Ionis Pharmaceuticals (NASDAQ: IONS) shares surged nearly 44% this past week after the developer of RNA-targeted therapies came out with positive data from two pivotal Phase III trials assessing a potential new indication for olezarsen as a treatment for severe hypertriglyceridemia (sHTG).
Olezarsen is an antisense oligonucleotide designed to lower the body’s production of apolipoprotein-CIII (apoC-III), a protein produced in the liver that regulates triglyceride metabolism in the blood. Olezarsen is already marketed in the United States, where it is the first FDA-approved treatment, as an adjunct to diet, to reduce triglycerides in patients with familial chylomicronemia (FCS) under the brand name Tryngolza®.
On September 2, Ionis said the 617-patient CORE trial (NCT05079919) and 446-patient CORE2 trial (NCT05552326) met its primary endpoint by showing an up to 72% placebo-adjusted mean reduction in fasting triglycerides at six months compared to placebo, as well as an 85% reduction in acute pancreatitis events with favorable safety and tolerability—results that Ionis has termed “highly statistically significant.”
“We believe these unprecedented results position olezarsen to meet the substantial unmet needs of people with sHTG, a patient population in great need for more effective triglyceride-lowering treatments to reduce the risk of potentially fatal acute pancreatitis,” Ionis founder and CEO Brett P. Monia, PhD, told analysts on a conference call.
Ionis plans to present detailed data at an upcoming medical conference, file a supplemental New Drug Application (sNDA) with the FDA for olezarsen in sHTG by year’s end, and if approved, launch the drug in that indication in 2026. Olezarsen is one of two launches the company is planning for next year. The other is Zilganersen, a potential first disease-modifying treatment for people with Alexander disease.
Ionis has not publicly estimated how much revenue it expects to generate from an sHTG indication for olezarsen, though Monia and other company executives have said that the drug has the potential to be a blockbuster, which is what industry calls drugs with sales of more than $1 billion.
“Based on this data, based on the patient population that’s addressable that we were talking about previously of greater than one million patients that have high-risk sHTG, we believe that we’ll be able to work effectively with these specialists and get them on olezarsen quickly and realize the blockbuster potential that this represents,” Kyle Jenne, Ionis’ executive vp and chief global product strategy officer, said on the analyst call.
Buying surge
The talk of blockbuster sales, plus positive CORE and CORE2 data, wowed investors enough to touch off a buying surge that sent Ionis shares soaring over two days.
From a close of $42.64 on August 29, Ionis shares jumped 35% to $57.49 on September 2, then rose another 5% to $60.49 on Wednesday, after reaching a 52-week high of $62.08 earlier that day. The stock dipped 2% Thursday to $59.35 on apparent profit-taking, but bounced back 3% Friday, finishing the week at $61.23.
Akash Tewari, global head of biopharmaceutical research and an equity analyst with Jefferies, wrote in a research note that his firm has raised its peak-year sales forecast for olezarsen 67%, from $1.5 billion to $2.5 billion, reasoning that the drug will reach more patients with sHTG as a result of the strong Phase III data. Tewari also raised his firm’s 12-month price target on Ionis shares 16% from $83 to $96, maintaining a “Buy” rating.
That’s a far cry from the $26 million in sales generated by Tryngolza during the first half of this year, most of which ($19 million) came during the second quarter. The drug was granted FDA approval in December 2024.
Jefferies forecasts olezarsen penetration reaching 13% of patients with triglyceride levels of greater than 880 mg/dL, a level classified as being sHTG; as well as 50% of sHTG patients with TG levels of 500–880 mg/dL with acute pancreatitis (AP) history; but only 1% of patients with TG levels above 500 mg/dL with no AP history.
“We think our penetration assumptions are still conservative,” Tewari said. “There could be further upside depending on pricing & pt adoption. Given the strong AP data, we think IONS could potentially get the pricing to the upper end of $10–20K net price range that mgmt. [management] had previously disclosed.”
Price question
On the call, Jenne deflected a question from Tewari about whether Ionis planned to raise its price for olezarsen in sHTG as a result of the data: “We’ll announce the price at the approval of the sHTG indication. And as I stated, it will reflect the value of olezarsen in that patient population.”
Tewari wasn’t alone in his upbeat outlook on Ionis shares.
“Taken together, we view these data as a best-case scenario for Ionis,” Myles R. Minter, PhD, a partner and biotechnology analyst with William Blair, wrote in a research note.
Beyond olezarsen, Minter added, “We view today’s top-line data as clinical validation for ApoC-III lowering in sHTG, particularly its effectiveness in lowering pancreatitis events.”
That validation will read through, Minter predicted, to other apoC-III silencers—both small interfering RNA candidates, such as plozasiran from Arrowhead Pharmaceuticals (NASDAQ: ARWR) and ALN-APOC3 from Alnylam Pharmaceuticals (NASDAQ: ALNY), as well as gene editing-based assets in lead optimization phases from two privately held therapeutics developers—MB-111 from Mammoth Biosciences and STX1400 from Scribe Therapeutics.
“Olezarsen’s statistically significant effect on AP [acute pancreatitis] positions IONS for a blockbuster 2H26 launch in sHTG,” BMO Capital Markets analyst Kostas Biliouris wrote in a research note, as reported by Seeking Alpha.
Biliouris upgraded his firm’s rating of the stock from “Market Perform” to “Outperform” and raised BMO’s 12-month price target on Ionis shares 75%, from $40 to $70. Numerous other analysts joined Biliouris and Tewari in raising their price targets on Ionis, including:
- H. Wainwright (Mitchell Kapoor)—Up 36% from $70 to $95, maintaining a “Buy” rating.
- Barclays (Gena Wang, PhD)—Up 34% from $58 to $78, maintaining an “Overweight” rating.
- Needham & Co. (Joseph Stringer, PhD)—Up 27% from $55 to $70, maintaining a “Buy” rating.
- Citigroup (David Lebowitz)—Up 22% from $69 to $84, maintaining a “Buy” rating.
- Morgan Stanley (Michael Ulz)—Up 14.5% from $62 to $71, maintaining an “Overweight” rating.
- RBC Capital Markets (Luca Issi, PhD)—Up 14% from $70 to $80, maintaining an “Outperform” rating.
- Leerink Partners (Mani Foroohar, MD)—Up 14% from $56 to $64, maintaining an “Outperform” rating.
- Goldman Sachs (Salveen Richter)—Up 12.5% from $40 to $45, maintaining a “Sell” rating.
Pressure on Arrowhead
Foroohar said Ionis’ success with olezarsen increases pressure on Arrowhead to succeed with plozasiran (ARO-APOC3), an RNA interference (RNAi) therapeutic that, like olezarsen, is designed to treat sHTG by reducing production of apoC-III.
Plozasiran is under study for sHTG in three Phase III trials that have all completed patient enrollment—SHASTA-3 (NCT06347003), SHASTA-4 (NCT06347016), and MUIR-3 (NCT06347133). In reporting results for the third quarter of its 2025 fiscal year last month, Arrowhead said it anticipated completing the primary portion of the trials in mid-2026 with topline data expected shortly thereafter, to be followed by regulatory submissions for review.
“For competitor ARWR, CORE data makes clinical differentiation an uphill battle (favoring IONS’ first-mover advantage),” Foroohar observed, adding that the CORE and CORE2 data “shifts the onus on ARWR to execute clinically and commercially to keep pace with IONS.”
Plozasiran is also under FDA review in FCS, for which Arrowhead has submitted a New Drug Application (NDA) based on positive data from the Phase III PALISADE trial (NCT05089084). The FDA has set a target action date of November 18 for plozasiran in FCS under the Prescription Drug User Fee Act (PDUFA).
Following Ionis’ announcement, Arrowhead also saw its stock jump nearly 17%, from $22.03 to $25.68—though the increase reflected more Novartis agreeing to license and develop Arrowhead’s ARO-SNCA, a preclinical stage small interfering RNA (siRNA) therapy candidate for Parkinson’s disease and other synucleinopathies, plus additional targets. The collaboration could generate more than $2.2 billion for Arrowhead, an RNAi-based drug developer based in Pasadena, CA.
Leaders and laggards
- Cybin (NYSE American: CYBN) shares slumped nearly 17% from $7.48 to $6.24 on September 2 after the psychedelic drug developer’s CEO Doug Drysdale stepped down effective that day. Cybin’s board has appointed co-founder and executive chairman Eric So as interim CEO and established a committee to conduct a search for a permanent CEO. “I look forward to executing on our strategy, advancing our clinical pipeline to successful approval of CYB003 and CYB004, and working closely with our partners as we move toward delivering innovative new therapies for patients in need,” So stated. CYB003 is a deuterated psilocin analog in Phase III studies for adjunctive treatment of major depressive disorder, while CYB004 is a deuterated N, N-dimethyltryptamine molecule in a Phase II study for generalized anxiety disorder.
- Mineralys (NASDAQ: MLYS) shares rocketed 86% Tuesday, from $15.48 to $28.86, as the company benefited from positive Phase III data published in the New England Journal of Medicine by AstraZeneca (London: AZN) for baxdrostat, a blood pressure treatment with a similar mechanism to Mineralys’ lead candidate lorundrostat. AstraZeneca reported that baxdrostat showed statistically significant and clinically meaningful reduction in systolic blood pressure in patients with hard-to-control hypertension in the BaxHTN trial (NCT06034743). Baxdrostat 2 mg lowered systolic blood pressure by 15.7 mmHg (9.8 mmHg placebo-adjusted) from baseline. AstraZeneca shares rose 3% over two days, from 11,850 pence Monday to 12,210 pence Wednesday, on the positive baxdrostat news. After the close of trading Tuesday, Mineralys priced an upsized $350 million underwritten public offering of 9,803,921 shares at $25.50 per share.