The Wind of Oligonucleotide Therapeutics Keeps Blowing: Arrowhead Pharmaceuticals Files IPO Prospectus Amid Strategic Deals and Pipeline Momentum

Amino Observation - Original Production by the Innovative Drug Team

Author | Sha Xiaowei

/ 01 /

Novartis Already "On Board"

In just two days, Novartis successively invested heavily to collaborate with Arrowhead and Argo Biopharma, covering chronic disease areas such as Parkinson's and cardiovascular diseases.On the surface, it is about pipeline supplementation, but in fact, it is a continuation of its long-term strategy.

On September 2, Novartis took the lead in reaching a global licensing and collaboration agreement with Arrowhead for the siRNA therapy ARO-SNCA. According to the agreement, Novartis paid an upfront fee of $200 million directly and will subsequently undertake potential milestone payments of up to $2 billion.

ARO-SNCA Utilizes Arrowhead's Proprietary Targeting RNAi Molecule (TRiM) Platform for Subcutaneous Administration and Delivery to the Central Nervous System, Aiming to Target the Gene Encoding α-Synuclein, and Is Considered a Potential Disruptive Therapy in the Field. Additionally, Under the Terms of the Agreement, Novartis Has the Option to Select Other Disease Targets Outside of Arrowhead’s Existing Pipeline to Leverage the Latter’s Technology Platform for Development.

What Novartis is interested in, essentially, is Arrowhead's CNS delivery platform.ARO-SNCA’s TRiM Platform Enables Subcutaneous Administration, Achieving Non-Invasive Blood-Brain Barrier Penetration via Transferrin Receptor Targeting Ligand, with Monthly or Quarterly Dosing and a Sufficient Safety Window. Previously, Arrowhead's CEO Stated That the Platform Has "Produced Impressive Preclinical Results Demonstrating Delivery to the Central Nervous System After Subcutaneous Injection, Including Distribution to Deep Brain Regions."

The next day, Novartis paid $160 million as an upfront payment, with potential milestone payments reaching up to $5.2 billion, once again partnering with Argo Biopharma. This collaboration involves four siRNA drugs, two of which are in the early stages of development for treating cardiovascular diseases.

This is the second major collaboration between the two parties in just over a year, highlighting Novartis' urgent need to strengthen its cardiovascular business.

Looking back at Novartis' layout in the small nucleic acid field, big moves have long become the norm. In 2019, Novartis spent $9.7 billion to acquire The Medicines Company, bringing in Leqvio, the world's first small nucleic acid drug targeting PCSK9.

This drug breaks the treatment limitations of traditional lipid-lowering medications, effectively controlling cholesterol with only two injections per year. After its launch, it quickly became one of the core growth drivers of Novartis' cardiovascular sector, allowing Novartis to truly experience the benefits of small nucleic acids.

From this point on, Novartis' layout in the small nucleic acid field has become increasingly deep.

In 2023, it acquired DTxPharma for $1 billion, obtaining the proprietary Falcon lipid nanoparticle delivery platform.

Since 2025, Novartis has accelerated its acquisition spree.In June, Novartis acquired Regulus Therapeutics for $1.7 billion, securing the microRNA therapy farabursen for the treatment of autosomal dominant polycystic kidney disease.

In August, there were reports that Novartis was planning to acquire Avidity Biosciences, a pioneer in the AOC (antibody-oligonucleotide conjugate) field, which currently has a market value of nearly $60 billion.

In September, Novartis successively closed the aforementioned two major deals, expanding its small nucleic acid pipeline from cardiovascular diseases to kidney diseases and further into neurological disorders. More importantly, its strategic layout is not limited to late-stage pipelines with higher certainty but also heavily invests in early-stage pipelines, core delivery technology platforms, and diversified technological approaches.

Overall, after several years of investment, Novartis' small nucleic acid pipeline has been fully rolled out, covering various technical types such as RNAi, ASO, and ligand therapies. The targets include more than 20 types such as PCSK9, ASGPR, apo(a), Tau, and miR-17, with indications spanning multiple fields including cardiovascular, neurology, infectious diseases, and rare diseases.

This kind of intensive investment essentially reflects a precise grasp of industry trends.Small nucleic acid drugs, with advantages such as precise targeting and long-lasting effects, are regarded as a core direction for next-generation drug research and development. In addition to Novartis, major pharmaceutical companies including Novo Nordisk, Regeneron, Roche, and Pfizer have also turned their attention to this field.

/ 02 /

More and More Biotechs Going Public

As large pharmaceutical companies continue to increase their investments, more biotech companies in the small nucleic acid赛道 are also succeeding.

In the past, Alnylam was almost the sole successful benchmark in the entire field: from Onpattro to Givlaari, Oxlumo, and then vutrisiran, Alnylam advanced RNAi drugs from research and development, through clinical trials, and into commercialization.

Especially with the commercial explosion of vutrisiran, Alnylam is finally seeing the dawn of profitability, which has also driven its market value to soar, currently exceeding $60 billion.

And recently,Arrowhead, the second player in RNAi, has also shown signs of its upcoming success.

If Alnylam is a model of "growth in favorable conditions," then Arrowhead is a typical example of "breaking through adversity."

As a platform company centered on RNAi therapeutic technology, Arrowhead has a broad pipeline layout, covering rare diseases and high-incidence diseases. However, due to its financing strategy mistakes, the company has been overshadowed by a tight cash flow.

The 2024 financial report shows that its cash balance was only $680 million, which, at the current pace of R&D investment, could only cover two years of expenses; compounded by the suspension of ARO-ENaC due to safety concerns and the failure of collaborative projects to meet clinical data expectations, financial pressures and R&D setbacks have cast a shadow over the company’s future.

Fortunately, turning points have emerged intensively within a year, and BD collaboration has become the key to resolving the financial dilemma.

In November 2024, its collaboration with Sarepta Therapeutics successfully closed. Arrowhead received a $500 million upfront cash payment, and Sarepta purchased its stock for $325 million. Milestone payments could reach up to $10 billion. By the end of July this year, a $100 million milestone payment had already been triggered, with an additional $200 million milestone payment expected to be triggered by the end of the year.

In early August, Sanofi reached an agreement with its subsidiary Visirna to obtain the exclusive rights for the development and commercialization of Plozasiran in Greater China. Visirna received an upfront payment of $130 million and potential milestones of $265 million.

Based on these partnership advancements, Arrowhead's management clearly stated in the Q3 earnings call that their cash reserves are now sufficient to last until 2028 and can support the commercial launch of multiple proprietary and partnered products.

The recent collaboration with Novartis further solidifies its cash flow: a $200 million upfront payment, plus potential milestone payments of up to $2 billion. On the day the collaboration with Novartis was announced, Arrowhead's stock price surged by 17%.

Looking at the longer term, since its stock price hit a record low in April this year, the increase has exceeded 200%.Obviously, as cash flow improves, the outside world is expecting Arrowhead to become the next Alnylam.

This is not difficult to understand. Arrowhead's technology in the small nucleic acid field is beyond doubt. The past difficulties were more due to the precarious financial reserves before achieving real commercial success, which made it hard to gain market recognition.

With the current cash flow gradually improving, Arrowhead is also in a critical transition period from research and development to commercialization. The core product Plozasiran is less than two months away from the U.S. PDUFA date of November 18, 2025, and is expected to be approved for marketing within the year. The company's related commercial construction is proceeding as planned, and the full team supporting the Familial Chylomicronemia Syndrome (FCS) market launch is about to be completed.

In addition, another indication of Plozasiran for the treatment of severe hypertriglyceridemia has completed Phase 3 clinical enrollment and is expected to be completed by mid-2026; the weight loss pipeline is advancing gradually, Alzheimer's disease also shows positive progress, and a dual-target (PCSK9+APOC3) therapy is expected to enter clinical trials within the year; the late-stage pipeline in collaboration with Takeda and Amgen is also expected to yield returns in the next two years.

The core product is about to be launched, with a rich and deeply diversified pipeline (multiple late-stage and early-stage projects), robust financial status (recently received substantial cash inflow), and possesses a technology platform driving future growth...In summary, as the small nucleic acid track continues to explode, Arrowhead is also reversing market expectations through a series of deals and clinical progress.

/ 03 /

A New Cycle for Small Nucleic Acids

Of course, the buzz around small nucleic acids is not just happening overseas.

In China, financing and clinical progress in this field are also ongoing. Not only is there the dark horse Argo Biopharma, but on September 8, Huaxi Biotech invested HKD 1.38 billion to subscribe for 11,568,300 shares of Sirnaomics, which had previously fallen into difficulties due to funding issues; At the ESC conference, Ribo partnered with Ribocure to jointly release four significant results of siRNA in the cardiovascular field; HR-SIR01, an siRNA drug developed by Hengrui Medicine, was included in the breakthrough therapy program; On September 17, Mabwell collaborated with Aditum Bio to establish NEWCO cooperation, jointly founding Kalexo Bio to advance the development of the cardiovascular siRNA therapy 2MW7141.

All trends indicate that small nucleic acid drugs have officially entered a new development cycle, from overseas to China, and from industry to capital. This round of growth has gained momentum and is well within expectations.

First, small nucleic acid drugs at the technical levelIt has an inherent advantage.

Compared with small molecules and antibody drugs, small nucleic acid drugsDirectly targeting mRNA or non-coding RNA, blocking protein generation at the source of gene expression. This characteristic gives it a unique advantage, whether in the precise regulation of defective genes in rare diseases or effective intervention on undruggable targets in chronic diseases and even CNS.

More crucially, with the maturation of chemical modification and delivery technologies, the stability and targeting of small nucleic acid drugs have significantly improved. The GalNAc conjugation technology enables highly efficient liver enrichment, the LNP system facilitates the breakthrough of the blood-brain barrier, and chemical modifications further reduce potential toxicity issues. Multiple technological optimizations have created a "platform" that continuously gives rise to new-generation products.

Secondly, the commercial explosion of the pioneers is also driving small nucleic acid drugs.Entering a New Stage.

The total number of small nucleic acid drugs approved globally has now increased to 22 (of which 3 have been withdrawn), showing a trend of expanding from rare diseases to chronic and common diseases, with even more impressive commercialization achievements.

A typical example is Vutrisiran, mentioned earlier. Since its launch in 2022, its sales have continued to rise, nearing $1 billion in 2024. Following the approval of the ATTR-CM indication in March this year, Vutrisiran has seen rapid growth, with second-quarter sales reaching $492 million, a year-over-year increase of 114%. This has also driven better-than-expected overall revenue growth for Alnylam.

Novartis' Leqvio is also experiencing rapid growth. In the first half of 2025, Leqvio's sales increased by 66% year-over-year, reaching $555 million, accounting for nearly one-third of the new revenue in Novartis' cardiovascular segment. More importantly, Leqvio has demonstrated the significant efficacy, affordability, and long-term compliance advantages of small nucleic acid drugs in large-scale chronic disease markets, such as hyperlipidemia.

When "the unlimited potential of technology" meets "the scalable realization of commerce," small nucleic acids are no longer "a promising future" but have entered a new cycle of substantial volume growth and value reassessment.

Of course, beneath the heat, the road is anything but smooth: the long-term safety needs continuous verification; the increasingly fierce global patent layout competition has also become a key strategic point. Whether these thresholds can be crossed will also determine a company's position in the new cycle.

But there is no doubt that, with unique therapeutic advantages and continuously maturing platform technologies, the trend of small nucleic acids will undoubtedly grow stronger.

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