The multibillion-dollar battlefield for "miracle drugs" against hepatitis B

GuangShengTang, once an obscure company, has suddenly become a soaring stock. In the past month, its share price has skyrocketed by over 220%. The catalyst for this continuous upward movement lies in the fact that GST - ZhongLin Bio, a subsidiary of GuangShengTang, has officially advanced its anti - hepatitis B virus drug, GST - HG141, into Phase III clinical trials.

To be fair, there is still a great deal of uncertainty between Phase III clinical trials and the final approval of a drug. Why does the market have such high expectations for GST - HG141? It all boils down to the urgent need for a "functional cure" for hepatitis B. As a country with a high burden of hepatitis B, China has 75 million hepatitis B virus carriers. Any clinical breakthrough can ignite the imagination of a multibillion - dollar market.

However, the reality is that there is still no specific drug that can "cure" hepatitis B to this day.

01 Why is Hepatitis B So Difficult to Conquer?

To this day, hepatitis B still remains shrouded in mystery, and its pathogenesis has not been fully elucidated.

The current mainstream view is that liver cell damage is not a direct result of the replication of the hepatitis B virus (HBV) within liver cells but is mediated by cytotoxic T - cell responses. After a person is infected with HBV, it triggers both cellular and humoral immune responses, as well as autoimmune reactions and disorders in immune regulation. While these immune responses aim to clear the virus, they also lead to the rupture and necrosis of infected liver cells, resulting in liver lesions.

Theoretically, clearing the hepatitis B virus can achieve a cure for hepatitis B, but the reality is far more complicated. After HBV invades liver cells, it forms covalently closed circular DNA (cccDNA) - a mini - chromosomal structure that can stably persist in the liver cell nucleus for a long time, becoming an ineradicable "virus reservoir." Existing drugs can only inhibit viral replication but cannot eliminate cccDNA. Even if the viral load in the blood is reduced to zero, these latent cccDNAs can remain "dormant" in liver cells for years or even decades. Once the medication is stopped, the virus may resurge, forcing patients to take medication for life.

Secondly, the game between the virus and the human immune system exacerbates the difficulty of virus clearance.

When infants are infected with HBV, their immune systems are not fully developed, making them prone to "immune tolerance" - they can recognize viral antigens but actively refrain from attacking, allowing the virus to multiply in liver cells. This tolerant state can last for decades, enabling the virus to "peacefully lurk" in the liver without obvious inflammation.

Although adult infected individuals can initiate an immune response, long - term exposure to the virus can lead to the "exhaustion" of specific T - cells: these immune cells, which are supposed to clear infected cells, over - express inhibitory receptors such as PD - 1 and CTLA - 4 on their surfaces, like being shackled, losing their killing ability. The large amount of surface antigen (HBsAg) secreted by HBV can "confuse" the immune system, inhibiting B - cells from producing neutralizing antibodies and forming a cycle of "immune silence."

Figure: The natural course of chronic hepatitis B, Source: Northeast Securities

Meanwhile, the high variability of the virus poses another obstacle. HBV replication relies on reverse transcriptase, which lacks a proof - reading function, leading to frequent mutations in the viral genome. These mutations can not only reshape the structure of viral proteins, inactivating drug targets (such as drug - resistant mutations in nucleoside drugs), but also disguise antigenic epitopes to evade immune recognition. Early drugs like lamivudine were gradually phased out due to a drug - resistance rate as high as 70%. Even more complex, multiple mutant strains may coexist in the same patient, forming a "quasispecies," like an ever - evolving "virus army," making it difficult for a single drug to cover all strains.

In addition, the "protection" of the liver microenvironment further strengthens the virus's survival advantage. The livers of chronic hepatitis B patients often accompany fibrosis. The fibrous septa formed by excessive collagen not only impede drug penetration but also stabilize cccDNA expression through a hypoxic and high - inflammatory - factor environment. Kupffer cells activated by the virus secrete a large amount of TGF - β, which promotes fibrosis and inhibits T - cell antiviral activity. Activated hepatic stellate cells release extracellular matrix, wrapping infected liver cells to form a physical immune isolation layer, hindering immune cell clearance.

This vicious cycle of "virus - inflammation - fibrosis" has plunged hepatitis B treatment into a "more complex as you treat" dilemma, making hepatitis B a synonym for "incurable" and constantly driving the exploration of new hepatitis B treatment drugs.

02 The Evolution History of Hepatitis B Drugs

The history of hepatitis B treatment can be traced back to the middle of the 20th century, and its development is closely related to the depth of human understanding of the biological characteristics of the virus.

In the era when the viral mechanism was not yet clear, doctors were almost helpless in the face of hepatitis B. Clinically, there were only liver - protecting drugs such as vitamins, glucurone, and inosine tablets. These drugs could relieve symptoms by reducing liver inflammation but could not stop viral replication. This stage was essentially a "non - treatment" state, where drugs could only soothe the damaged liver and had no deterrent effect on the virus itself.

It was not until 1986 when interferon α was approved that a new era of antiviral treatment began. Interferon inhibits the virus by activating the host's immune response, but with a response rate of less than 30% and severe side effects such as flu - like symptoms and bone marrow suppression, most patients were discouraged. In 1998, the first nucleoside drug, lamivudine, was launched. It terminates DNA chain extension by inhibiting viral reverse transcriptase and can reduce the viral load by tens of thousands of times in the short term. However, its one - year drug - resistance rate was as high as 20%, and the cumulative five - year drug - resistance rate exceeded 70%, forcing the rapid iteration to the second - generation adefovir dipivoxil. However, the latter has weak antiviral efficacy and renal toxicity, and can only be used as a salvage treatment option.

In 2005, the emergence of entecavir and tenofovir disoproxil fumarate (TDF) reshaped the hepatitis B treatment landscape. These two drugs improved the HBV DNA negative conversion rate to over 90% by enhancing the inhibition of viral reverse transcriptase, and the five - year drug - resistance rate was less than 1.2%. However, these drugs still have a fatal flaw: they cannot eliminate cccDNA in the liver cell nucleus, requiring patients to take medication for life. Even if the viral load cannot be detected continuously, the recurrence rate within five years after stopping the drug still exceeds 50%, and long - term use is associated with risks of kidney damage and bone metabolism disorders.

Based on TDF, Gilead launched tenofovir alafenamide fumarate (TAF) in 2016. Through a prodrug design, it precisely delivers the active ingredient to the liver, reducing the risk of renal toxicity by 90% while maintaining efficacy and significantly improving bone safety. However, even though it is hailed as the "miracle drug for hepatitis B" by the outside world, the HBsAg clearance rate of TAF still hovers below 3%, and the limitation of "inhibition rather than cure" has not been broken.

Facing this dilemma, the current ideal goal of hepatitis B treatment is functional cure, which means that after a limited course of treatment, HBsAg and HBV DNA in the serum cannot be detected continuously, HBeAg becomes negative (with or without HBsAg seroconversion), residual cccDNA can exist for a long time, but liver inflammation is relieved, liver histopathology is improved, and the incidence of end - stage liver disease is significantly reduced.

The breakthrough direction for "functional cure" mainly relies on the parallel development of combination therapies and new drugs.

The combination of siRNA and immune modulators can relieve immune suppression by degrading viral mRNA and activate exhausted T - cells at the same time, increasing the functional cure rate from less than 10% to 30%, and up to 47% in patients with low HBsAg (<1000 IU/mL). Antisense oligonucleotides (ASO) such as Bepirovirsen and domestic AHB - 137 can precisely silence viral genes, simultaneously suppress HBsAg and HBV DNA, and interfere with cccDNA transcription products. Capsid modulators (such as GuangShengTang's GST - HG141) can block virus maturation by interfering with capsid assembly and indirectly deplete the cccDNA pool. Their combination with HBsAg inhibitors (such as GST - HG131) is expected to quickly clear antigens and create a window for immune counter - attack.

The exploration of immunotherapy has also made breakthroughs. Therapeutic vaccines (such as BRII - 179) combined with antiviral drugs can reshape specific immune responses; immune checkpoint inhibitors target the key pathways of T - cell exhaustion (such as PD - 1) to reverse the suppression of the immune microenvironment. By interfering with the negative immune regulation network (such as the USP21 gene - related pathway), they can break the deadlock of immune tolerance and form a synergistic killing effect with direct antiviral drugs.

Historical experience shows that breaking through the cure bottleneck always depends on disruptive technologies. When the global hepatitis B drug research and development is trapped in the dilemma of "inhibition rather than cure," Chinese pharmaceutical companies are quietly opening up new battlefields for breakthrough.

03 Awaiting the Breakthrough

With the popularization of hepatitis B vaccination and virus detection, the number of hepatitis B virus carriers in China has significantly decreased.

The results of the fourth national sero - epidemiological survey of hepatitis B showed that in 2024, the positive rate of hepatitis B surface antigen in China dropped to 5.86%, corresponding to about 75 million chronic hepatitis B virus (HBV) carriers, a 19.4% decrease compared to 93 million cases in 2014. Notably, the positive rate among children under 5 years old was only 0.3%, which helped China achieve the hepatitis B prevention and control target of the Western Pacific Region of the World Health Organization ahead of schedule.

However, the number of chronic hepatitis B patients still remains as high as 20 million, ranking first in the incidence of infectious diseases in China, and the public health challenge remains severe. Meanwhile, the urgent need for "functional cure" among these 75 million carriers is driving the reconstruction of a multibillion - dollar market. Existing drugs can only inhibit viral replication, and innovative therapies have become the core engine of industrial transformation. In this round of industrial transformation, domestic pharmaceutical companies are forming unique competitiveness in cutting - edge fields such as combination therapies and immune regulation through differentiated layouts, reshaping the global hepatitis B treatment landscape.

Recently, GuangShengTang, whose stock price has soared, has adopted a "triple - therapy" strategy: its core oral capsid inhibitor, GST - HG141, blocks the replenishment of cccDNA by interfering with viral capsid assembly and is simultaneously advancing in Phase III clinical trials; the oral HBsAg inhibitor, GST - HG131, can clear 87% of surface antigens as a single drug, breaking down the immune suppression barrier. The combination of these two drugs with nucleoside drugs forms a "triple - block" mechanism - simultaneously blocking viral replication, depleting the cccDNA pool, and clearing residual antigens. This program has been included in the national green channel for review and approval and is expected to become the world's first oral cure program.

However, in the field of capsid inhibitors, Moroxydine mesylate (GLS4) from DongYangGuang Medicine and ZM - H1505R from ZhiMeng Medicine have also entered Phase III clinical trials, and the competition in this field is likely to intensify.

In the field of small nucleic acid drugs, BoWang Pharma's BW - 20507 targets the HBV mRNA S region and is administered subcutaneously once every four weeks, achieving a 56% HBsAg clearance rate in patients with baseline HBsAg <1000IU/mL. Other companies with similar layouts include TengShengBo Yao (Elebsiran), XingYaoKunZe (HT - 101), HengRui Medicine (HRS - 5635), ZhengDa TianQing (TQA - 3038), HaoBo Medicine (AHB - 137), etc.

Combination therapies have become the core battlefield for achieving "functional cure." Combinations such as siRNA + capsid inhibitor, ASO + immune checkpoint blocker, therapeutic vaccine + nucleoside drug, etc., use a sequential strategy in time and space to break the "triangle dilemma" of virus latency, immune exhaustion, and antigen load. For example, HengRui Medicine's HRS9950 (TLR8 agonist) combined with an ASO program first degrades antigens with ASO to relieve immune suppression and then activates exhausted T - cells with the TLR8 agonist to restore surveillance, achieving a synergistic breakthrough.

From the stubborn barriers built by the virus, to the continuous breakthroughs in drug iteration, and then to the collective breakthrough of Chinese solutions, the core of the "next - generation" hepatitis B battle has always revolved around the eager desire of millions of patients for a "cure." The continuous breakthroughs of emerging therapies are gradually bringing the cure of hepatitis B from the realm of the impossible to reality.

However, on the other side of the opportunity lies risk. Among the large number of companies entering the field, there are bound to be a group of losers. Behind this "multibillion - dollar" battle may be an abyss.

This article is written based on publicly available information and is only for information exchange purposes and does not constitute any investment advice.

This article is from the WeChat official account "Medical Glow", author: Qing Li. Republished by 36Kr with permission.