody gives him even greater confidence in their future success. Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com . Follow her on LinkedIn and Twitter @chicat08 .

Pictured: 3D illustration of degradation of motor neurons/iStock, Dr_Microbe Wave Life Sciences continues to have issues with its antisense oligonucleotides. In 2021, the company shelved its lead antisense candidates for Huntington’s disease, and on Tuesday, it said goodbye to another being developed for ALS and frontotemporal dementia. In a Phase Ib/IIa trial of 35 people with C9orf72 (C9)-associated ALS or frontotemporal dementia (FTD), WVE-004 failed to show any clinical benefit after 24 weeks, Wave reported. Based on these data and a lack of biomarkers likely to predict clinical benefit, the company is discontinuing asset development. Five to 10% of ALS cases in the U.S. are familial, according to the NIH. Of these, 25% to 40% are caused by a hexanucleotide repeat expansion in the C9orf72 gene. Mutations in this gene have also been identified as a common cause of FTD. WVE-004 was designed to lower levels of the C9orf72 protein. The therapy aims to rescue normal C9orf72 protein by selectively targeting transcriptional variants containing the hexanucleotide repeat expansion. Mutations in the C9orf72 gene cause the accumulation of G4C2 RNA, which produce poly(GP) proteins. While studies have shown poly(GP) to be an effective biomarker by which to test therapies targeting C9orf72, Wave reported that reductions in this marker did not correlate to clinical benefit. The company did report “potent and durable target engagement,” with poly(GP) falling by up to 50%, perhaps providing positive signals for other programs. “These data reinforce that our preclinical data on target engagement and pharmacology are translating in the clinic,” Paul Bolno, CEO of Wave, said in a prepared statement. Paul Bolno Bolno said he’d hoped for better after data from the Ib/IIa FOCUS-C9 study, announced in April 2022, showed target engagement across all treatment groups. “Following our initial positive single dose data last year, we advanced WVE-004 with the hope that its potency and differentiated pharmacology may deliver a better result than C9orf72-targeting oligonucleotides discontinued by others in the field,” he said in the same statement. ASO Hits and Misses Antisense drugs targeting C9-ALS have had a bad run recently. In March 2022, Biogen and Ionis discontinued their ASO, BIIB078, after it also failed to show clinical benefit in the Phase I trial. But ASOs have also succeeded in ALS—namely, Biogen’s Qalsody (tofersen), which won FDA approval in April for superoxide dismutase 1 (SOD1)-ALS. The SOD1 protein is highly expressed in motor neurons, and the underlying SOD1 gene is mutated in up to 20% of familial cases of ALS and 2% of all cases. Merit Cudkowicz “I think the genetic mutation that causes C9 ALS is much more complicated than SOD1,” said Merit Cudkowicz, chief of the neurology department at Massachusetts General Hospital and co-principal investigator of Biogen’s VALOR study, told BioSpace. “It is a hexanucleotide repeat, intronic—and that field is still learning the best way to approach therapies for C9 ALS.” Cudkowicz is also an institutional consultant for Wave. Cudkowicz said that she believes antisense therapies are still highly relevant for other genetic forms of ALS “and maybe still for C9 in other ways.” Antisense therapies also have the potential to treat sporadic forms of ALS, Cudkowicz said, pointing to Cambridge, Massachusetts–based QurAlis, whose splice switching ASO, QRL-201, protects neurons against neurodegeneration, the company’s founder and CEO, Kasper Roet, told BioSpace in a previous interview. In terms of what led to the lack of clinical effect for WVE-004, Bolno said that C9-ALS/FTD biology is complex, “and we can only conclude at this time that there may be other biological factors that impact outcomes beyond those addressed in the design of WVE-004.” Looking ahead, Wave’s focus “remains on diseases where biomarkers correlated with functional outcomes are available,” Bolno told BioSpace via email. This includes a key readout from the Phase Ib/IIa SELECT-HD study in Huntington’s disease, which he said remains on track for the second half of this year. Bolno said that Wave would not exclude ALS as a therapeutic area in the future “if there was a clinically validated biomarker correlated with functional outcomes available to guide to clinical development.” Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.