SMN1 x SOD1

Novartis is committing $100 million to Voyager Therapeutics to see if the biotech’s technology can lead to new gene therapies for Huntington’s disease and spinal muscular atrophy. According to deal terms announced Tuesday, the sum is an upfront payment that includes a $20 million equity investment in Voyager. Milestone payments could bring the Lexington, Massachusetts-based biotech up to $1.2 billion more. If the partnership leads to commercialized therapies, Voyager would also receive royalties from sales. Gene therapies reach their bodily destinations carried aboard an engineered virus. The therapy’s genetic cargo is enveloped by a protein shell called a capsid. Voyager’s TRACER technology platform discovers capsids that can target particular types of tissue. In addition to better safety and efficacy, the company contends its technology can lead to capsids with certain desirable properties, such as the ability to cross the blood brain barrier. Penetrating into the brain is important for gene therapies that address central nervous system (CNS) disorders such as Huntington’s and spinal muscular atrophy (SMA). Novartis already has a presence in SMA with Zolgensma, a gene therapy approved by the FDA in 2019. But Zolgensma comes with the risk of liver complications. The collaboration with Voyager could give Novartis a way to develop a gene therapy that is safer and more effective. The agreement grants Novartis access to TRACER capsids related to SMA. The pharmaceutical giant is responsible for development and commercialization of the SMA gene therapy. In Huntington’s, Voyager will handle preclinical development while Novartis is responsible for clinical development and commercialization. “We believe Voyager’s TRACER capsids hold promise for enabling next-generation gene therapies for diseases of the central nervous system, aligning well with our deep neuroscience expertise and gene therapy leadership at Novartis,” Fiona Marshall, president of biomedical research at Novartis, said in a prepared statement. The deal deepens the relationship between Novartis and Voyager. In 2022, the Swiss pharma giant paid $54 million up front to begin a partnership to discover capsids for three undisclosed CNS targets. So far, Novartis has licensed two of them, paying a $25 million option exercise payment last April, according to Voyager securities filings. Details about those targets are still scant, but Voyager said they are distinct from the company’s internal and partnered pipeline. Voyager said in a Tuesday regulatory filing that it expects to submit an investigational new drug application in the first half of this year for VY-TAU01, its antibody drug candidate that targets the tau protein to treat Alzheimer’s disease. If cleared for clinical testing, a Phase 1 study would begin in healthy adults later this year followed in 2025 by a multiple-ascending dose arm enrolling patients with mild cognitive impairment or early Alzheimer’s. Voyager’s amyotrophic lateral sclerosis program aims to silence the SOD1 gene, which drives the disease when mutated. The company said it expects this program will be ready for an investigational new drug application in mid-2025. In addition to the Novartis alliance, Voyager has a partnership with Neurocrine Biosciences in Parkinson’s disease, the neuromuscular disorder Friedreich’s ataxia, and five gene therapies for undisclosed indications. Voyager also struck a 2021 deal with Pfizer giving the pharma giant the right to select capsids stemming from the TRACER platform. According to Voyager securities filings, Pfizer exercised an option for a capsid for a potential gene therapy for a rare neurological disease but declined to option a capsid for a cardiovascular disease. Voyager is still in the process of completing its financial reports for 2023. But the company gave a preliminary estimate of a $230.7 million cash position as of the end of the year—not including the $100 million coming from Novartis. The company expects the combined cash, along with payments expected from its Neurocrine alliance, will be enough to fund operations into mid-2026.

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.