Branaplam

Nearly six months ago, PTC Therapeutics reported positive interim data for a drug in mid-stage development for Huntington’s disease, an inherited neurological disorder with limited treatment options and a history of stymied drug research efforts. The PTC drug’s data readout prompted another company to make an unsolicited bid for the program. Rather than jump at the offer, PTC decided to see if others might also be interested in the asset. Novartis has won this competitive process. On Monday, the companies announced the Swiss pharma giant is paying $1 billion up front to license global rights to the PTC Huntington’s drug, PTC518. PTC is still responsible for completing the ongoing placebo-controlled portion of the Phase 2 test of PTC518, and the Warren, New Jersey-based biotech will lead planned discussions with the FDA later this month to discuss the Phase 3 clinical trial. Novartis will take over the program for its pivotal study and is also responsible for the drug’s manufacturing and commercialization, though the deal calls for the companies to share profits from U.S. sales of an approved product — 60% to Novartis and 40% to PTC. The biotech is in line for up to $1.9 billion in milestone payments from Novartis plus royalties from sales of the drug in other markets. This deal is expected to close in the first quarter of 2025. Exclusive Heard at HLTH 2024: Insights from Innovative Healthcare Executives Executives from Imagine360, Verily, BrightInsight, Lantern, and Rhapsody shared their approaches to reducing healthcare costs and facilitating digital transformation. By MedCity News Huntington’s stems from a genetic mutation that leads to defective versions of huntingtin, a protein key to neuronal function. Mutated huntingtin causes neuronal damage and cell death that affects movement, speech, and swallowing. The disease also leads to behavioral, cognitive, and motor symptoms. Drugs used to treat Huntington’s address certain disease symptoms. There are no approved therapies that delay Huntington’s onset or slow its progression. PTC518 is a small molecule that affects the splicing of messenger RNA in order to reduce levels of a target protein. The drug comes from the same PTC technology that yielded Evrysdi, an mRNA-splicing drug that won FDA approval in 2020 as a treatment for the rare muscle disease spinal muscular atrophy (Evyrsdi is marketed by Roche under a partnership). The PTC518 data that prompted deal interest from other companies are interim results from a Phase 2 test showing the once-daily tablet led to dose-dependent lowering of mutant huntingtin protein in the blood and cerebrospinal fluid. The company also reported favorable trends on several clinical assessments of Huntington’s. PTC said the drug was safe and well tolerated by study participants. Additional Phase 2 data are expected in the second quarter of 2025. Huntington’s drug research has yielded many disappointments. In 2021, Roche halted a Phase 3 test of tominersen at the recommendation of the trial’s independent data monitoring committee. The drug candidate, an antisense oligonucleotide from Roche’s partnership with Ionis Pharmaceuticals, is designed to bind to mRNA in order to prevent production of mutant huntingtin. Roche has not given up on this drug entirely. In 2022, the pharma giant revealed plans for a new Phase 2 trial in younger Huntington’s patients with less severe disease. More recently, Sage Therapeutics reported it would stop dosing of dalzanemdor, a small molecule that had reached Phase 2 testing in Huntington’s. The November decision was based on the recommendation of independent observers of the clinical trial. Novartis has also experienced disappointment in Huntington’s. Its internally discovered drug candidate, branaplam, was initially developed as a treatment for spinal muscular atrophy before the company changed the small molecule’s focus to Huntington’s. In 2022, Novartis suspended dosing of branaplam after findings suggested the experimental drug may have caused peripheral neuropathy in some study participants. The mid-stage study was subsequently discontinued. presented by Market Trends to Watch for Health Systems and Their Specialty Pharmacies The future looks bright for the integrated specialty pharmacy model – for health systems, providers, and most importantly, for patients. By Jake Gaffey, MBA, Chief Strategy Officer at Shields Health Solutions In a note sent to investors, Leerink Partners analyst Joseph Schwartz said Novartis seems like a logical partner for PTC518, as branaplam’s approach to Huntington’s was similar to the PTC drug. In a Monday conference call, PTC executives said besides Novartis’s competitive financial offer, the pharma giant was selected because of its experience developing neuroscience drugs. William Blair analyst Sami Corwin wrote in an investor note that the deal makes financial sense for PTC, which last week struck a $150 million deal to sell the priority review voucher (PRV) it received for the recent FDA approval of gene therapy Kebilidi for an inherited enzyme deficiency. She said PTC now has additional funds to support its drug portfolio without needing to also pay for a pivotal clinical trial. “We see the $1 billion upfront payment, in addition to the $150 million PRV sale, as providing the company with sufficient financial funds to reach cash flow break even in the future without the need to raise additional funds,” Corwin said. “In addition, the deal provides PTC with a strategic partner that has experience developing drugs for CNS-based diseases, which could accelerate the clinical development and bolster the commercialization of PTC518, in our view. We also see the deal as validating PTC518 and PTC’s splicing platform.” In the hands of a big pharma company with neuroscience experience, William Blair gives PTC518 a 50% probability of success, modeling peak revenue of $5 billion, about $1.43 billion of which would go to PTC. In the nearer term, PTC is preparing to meet with the FDA later this month to discuss the design of the Phase 3 study. Schwartz noted that PTC is seeking alignment with the regulator on using lowering of huntingtin levels as a potential surrogate endpoint to support accelerated approval. This endpoint could also serve as the primary endpoint of a Phase 3 study supporting a traditional approval.

COLD SPRING HARBOR, N.Y., March 6, 2024 /PRNewswire/ -- Spinal muscular atrophy, or SMA, is the leading genetic cause of infant death. Less than a decade ago, Cold Spring Harbor Laboratory (CSHL) Professor Adrian Krainer showed this brutal disease can be treated by tweaking a process called RNA splicing. This breakthrough resulted in Spinraza, the first effective treatment for SMA. It also opened a new frontier in drug development. Now, CSHL research could push RNA-splicing drugs even further. CSHL Associate Professor Justin Kinney, Krainer, and postdoc Yuma Ishigami have figured out why some splicing-based drugs tend to work better than others. Continue Reading The field of RNA therapeutics is booming. But not all drugs are created equal. CSHL scientists Justin Kinney and Adrian Krainer recently teamed up to investigate why some RNA-splicing-based therapies work better than others. Image: © Artur - stock.adobe.com RNA splicing determines which gene segments are used to build a protein. Krainer had designed Spinraza to home in on the exact spot where the drug would modify the production of a specific protein SMA patients need. Not all splice-modifying drugs are so intentionally constructed. Some have been found to change RNA splicing without scientists fully understanding how. That's true for a recently approved SMA drug, risdiplam. To better understand how this drug works, the Kinney and Krainer labs analyzed risdiplam's interactions with RNA. They also examined RNA's interaction with another drug, branaplam. The researchers measured the drugs' effects on splicing throughout the genome and on hundreds of variations of their intended targets. From there, they modeled how each drug identifies its targets among all RNA inside a cell. Both risdiplam and branaplam alter RNA splicing to generate the protein needed to treat SMA. However, the researchers found that risdiplam is more specific. Their quantitative models explain how. In the simplest terms, branaplam binds to RNA in two different ways—whereas risdiplam only binds in one way. This finding could help researchers alter the chemical structure of branaplam so that it might someday treat Huntington's disease—a fatal, currently incurable neurodegenerative disorder. The researchers also found something else. Combining splice-modifying drugs that target the same gene segment in different ways usually has a greater effect than either drug alone. "You get synergistic interactions," Kinney explains. "We found synergy is a general property of splice-modifying drugs. This might provide a basis for using drug cocktails instead of individual drugs." The finding could help researchers identify drug combinations with the potential to improve patient outcomes. And that could lead to new therapeutic strategies for SMA and other diseases. For example, the Krainer lab recently investigated RNA splicing in pancreatic cancer. "Our new study provides insights into the action and specificity of splice-modifying drugs," Krainer says. "This should facilitate the development of more effective drugs and drug combinations for a variety of diseases." About Cold Spring Harbor Laboratory Founded in 1890, Cold Spring Harbor Laboratory has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. Home to eight Nobel Prize winners, the private, not-for-profit Laboratory employs 1,000 people including 600 scientists, students and technicians. For more information, visit SOURCE Cold Spring Harbor Laboratory