Novartis will partner with PTC Therapeutics to expand the use of PTC’s small molecule splicing platform to develop PTC’s PTC518 Huntington’s disease program and an unspecified number of related molecules, through an up-to-$2.9 billion exclusive global license and collaboration agreement, the companies said today.
PTC518 is an oral small molecule now under study in the ongoing Phase II PIVOT-HD trial (NCT05358717). In June, PTC reported interim results from the trial showing that PTC518 treatment resulted in durable, dose-dependent reduction in blood and cerebrospinal fluid (CSF) mutant Huntingtin protein (HTT) levels as well as early signals of dose-dependent benefit on key clinical measurements at 12 months.
Dose-dependent reductions of HTT in blood and cerebrospinal fluid showed a 1.33% change from baseline after 12 months among patients dosed with 10 mg of PTC518, compared with reductions of an even 2% in patients dosed with 5 mg, and 4.9% in placebo patients.
Novartis plans to assume oversight of development, manufacturing and commercialization of PTC518 after completion of PIVOT-HD, which is expected to occur in the first half of 2025.
“This agreement with PTC is intended to bolster our neuroscience pipeline and reflects our strategic focus and commitment to explore new and potentially transformative approaches for neurodegenerative diseases with high unmet needs,” Novartis CEO Vas Narasimhan, MD, said in a statement. “We look forward to building on our expertise in neurodegenerative diseases and experience in HD with the intention to advance this potential first in class oral therapy for the HD community.”
The collaboration with PTC returns Novartis to the competition among drug developers to develop and bring to market a treatment for Huntington’s disease, nearly two years after the pharma giant halted development of branaplam in February 2023 following a clinical setback.
Six months earlier, Novartis halted the dosing of branaplam in adults with HD in the Phase IIb VIBRANT-HD trial (NCT05111249), after a regularly-scheduled data review by the study’s independent Data Monitoring Committee (DMC) showed “possible side effects—specifically that branaplam might be causing peripheral neuropathy,” according to a letter from the Huntington’s Disease Society of America.
Because PTC518 is an oral small molecule drug, and because PTC had discussed possible accelerated approval pathway with the FDA, “We believe investors are increasingly revisiting the company’s Huntington’s program, Sami Corwin, PhD, an analyst with William Blair, wrote in a research note last week before the Novartis announcement.
“High commercial potential”
“Positive regulatory discussions supporting a pathway to accelerated approval could provide significant upside to the stock given the high commercial potential of a small molecule compared to other modalities,” Corwin added.
The collaboration will combine Novartis’ drug development expertise with PTC’s ability to develop small molecule splicing therapies through a platform designed to identify small molecules affecting messenger RNA (mRNA) splicing, which PTC has applied toward treating diseases of high unmet need.
The platform carries out splicing through a spliceosome consisting of five small nuclear RNPs (snRNPs) that assemble around the splice sites serving as boundaries between each exon and intron on precursor mRNA (pre-mRNA). The first step in spliceosome assembly is mediated by snRNPs U1 and U2. Accorcding to PTC, the splicing modifiers identified by the platform are designed to modify the U1–pre-mRNA interaction, functioning as molecular ‘glue’ to strengthen the interaction at the splice site to help make splicing more efficient.
PTC’s platform identified the first-ever approved small molecule splicing modifier, the spinal muscular atrophy (SMA) drug Evrysdi® (risdiplam), marketed by Roche through a collaboration launched in 2011 and involving the SMA Foundation. Last year, PTC sold 67% of its royalty interest in the drug to Royalty Pharma in an up-to-$1.5 billion deal.
Since partnering on Evrysdi, PTC said, it has applied what it has learned from that program to broaden the platform in order to support discovery programs across therapeutic areas that include neurodegenerative disease, oncology, and metabolism.
However, just last week, PTC halted its development of its amyotrophic lateral sclerosis (ALS) candidate utreloxastat (PTC857) after the drug missed the primary endpoint of the global Phase II placebo-controlled CardinALS (NCT05349721), namely statistically significant lowering of plasma neurofilament light chain (NfL), a biomarker of neuronal damage.
That news sent PTC shares sliding 5% over two trading days, from $46.01 November 26 to $43.88 on Friday. Today, however, PTC shares jumped 19%, closing at $52.07, then rising another 2% in after hours trading, to $52.90 as of 7:30 p.m. ET.
“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,” Corwin wrote today of the collaboration. “We also see the deal as validating PTC518 and PTC’s splicing platform.”
$1 billion upfront
In PTC’s latest collaboration for PTC518, Novartis has agreed to pay PTC $1 billion upfront and up to $1.9 billion in payments tied to achieving development, regulatory, and sales milestones, and double-digit tiered royalties on sales generated outside the U.S. PTC will retain a 40% share of U.S. profits and losses, with the other 60% going to Novartis.
Novartis and PTC said they expect their collaboration agreement to close in the first quarter of 2025, subject to customary closing conditions that include regulatory clearance.
“PTC will use the proceeds of this transaction to expand our splicing platform as well as to support commercial and development portfolio activities,” PTC’s CEO Matthew B. Klein, MD, stated. “We are excited to collaborate with Novartis to accelerate the potential of PTC518 for the hundreds of thousands of HD patients worldwide in need of a therapy designed to be well-tolerated and an effective disease-modifying therapy.”
The collaboration with PTC marks Novartis’ latest in a flurry of drug discovery partnerships launched in recent weeks.
On November 20, Novartis launched a potentially more than $2 billion research collaboration and license agreement with Schrödinger to advance “multiple” small molecule candidates into Novartis’ portfolio for further development. Two days earlier, Novartis committed up to $745 million plus potential royalties to partner with Ratio Therapeutics on developing a Somatostatin Receptor 2 (SSTR2) radiotherapeutic candidate for cancer.
In October, Novartis agreed to pay Monte Rosa Therapeutics $150 million upfront toward a potentially more than $2.1 billion collaboration to develop T and B cell-modulating molecular glue degraders targeting the VAV1 protein in multiple therapeutic areas, starting with its Phase I autoimmune disease candidate MRT-6160.
And in September, Novartis paid Generate:Biomedicines $65 million upfront to launch a potentially more than $1 billion partnership to discover and develop protein therapeutics for multiple unspecified disease areas, using Generate’s generative AI platform.
