Ionis Pharmaceuticals NASDAQ: IONS highlighted a busy slate of regulatory decisions, clinical readouts and partnered programs during a presentation at RBC Capital Markets’ Global Healthcare Conference, with Chief Development Officer Holly Kordasiewicz saying the company is moving from recent launches into a broader commercial and late-stage development phase.
Kordasiewicz said Ionis had its first two independent launches last year with TRYNGOLZA in familial chylomicronemia syndrome, or FCS, and DAWNZERA in hereditary angioedema, or HAE. She said the company is now preparing for two PDUFA dates this year for wholly owned programs: TRYNGOLZA in severe hypertriglyceridemia, or SHTG, in June, and zilganersen for Alexander disease at the end of the year.
She also pointed to five phase 3 readouts this year, including bepirovirsen, which she said was positive and is expected to be presented later this month at EASL. Other expected readouts include CARDIO-TTRansform in ATTR cardiomyopathy and the HORIZON study of pelacarsen in Lp(a) lowering.
Biogen Tau Program Moves Toward Phase 3
Asked by RBC senior biotechnology analyst Luca Issi about recently disclosed top-line data from Biogen’s tau program in Alzheimer’s disease, Kordasiewicz said she was “really excited” by the results and described the approach as a new mechanism using an oligonucleotide to lower intracellular tau by stopping production of the protein.
She said Ionis’ phase 1 study showed robust reductions in cerebrospinal fluid tau and reversal of tau PET, which she described as the first demonstration of clearance of pathological tau in an Alzheimer’s disease brain. In the CELIA phase 2 study, which Biogen reported on last week, Kordasiewicz said the biomarker findings were replicated and that the study showed benefit on cognitive endpoints.
“They are in line with what has been shown with amyloid therapies and in some cases exceed it,” Kordasiewicz said, adding that the results met Biogen’s pre-specified criteria to move into phase 3. She said placebo performance did not appear unusual based on available biomarker and cognition data, and that all doses showed benefit. More complete data are expected at AAIC in July.
TRYNGOLZA SHTG Decision Expected June 30
For TRYNGOLZA in severe hypertriglyceridemia, Kordasiewicz said discussions with regulators are progressing as planned ahead of the June 30 PDUFA date. She cited phase 3 efficacy data showing an 85% reduction in acute pancreatitis events in people with high triglycerides and said the therapy received breakthrough therapy designation based on those data.
On questions about observed liver fat changes, Kordasiewicz said Ionis does not view the finding as a safety signal and does not expect monitoring requirements, a REMS or a boxed warning. She characterized the finding as an on-mechanism biomarker signal associated with rapid triglyceride lowering and said patients from CORE I and CORE II who entered an open-label extension are being followed for more than two years, with liver fat stabilizing and trending back toward baseline over time.
Kordasiewicz said Ionis sees about 3 million patients with triglycerides above 500 mg/dL, with an initial focus on roughly 1 million high-risk patients, including those above 880 mg/dL and those above 500 mg/dL with a history of acute pancreatitis. She said Ionis set a $40,000 wholesale acquisition cost after physician and payer research designed to support broad access.
She also explained the company’s increase in peak revenue expectations for TRYNGOLZA from more than $1 billion to more than $3 billion. The initial move to more than $2 billion was driven by demand research following the phase 3 results, while the move to more than $3 billion followed pricing work, she said.
Angelman Study Enrollment Continues
In Angelman syndrome, Kordasiewicz said the open-label HALO phase 1 study showed improvement across motor, communication and cognition domains, with benefits seen across physician-administered, physician-reported and parent-reported measures. Ionis is enrolling the phase 3 REVEAL study and plans to complete enrollment this year, with a one-year primary endpoint expected to read out next year.
Kordasiewicz said Biogen previously passed on the program because of endpoint risk and a desire for more information, while Ionis wanted the program back as part of its strategy to build a neurology portfolio. Ionis is using expressive communication as the primary endpoint, which Kordasiewicz said was the top priority identified by caregivers and had the strongest early effect and most stable natural history in the company’s data.
Ionis will watch upcoming Ultragenyx data, particularly for the placebo effect in Angelman syndrome over a one-year study period, she said. Kordasiewicz estimated there are about 100,000 individuals with Angelman syndrome in the U.S. and major markets and said pricing would be considered within the range for rare neurological diseases, though it is too early to be specific.
Cardiovascular and Alexander Disease Updates
Discussing CARDIO-TTRansform in ATTR cardiomyopathy, Kordasiewicz said the study includes a contemporary patient population, including 819 patients on tafamidis at baseline. However, she said the trial is not powered to show statistical significance for the add-on-to-tafamidis secondary analysis, which is sixth in the hierarchy. She said expectations are based on prior silencer data, with any tafamidis findings representing potential upside.
For pelacarsen in Lp(a), Kordasiewicz said the ongoing outcomes study is testing whether lowering the “largest untreated risk factor in cardiovascular disease” can deliver clinical benefit. She said feedback from key opinion leaders suggests a 10% to 15% relative risk reduction could be enough to support treatment, given the human genetics linking Lp(a) to independent cardiovascular risk.
On zilganersen in Alexander disease, Kordasiewicz said Ionis achieved statistical significance on a clinically meaningful primary endpoint in an ultra-rare population and received breakthrough therapy designation. She said the disease is progressive, neurodegenerative and often fatal, with no available treatments, and that Ionis’ data showed stabilization on the motor endpoint while secondary endpoints favored zilganersen. An expanded access program is open and enrolling, she said.
About Ionis Pharmaceuticals NASDAQ: IONS
Ionis Pharmaceuticals, Inc is a biotechnology company focused on the discovery and development of RNA-targeted therapies designed to modulate gene expression. The company's proprietary antisense oligonucleotide (ASO) technology enables the selective binding of short synthetic strands of nucleic acids to messenger RNA (mRNA), thereby inhibiting or altering the production of disease-causing proteins. Ionis' pipeline spans a range of therapeutic areas, including neurological disorders, cardiovascular conditions, metabolic diseases and rare genetic disorders.
Since its founding in 1989 by Dr.
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