Will RNAi Break Through Hepatitis B? Alnylam's Rising Valuation and Pipeline Spotlight
Recently, the stock price of Alnylam Pharmaceuticals, a global leader in RNAi therapeutics, hit a new high, peaking at $212 on October 14, 2021, and its market capitalization exceeded $25 billion for the first time. Looking back over the past two decades, Alnylam’s development has closely mirrored the trajectory of RNAi technology. Highly anticipated during the first decade of the 21st century, the company encountered significant challenges along the way, but the technology ultimately made a strong comeback, entering the slope of enlightenment on the Gartner Hype Cycle.
The resurgence of RNAi technology has been driven by advances in delivery systems. siRNA faces two major challenges in entering cells: first, exposure to blood compromises its stability and triggers immunogenicity; second, the large, negatively charged siRNA molecules cannot cross cell membranes on their own. The third-generation GalNAc (N-acetylgalactosamine)-based delivery platform, with its low immunogenicity, low cytotoxicity, and high targeting specificity, has addressed several limitations encountered with second-generation lipid nanoparticle (LNP) delivery in liver diseases. This has enabled siRNA therapeutics to make significant strides in hepatology, supporting the approval and market launch of four products to date.
The GalNAc trend led by Alnylam has given it a significant first-mover advantage. This is why all siRNA products approved for market launch to date are associated with Alnylam. Having achieved phased milestones, RNAi technology is now targeting the larger, more complex, and more challenging liver disease market.Hepatitis B May Become One of the Next Frontiers Conquered by RNAi
Tracing Alnylam’s strategic layout in the hepatitis B field, its lead candidate entered clinical trials as early as 2016, two years ahead of Arrowhead Pharmaceuticals, which is currently a frontrunner. On October 15, 2021, Vir Biotechnology, Alnylam’s partner in hepatitis B, announced that preliminary results from the Phase II clinical study of VIR-2218 would be presented orally at the AASLD (American Association for the Study of Liver Diseases) conference in November. This drug is ALN-HBV02 from Alnylam mentioned earlier; in China, it is being developed by Brii Biosciences and is therefore known as BRII-835.
In fact, it is not just Alnylam or Vir Bio; many other multinational pharmaceutical companies and biotech firms are also attempting to achieve a functional cure for hepatitis B via the RNAi pathway. So, how is this niche sector developing? Have we begun to see the dawn of a functional cure for hepatitis B?
In the field of RNAi technology, delivery systems have long been at the center of discussion. Lipid nanoparticles (LNPs) have served as the cornerstone method for siRNA delivery for an extended period, and Alnylam has continuously optimized its LNP delivery platform during its first decade of development.
In August 2018, ONPATTRO (patisiran), developed by Alnylam, received approval from the U.S. FDA, becoming the first RNAi therapeutic approved globally for the treatment of polyneuropathy caused by hereditary transthyretin (TTR)-mediated amyloidosis in adults. With the iteration of delivery technologies, this innovative drug has also become the sole product launched by Alnylam on its second-generation lipid nanoparticle (LNP) delivery platform.
Prior to the approval of ONPATTRO, Alnylam had already made significant strategic investments in new delivery technologies centered around GalNAc. Since the approval of its first product, Alnylam has subsequently gained approval for additional products, including Givlaari for the treatment of acute hepatic porphyria (AHP) and Oxlumo for the treatment of primary hyperoxaluria type 1 (PH1). Novartis’s Leqvio, indicated for lowering low-density lipoprotein cholesterol (LDL-C), also utilizes this novel GalNAc delivery technology.
Following Alnylam’s successful commercialization of this technology, other siRNA companies, such as Arrowhead and Dicerna, have begun to adopt this delivery approach. Moreover, since the GalNAc mechanism can also be applied to antisense oligonucleotides (ASOs), ASO leaders like Ionis have started to actively strategize in this direction.
In this novel delivery approach, GalNAc is conjugated with siRNA to leverage the binding affinity between GalNAc and ASGPR (asialoglycoprotein receptor), which is specifically expressed on hepatocytes, thereby enabling precise delivery of siRNA to the liver.
The advantages of GalNAc delivery technology are very obvious; the efficiency of drug delivery to the liver will be greatly enhanced, but its application scenarios are limited to the field of liver diseases.Certainly, according to the public information disclosed on Alnylam’s official website, they appear to have identified new conjugate molecules capable of delivering therapeutics to the eye and the central nervous system (CNS). However, the specific technologies have not yet been disclosed, nor are they the core focus of our discussion in this article.
In summary, owing to the potent efficacy of GalNAc delivery technology, approximately half of Alnylam’s current product pipeline is focused on liver diseases, including well-known refractory conditions such as non-alcoholic steatohepatitis and α-1 antitrypsin deficiency-associated liver disease.Given this extensive focus on severe liver diseases, hepatitis B—one of the most widespread infectious diseases globally—is naturally among Alnylam’s key targets.
In October 2017, Alnylam and Vir Biotechnology entered into a collaboration agreement worth up to $1 billion to jointly develop and commercialize RNAi therapies for various infectious diseases, with ALN-HBV02 being the first product under this partnership.
During that period, Alnylam’s products experienced consecutive safety issues. In October 2016, clinical trials for both ALN-AAT and revusiran were halted due to safety concerns, causing Alnylam’s stock price to nearly halve within a single day. However, Alnylam did not abandon these therapeutic areas; instead, it responded by upgrading its products, with ALN-HBV02 being one such example.
After Vir Bio took over, ALN-HBV02 was renamed VIR-2218. Shortly thereafter, in October 2018, Vir Bio transferred the Greater China rights for this product to Brii Biosciences. Therefore, in China, this product should be referred to as BRII-835.
According to data from the *2020 China Health Statistics Yearbook*, the annual number of new hepatitis B cases in China exceeded 1 million between 2017 and 2019. It is estimated that there are approximately 86 million hepatitis B carriers in China, of whom around 28 million require standardized treatment.
Current mainstream medications for hepatitis B are primarily nucleos(t)ide analogs, such as entecavir and tenofovir. Most of these drugs have exceeded their patent periods, resulting in a large number of generic products on the market. Nevertheless, the originator companies continue to generate significant revenue from these products. In the Q3 2021 quarterly report released in October, Bristol Myers Squibb’s Baraclude (entecavir) achieved $105 million in revenue; Gilead’s Vemlidy (tenofovir alafenamide fumarate) maintained strong performance, with single-quarter sales reaching $208 million, a year-on-year increase of 17.5%, and cumulative sales of $589 million for the first three quarters, representing a year-on-year growth of 26.9%. These medications, which have been on the market for over a decade or even two decades, remain the cornerstone of current hepatitis B treatment.
Current antiviral therapies for hepatitis B can only suppress HBV replication, requiring patients to take medication for life. Moreover, existing treatments do not inhibit the expression of hepatitis B antigen proteins, such as the hepatitis B surface antigen (HBsAg). These antigen proteins continue to impair patients’ immune function and may also lead to cell necrosis and inflammation, thereby contributing to the development of liver cirrhosis.Therefore, given that a complete cure for hepatitis B is not currently achievable, the pragmatic approach is to first aim for a functional cure of hepatitis B.
Regarding the functional cure of hepatitis B, we cite here the description from the “Expert Consensus on Clinical Cure (Functional Cure) of Chronic Hepatitis B,” published in 2019 by the Branch of Infectious Diseases and the Branch of Hepatology of the Chinese Medical Association:
Clinical cure (also known as functional cure) of chronic hepatitis B (CHB) refers to the state achieved after a finite course of treatment, characterized by persistently undetectable serum HBsAg and HBV DNA, HBeAg seroclearance, with or without HBsAg seroconversion, alleviation of hepatic inflammation, improvement in histopathology, and a significant reduction in the incidence of end-stage liver disease. This is currently recommended as the ideal therapeutic goal in the latest domestic and international guidelines for the prevention and treatment of CHB.
In layman's terms, it involves controlling the expression of hepatitis B virus (HBV) antigen proteins and restoring the function of the body’s immune system, thereby enabling patients to curb the harmful effects of HBV through their own immune responses without the need for long-term medication.
Therefore, the clinical study data disclosed for the RNAi therapeutics we have seen so far all revolve around hepatitis B antigen proteins, with HBsAg being the most frequently reported.
In this highly focused niche, the leading products exhibit a high degree of similarity.The primary active ingredients are all siRNAs, and the delivery route for each adopts the GalNAc technology platform. This applies to BRII-835 from Brii Biosciences, JNJ-3989 developed by Johnson & Johnson in collaboration with Arrowhead Pharmaceuticals, and RG6346 (RO7445482) developed by Roche in partnership with Dicerna Pharmaceuticals, as mentioned earlier. Furthermore, this similarity is reflected in their clinical studies, where these products have demonstrated highly comparable performance.
Based on the monotherapy clinical results, the hepatitis B surface antigen (HBsAg) levels in subjects continued to decline for a period after dosing, reaching a nadir before slowly rising again. This trend was observed in the monotherapy studies of both BRII-835 and JNJ-3989. The intuitive interpretation of this result is thatRNAi monotherapy for hepatitis B is effective, but achieving a functional cure remains unlikely.
If monotherapy proves ineffective, dual-drug regimens are employed. Recognizing this issue, several companies have actively begun exploring combination therapies with other hepatitis B drugs, achieving promising clinical outcomes in these combination treatments.
First, most drugs have been chosen to be used in combination with nucleos(t)ide analogs.
Johnson & Johnson’s JNJ-3989, a liver-targeted, subcutaneously administered siRNA antiviral agent, demonstrated in combination with nucleos(t)ide analogs that 39% of patients achieved a sustained response—defined as an HBsAg reduction of more than 1 log—within 48 weeks after the last dose of JNJ-3989.10IU/mL. In the abstracts for the AASLD Annual Meeting scheduled for November 2021, which have already been released, partial clinical data from the REEF-1 study were disclosed. This study evaluated the combination of JNJ-3989 and JNJ-6379 with nucleos(t)ide analogues. The data showed that high-dose JNJ-3989 (≥100 mg) combined with nucleos(t)ide analogues maintained robust viral control, with 19.1% and 16.3% of patients in the 200 mg and 100 mg groups, respectively, achieving the primary endpoint. In contrast, the combination of JNJ-3989 with JNJ-6379 (a capsid assembly modulator) yielded less satisfactory results.
In clinical studies of RG6346 analogs, the patient cohort with the longest follow-up duration (1.5 mg/kg) exhibited a mean reduction in HBsAg levels of 1.40 log from baseline at Day 448.10IU/mL。
On this basis, some drugs have further explored additional combination therapies.
Vir Bio selected PEG-IFN-α as the combination partner for VIR-2218 (BRII-835). According to data presented at EASL 2021 in July 2021, among 12 participants receiving doses of 100 mg or 200 mg, four participants achieved a sustained reduction in hepatitis B surface antigen levels of >1 log by Week 48.10IU/mL, with an absolute HBsAg level below 100 IU/mL. Likewise, the company will further disclose Phase II clinical data for VIR-2218, both as monotherapy and in combination with pegylated interferon, at the upcoming AASLD Annual Meeting in November.
All three leading drug candidates have adopted combination therapies based on RNAi therapeutics plus other agents. Clinical results consistently point to the same conclusion: with appropriate dosing regimens, patients receiving combination therapy can maintain low levels of hepatitis B surface antigen (HBsAg) for a period of time even after discontinuation. However, further exploration is needed to identify the optimal combination partners and treatment regimens.
Among domestic companies, Brii Biosciences has advanced the furthest in the development of hepatitis B RNAi therapeutics.Brii Biosciences is an international innovative pharmaceutical company focused on infectious diseases and central nervous system (CNS) disorders. It was listed on the Hong Kong Stock Exchange in July 2021. During the nearly two-year pandemic, Brii Biosciences was one of the few innovative drug developers that advanced its COVID-19 neutralizing antibodies into Phase III clinical trials. The combination therapy of BRII-196/BRII-198 achieved positive interim results in international Phase III clinical trials and submitted an Emergency Use Authorization (EUA) application to the U.S. FDA in October 2021.
If Brii Biosciences’ success in COVID-19 therapeutics exemplifies its capabilities in independent R&D and its profound understanding of infectious disease treatment, then its strategic footprint in other infectious disease areas demonstrates that its business development (BD) prowess is no less formidable than its research and development strengths.
In line with international trends, Brii Biosciences has also opted for combination therapy based on RNA interference (RNAi), pairing it with BRII-179 (VBI-2601), a product licensed from VBI Vaccines.
In December 2018, Brii Biosciences publicly announced the establishment of multiple research collaborations, with BRII-835 and BRII-179 prominently featured. In retrospect, the strategy for this drug combination appears to have been determined at that time. Regarding the clinical development of these two products, Brii Biosciences has also prioritized the development of combination therapies, while advancing only the China portion of global multicenter studies for monotherapy.
So why did Brii Biosciences choose the combination of these two products?
BRII-835 has been extensively discussed above; its primary mechanism is to suppress the expression levels of HBV proteins, including hepatitis B surface antigen (HBsAg). The reduction in HBsAg expression helps restore the patient’s own immune response against hepatitis B virus infection.
BRII-179, by contrast, takes a different approach. BRII-179 is a recombinant protein-based immunotherapy that induces HBV-specific adaptive immune responses by simultaneously targeting B cells and T cells, thereby achieving sustained immune control.
When these two drugs are combined, BRII-835 targets the virus by reducing hepatitis B surface antigen (HBsAg) expression and inhibiting the ability of the hepatitis B virus (HBV) to affect the immune system; BRII-179 targets the immune system by enhancing its capacity to eliminate HBV. By simultaneously addressing HBV-induced immune suppression from two distinct angles, this combination therapy may converge on the goal of functional cure, achieving a synergistic effect greater than the sum of its parts (1+1>2).
Brii Biosciences has maintained a strategic focus on the siRNA field since before its establishment in 2018. As a pillar technology grounded in biological theory, siRNA holds significant potential for future growth. Brii Biosciences’ competitive advantage lies in its extensive industry network, which enables early-stage collaborations with cutting-edge technology companies and industry pioneers. By leveraging mutual deep insights into disease mechanisms, these partnerships facilitate the targeted development of innovative combination therapies.
In today’s era, where the license-out model has been validated, a review of successful business development (BD) strategies invariably hinges on three key aspects:Foremost is sensitivity to future trends,The ability to identify the future direction of industry development at an early stage of a project, and early intervention also reduces the company's BD costs to some extent;Second, adopt development strategies tailored to local conditions.Gain an in-depth understanding of the healthcare industry landscape both domestically and internationally, integrating drug R&D with regional strengths in disease profiles and technological capabilities;Finally, to validate feasibility, the ultimate foundation lies in the company’s comprehensive understanding of the disease.Understand patients' pain points and clinical needs, and promptly integrate these key insights into drug development.
China’s biopharmaceutical industry has just completed the transition from pure generic manufacturing to follow-on innovation, with emerging products showing potential for best-in-class status and gradually advancing toward first-in-class breakthroughs. In this process, proactively strategically licensing in promising overseas pipelines serves as an effective transitional strategy on the path to achieving first-in-class innovations.
Of course, on the path of development, a company’s forward-looking vision, advanced clinical R&D capabilities, and the execution power of its marketing team are all indispensable. All these elements require a sufficiently outstanding management team to drive them. Taking Brii Biosciences as an example: the company has not only made extensive strides in siRNA therapies, but its independently developed neutralizing antibodies for COVID-19 have also rapidly advanced to Phase III clinical trials, potentially entering the commercialization stage soon to compete with international pharmaceutical giants. For a biopharmaceutical company that has been established for less than four years, it would be difficult to achieve such comprehensive progress without the support of an experienced management team.
In the future, particularly in fields with a notably large patient population in China, such as hepatitis B, there will be an even greater need for companies like Brii Biosciences to introduce globally innovative products to the Chinese market, enabling patients to benefit from advances in diagnosis and treatment driven by the rapid development of biotechnology at a faster pace and lower cost.