Oligonucleotide Therapeutics on the Verge of Commercial Breakthrough: Opportunities for Innovative Biopharma Companies

Small nucleic acid drugs have always been well-received in the market but have not gained significant traction.

In 2020, the global sales of nucleic acid drugs were approximately US$3.5 billion. Among them, the highest sales were for Spinraza (i.e., Nusinersen Sodium) co-developed by Ionis and Biogen, generating revenue of US$2.052 billion, a figure far lower than the US$14.68 billion achieved by that year's global pharmaceutical sales champion, Adalimumab.

For most people, small nucleic acid drugs are a distant concept, with indications mostly targeting rare diseases. For instance, Spinraza is used to treat spinal muscular atrophy, a rare and fatal genetic disorder, with an incidence rate of 1:6000-1:10000 in newborns. Therefore, even though it has been nearly 20 years since the development of such drugs began, and despite the continuous market entry of new drugs since 2018, leading pharmaceutical companies specializing in small nucleic acid drugs still seem to struggle to establish an overwhelming advantage over their competitors in any major disease area.

However, this situation is changing. In early August this year, Alnylam, the global flagship company in small nucleic acid drugs, announced positive results from a Phase III clinical trial called APOLLO-B for its siRNA drug Patisiran. Data showed that Patisiran significantly improved symptoms in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), enhancing 6-minute walk test metrics and quality of life. Patisiran also demonstrated good safety and may be launched within the year. At this point, Alnylam's product and pipeline system has taken the lead in multiple indications within the ATTR disease field. In other words, Alnylam has established a leading position in the ATTR disease area.

Upon the release of the news, the long-depressed stock price of Alnylam soared nearly 48%, with its market value reaching $25.5 billion. After years of ups and downs in the global clinical market, small nucleic acid drugs have finally arrived at the eve of commercial explosion.

ATTR is not a specific disease but a general term for a class of diseases.

If the ATTR lesions occurring in various organs are all taken into account, the number of newly diagnosed patients with such diseases globally reaches hundreds of thousands each year. Due to the lack of sufficiently efficient clinical solutions, ATTR has remained a focal point for research and development among major pharmaceutical companies. Apart from small nucleic acid drugs, multiple approaches including traditional drugs and gene therapy have been deployed. This is one of the reasons why Alnylam's breakthrough in ATTR treatment has drawn significant attention.

Specifically, ATTR is a disease caused by the deposition of transthyretin (TTR) in various organs. TTR protein is mainly produced by the liver, and if it undergoes pathological changes due to genetic mutations or acquired factors, TTR protein can deposit as fibrils in multiple organs such as the heart, digestive tract, urinary system, and nervous system, thereby affecting their functions. For instance, ATTR-CM in the APOLLO-B trial refers to the fibrillar deposition of TTR protein in the heart, which is the most harmful type of ATTR disease. It usually leads to a high incidence of heart failure, with 200,000 to 300,000 people developing ATTR-CM each year.

In terms of treatment options, apart from the three generations of small nucleic acid drug systems developed by Alnylam, there are also two TTR stabilizers that are quite active in the market: Tafamidis from Pfizer and Acoramidis from BridgeBio. Additionally, there is Eplontersen, an ASO nucleic acid drug developed by Ionis and AZ, and NTLA-2001, a gene-editing drug developed by Intellia and Regeneron. However, these drugs either have unsatisfactory efficacy or safety data, or their development progress is lagging behind. Therefore, Alnylam's advantage in ATTR has become very clear.

Specifically, Tafamidis, the world's first approved ATTR drug, has been consistently targeted for replacement by competing products due to its poor efficacy and safety profiles, as well as its inability to halt or reverse the disease. Meanwhile, Acoramidis, a rising contender, temporarily withdrew from the competition after failing to meet the primary clinical endpoint in a Phase III clinical trial for ATTR-CM that concluded at the end of last year. In addition, Eplontersen, the next-generation product from nucleic acid drug giant Ionis in the TTR field, and NTLA-2001, a key representative of gene-editing drugs, are still far from registration and market entry. The former has just initiated a Phase III clinical trial, with meaningful clinical data not expected until 2025, while the latter’s early-stage clinical trial for ATTR has only recently completed patient enrollment and remains in a very early stage of commercial development.

Since the first small nucleic acid drug was approved for marketing, nearly 10 small nucleic acid drugs have been successively marketed worldwide, but their influence in clinical treatment has been very limited.This time, Alnylam's consecutive development of multiple generational products dominating the ATTR field, which affects a large patient population, is undoubtedly a significant milestone in the commercialization process of small nucleic acid drugs.

For any pharmaceutical company, conquering the high ground of a disease represents a significant victory in its development journey. Particularly for innovative companies deeply engaged in the frontier technology of small nucleic acid drug development, this is an exceedingly difficult yet correct endeavor.

In fact, if we carefully analyze the clinical strategy adopted by Alnylam, it is not difficult to find that although ATTR is not the only area where Alnylam has focused its efforts (for example, Inclisiran, which has already been out-licensed, has shown great potential in the cardiovascular disease field), the company has indeed put considerable thought into this disease area with a large patient population.

Specifically, Alnylam has gradually captured the market by continuously exerting efforts in both vertical and horizontal dimensions. In the vertical dimension, through rapid technological iteration, Alnylam has developed three generations of small nucleic acid drug products targeting the same disease area, forming an encirclement against competitors. In the horizontal dimension, during the development of drugs within the same generation, Alnylam starts with relatively simple indications and progresses gradually, thereby advancing clinical trials with a lower-risk strategy.

Vertically, Patisiran is actually Alnylam's first-generation product in the ATTR disease field, which was approved for marketing as early as August 2018. In June this year, Alnylam's second-generation product for ATTR disease, Vutrisiran, was also approved for marketing. Similar to Patisiran, Vutrisiran’s first indication chose the smaller patient group of hATTR-PN, and after achieving phased commercial success, it was further pushed by Alnylam for application in ATTR-CM. Currently, Vutrisiran's ATTR-CM indication clinical trial Hellios-B is in the critical Phase III.

Compared with the earlier Patisiran, the iteration of Vutrisiran mainly reflects the adoption of the more advanced GalNAc conjugated drug delivery platform. The method of administration has changed from intravenous to subcutaneous, and the dosing cycle has been extended to once every 3 months, or even once every 6 months, significantly improving the operability for clinicians and the medication adherence for patients.

In addition, Alnylam has another third-generation ATTR drug, ALN-TTRsc04. Designed using lkaria technology, ALN-TTRsc04 further extends the dosing interval compared to the second-generation drug Vutrisiran, with the potential to achieve an annual dosing schedule akin to a vaccine, requiring only one injection per year. However, despite demonstrating high stability and efficacy in preclinical studies, ALN-TTRsc04 is still in a relatively early stage.

This shows that, from Patisiran to Vutrisiran, and then to ALN-TTRsc04, Alnylam has relied on self-evolution to develop generation after generation of products, becoming the leader in the ATTR treatment field. This process is very similar to Vertex Pharmaceuticals' gradual dominance in the cystic fibrosis treatment field.

In terms of breadth, the situation is relatively straightforward. As mentioned earlier, Patisiran was initially approved for hATTR-PN, a relatively small disease area with only 20,000 to 30,000 patients globally each year. For Alnylam, the greater value of hATTR-PN lies in validating the commercialization of Patisiran itself, rather than serving as a tool for expanding commercialization.

As new indications such as ATTR-CM are added to Patisiran, the eligible patient population for this innovative drug is rapidly expanding, and its own commercial and clinical value is also dramatically increasing within a manageable R&D risk. As Dr. Yang Lu, founder and CEO of Sirnaomics, previously stated in an interview with VCBeat, "The development of new drugs is a protracted battle, a gradual and progressive process. For a company to go far, it must proceed steadily—this is especially true for the creation of small interfering RNA drugs."

Of course, Alnylam's sophisticated strategy in drug clinical trials would be merely illusory without the support of a critical small nucleic acid drug delivery platform.

In theory, small nucleic acid drugs are an ideal type of drug that can provide solutions for many challenging diseases in clinical practice.

On one hand, the drug-like properties of these medications are relatively high. Under current technological conditions, small nucleic acid drugs can silence any gene within the liver. Theoretically, as more delivery technologies are developed, small nucleic acid drugs could target every gene in the entire genome, whereas traditional small molecule drugs and antibody drugs can only target about 4% of gene products with marketed drugs.

On the other hand, small nucleic acid drugs have a relatively long half-life, resulting in a longer dosing cycle. Moreover, compared to gene therapy, small nucleic acid drugs only involve mRNA without affecting the genome, which means they offer higher safety.

But in reality, small nucleic acid drugs still face many challenges. For instance, after injecting small nucleic acid drugs into patients, how can the drugs remain in the body for a sufficient period? Additionally, how to precisely deliver therapeutic small nucleic acids into target cells to exert their therapeutic function while minimizing harm to normal cells is one of the core issues faced by small nucleic acid drugs, requiring the development of suitable drug delivery systems to address. Previously, several multinational pharmaceutical companies failed in the research and development of small nucleic acid drugs, largely due to the lack of an effective drug delivery platform.

At present, with the continuous exploration of global small nucleic acid drug development companies including Alnylam, scientists have found some drug delivery systems with relatively ideal performance in drug development. This has placed small nucleic acid drugs at a turning point for application explosion.

Specifically, the mainstream small nucleic acid drug delivery systems include Lipid Nanoparticle (LNP) delivery systems, conjugate delivery systems, polymeric nanoparticle delivery systems, etc. Among them, LNP is the earliest applied delivery system, using lipids to form nanoscale particles with a vesicle structure composed of a phospholipid bilayer. By loading nucleic acid drugs into LNPs, the encapsulated nucleic acid drugs can be protected from degradation and clearance, and their transport across cell membranes to the target site can be promoted.

The first-generation ATTR product Patisiran developed by Alnylam, as mentioned earlier, uses LNPs to deliver small nucleic acids that target and degrade the mRNA involved in the production of TTR protein. The disadvantage of LNPs as a delivery platform lies in the fact that the fundamental principle dictates that this type of small nucleic acid drug primarily targets the liver, which can easily trigger adverse reactions such as allergies. Later, Alnylam developed a conjugated delivery system represented by GalNAc, which improved the targeting specificity of small nucleic acid drugs and reduced drug clearance in circulation. However, it is still mainly used for liver administration and faces challenges with endosomal escape.

With the continuous iteration of delivery technologies, polymeric nanoparticle delivery systems similar to the LNP delivery mechanism have emerged. These systems offer stability and controlled release, can encapsulate large amounts of genetic material, allow for co-delivery, and can be easily surface-modified to enhance stability, transport characteristics, targeting, or uptake. Among these, a representative example is Sirnaomics' proprietary Peptide Nanoparticle (PNP) delivery platform.

According to Dr. Yang Lu, founder and CEO of Sirnaomics, in a previous media interview, he introduced that in the LNP system, small interfering nucleic acid molecules are encapsulated inside hollow nanoparticles, while in the PNP system, peptides and small interfering nucleic acid molecules are entangled and coiled together, thereby enabling the PNP system to possess higher targeting and efficiency in entering cells.

"Compared with GalNAc conjugation technology, the PNP delivery system is still relatively in its early stages, with only the successful example of STP705 in Phase II clinical trials," said Dr. Lu Yang. "However, considering its application attempts in cancer treatment and fibrotic disease treatment, it is evident that this delivery system holds tremendous potential for the application of nucleic acid interference drugs."

VCBeat learned that currently, Sirnaomics has applied its PNP technology, which is covered by global intellectual property rights, to the development of small nucleic acid drugs for various indications to treat diseases including cancer, fibrotic diseases, and viral infections. Additionally, through its self-innovated and optimized GalNAc conjugation technology, the company is specifically developing drugs for liver metabolic diseases. At this stage, Sirnaomics' two core candidate products are undergoing safety and efficacy evaluations in clinical trials and have entered the intense development phase prior to large-scale commercialization.

Notably, if we review Sirnaomics' pipeline layout, it's not difficult to see that it also conceals a logic similar to Alnylam's纵横strategy.

In terms of vertical development, Sirnaomics' core products, STP705 and its upgraded version STP707, utilize different peptide nanoparticles. STP705 is specifically designed for localized treatment, while STP707 is more suitable for systemic clinical administration. STP122G, supported by the proprietary GalNAc technology platform, demonstrates clear targeting of hepatocytes and long-lasting target knockdown. All three candidates adopt a horizontal layout strategy of advancing multiple indications simultaneously.

At the same time, in the selection of indications, Sirnaomics has adopted an approach of starting with relatively niche diseases and then breaking boundaries into more common diseases.

Taking STP705 as an example, it has not only served as a breakthrough in clinical trials for the treatment of squamous cell carcinoma (SCC) but has also further expanded into clinical trials for the treatment of basal cell carcinoma (BCC), which has significant clinical demand, and has even extended to clinical trials for liver cancer treatment.

An incidental finding in clinical trials has further advanced STP705 into the field of medical aesthetics for fat reduction, with clinical trials already proceeding rapidly. As clinical trials targeting various indications continue to progress and expand, STP705 is expected to become a significant drug covering multiple therapeutic areas such as oncology, fibrotic diseases, and medical aesthetics in the future.

The expansion of clinical development for systemic intravenous administration through STP707 is continuing with a similar strategy. Initially, a "basket" Phase I trial targeting liver cancer will pave the way for subsequent Phase II clinical trials, establishing a solid foundation including confirmation of optimal clinical indications, dosage, and scheduling parameters. This will then extend to the treatment of non-small cell lung cancer and systemic metastatic squamous cell carcinoma.

The phase I clinical trial of STP707 for the treatment of primary sclerosing cholangitis also showed some breakthroughs. The subsequent multi-faceted development strategy laid the foundation for the later treatment of pulmonary fibrosis and renal fibrosis.

As Sirnaomics' first GalNAc RNAi candidate drug advanced to clinical trials, STP122G will progressively expand in the anticoagulant therapy field through the optimized GalAhead™ structural design developed via proprietary innovation.

Given Sirnaomics' deep presence in both China and the U.S., its pipeline expansion plans and late-stage clinical development strategies are implemented with comprehensive consideration of the broad demands of the global market and the specific urgent clinical needs in China. For instance: by first advancing multiple clinical trials in the U.S., and after obtaining a series of clinical data and gaining extensive experience in addressing regulatory requirements, the company accelerates the clinical trial process and market commercialization in China. Another example: through STP707 entering the fast track for "orphan drug" clinical indications (Primary Sclerosing Cholangitis) in the U.S., it provides solid clinical data and regulatory support for the same indication which has significant clinical urgency and market demand in China.

Nowadays, small nucleic acid drugs are about to complete the last mile before the market explosion, and will usher in a golden development period in the global pharmaceutical industry. We also look forward to this theoretically ideal drug providing more efficient clinical solutions for all humanity in more disease areas in developed countries and China.