MNC Roche took out a "machete".

In Roche's 2024Q2 PPT presentation, there are 5 pipelines in the anti-infection pipeline echelon, 4 of which are Ruzotolimod (TLR7 agonist), Xalnesiran (small interfering RNA), PDL1 LNA and HBsAg monoclonal antibody, all of which are in Phase I and II clinical trials.

When it comes to the presentation of 2024Q3, the situation has changed. Roche cut off the above 4 pipelines with the target indication of hepatitis B at one time. The company did not give a specific reason for the "clearance". The most speculation in the market is that the clinical pipeline data is "unsatisfactory + Roche streamlines the pipeline to focus its energy and investment on core areas".

However, for Roche, the anti-infection sector has always been a relatively marginal module of the company. In the key drivers introduced by the company in 2024Q2 after 2025, the molecules of the anti-infection (hepatitis B) sector were not listed, but the previously marginal sector cardiovascular metabolism field has cooperated to develop two potential blockbuster products, oral GLP-1 and the new generation of antihypertensive drug Zilebesiran.

In addition, Roche is not the only MNC that has cleared its own hepatitis B pipeline with one click.

Johnson & Johnson has also cleared its positions with one click

Coincidentally, Johnson & Johnson once gave up the company's hepatitis B pipeline echelon at one time.

In July 2023, when Johnson & Johnson presented its 2023Q2 performance, its pipeline showed that JNJ-3989 (HBV siRNA), JNJ-3283 (PD-1 monoclonal antibody), JNJ-0440 (capsid assembly regulator CAM), JNJ-4964 (oral TLR7 agonist) and other hepatitis B pipelines were removed from the company's R&D pipeline display, and another pipeline that has attracted much attention from the market, JNJ-6379, was abandoned by Johnson & Johnson as early as 2022 due to poor effectiveness.

Similarly, the anti-infection sector is also in a relatively awkward position for Johnson & Johnson. Johnson & Johnson's strengths are in tumors, autoimmunity and neuroscience sectors, and streamlining the hepatitis B pipeline can also be regarded as focusing on more effective areas.

In fact, Johnson & Johnson and Roche are actually quite similar in the direction of hepatitis B development. It can be seen that both have explored the development of small nucleic acid therapy, TLR7 agonists and PD-1.

But it is worth noting that some of Johnson & Johnson's hepatitis B pipelines have been abandoned and welcomed another MNC takeover party. JNJ-3989 is an siRNA molecule that can target all hepatitis B virus (HBV) RNA. In 2018, Johnson & Johnson obtained a license from Arrowhead. In October 2023, Johnson & Johnson and GSK signed a global development and transfer agreement for JNJ-3989. In the future, it will be solely responsible for all future development and commercialization activities, and bear the advance payment and milestone payment that needs to be paid to Arrowhead in the future.

The existing phase II clinical data of JNJ-3989 show that although the use of single-drug treatment can significantly reduce the level of hepatitis B surface antigen (HBsAg) in patients, and patients still have a sustained HBsAg response after stopping the drug, the proportion of patients who achieve HBsAg clearance is relatively small; in the process of seeking combined use, the combination of JNJ-6379 (capsid inhibitor) and Nivolumab (PD-1) failed to improve the efficacy, while the combination of JNJ-3989 and long-acting interferon has achieved a more obvious effect. After JNJ-3989 first induces the initial decrease in HBsAg in patients, the addition of long-acting interferon further increases the decrease in HBsAg, and 19% of patients have at least one HBsAg clearance.

Roche also has a small nucleic acid drug Xalnesiran (RG6346) in its pipeline this time. Xalnesiran is an siRNA drug targeting the HBsAg coding region of the HBV genome. According to the published clinical data, the HBsAg clearance rates of Xalnesiran combined with long-acting interferon for 48 weeks were 6.7%, 17.6% and 30.0% respectively. Whether Xalnesiran can be successfully taken over by buyers in the future can only be said to be difficult.

The thorny hepatitis B track

Although there is a huge clinical demand for curing hepatitis B, the main goal of current research and development is functional cure rather than complete cure.

There are three clinical treatment milestones for anti-hepatitis B virus treatment: partial cure, functional cure, and complete cure (the difference is as follows). Partial cure can still be achieved. The difference between functional cure and complete cure is that functional cure fails to clear the covalently closed circular DNA and HBV DNA integrated into the genome in the liver. Functional cure means that after a period of treatment, the patient's immune system is sufficient to suppress the hepatitis B virus, and the drug can be safely stopped, liver damage is restored, and the risk of liver cancer is minimized. However, since the hepatitis B virus still exists, as the patient's immunity decreases, there is still a possibility of recurrence.

At present, the first-line drugs for hepatitis B are mainly divided into two categories: interferon and nucleoside (acid) analogs. Although these two categories of drugs have certain efficacy, they require lifelong treatment and cannot eliminate hepatitis B virus in a short period of time, and the cure rate is low.

The reason why hepatitis B is difficult to treat is that the core is that the HBV virus will enter and infect hepatocytes through NTCP on the liver cell membrane as a receptor, and establish its genome in it, that is, covalently closed circular DNA (cccDNA) with chromosomal characteristics. At the same time, the HBV virus may also insert some gene fragments encoding surface antigens into the host liver cell genome. These two parts are difficult to target and eliminate.

The elimination of cccDNA has become the main research and development direction of global hepatitis B drug developers, which can be divided into two categories: direct targeting of cccDNA and indirect targeting of cccDNA. However, direct targeting of cccDNA has always been a huge challenge for the development of hepatitis B drugs. Currently, the drugs under development are more indirectly targeting cccDNA, which can achieve the elimination of cccDNA by affecting the life cycle of cccDNA, mainly including entry inhibitors, capsid inhibitors, small nucleic acid therapy and HBsAg inhibitors.

In terms of entry inhibitors, Gilead's Bulevirtide is at the forefront. Its principle is to competitively bind to the liver cell surface receptor NTCP with HBV to block HBV from entering and infecting liver cells. In the past phase II clinical data, Bulevirtide monotherapy was not ideal. It achieved relatively good results in combination with interferon for 48 weeks, and 20% of patients achieved HBsAg clearance. The market is waiting for the release of its phase III data.

The development of viral nucleocapsid assembly inhibitors (CpAM) has not progressed smoothly. In short, CpAM affects the replication of HBV DNA and severely weakens the toxicity and re-infection ability of progeny viruses by interfering with the assembly and function of HBV viral nucleocapsid. There has been no shortage of overseas companies exploring this direction in the past. For example, Pioneer Assembly has developed a series of pipeline echelons, which eventually ended their research and development due to insufficient efficacy, liver toxicity and active termination. In addition, Roche and Johnson & Johnson's CpAM were subsequently abandoned or terminated by their own companies.

At present, the siRNA and ASO therapy routes have a good momentum. The general principle is to block HBV transcripts and induce their degradation. In addition to the above-mentioned JNJ-3989 and Xalnesiran, GSK's 3228836 and Vir's VIR-2218 have shown that more than 25% of patients have achieved hepatitis B surface antigen clearance in the second phase of clinical trials. However, the HBV DNA re-positivity rate and the sustainability of the efficacy are more challenging for the actual efficacy of the drug.

In addition, there are also very positive progress in the direction of HBsAg inhibitors and ASO. In a phase II clinical trial of Replicor's HBsAg inhibitor REP2139/REP2165 combined with interferon and tenofovir disoproxil fumarate triple therapy, up to 60% of patients achieved hepatitis B surface antigen clearance in 48 weeks, and 60% of patients achieved surface antibody positive conversion.

Domestic progress

According to statistics, there are about 86 million people infected with hepatitis B virus in China, and the number of surface antigen carriers is the largest in the world, and there are not a few hepatitis B drug research and development companies.

From the perspective of development direction, siRNA therapy and nucleocapsid inhibitors are the routes that domestic pharmaceutical companies participate in the most.

In terms of siRNA therapy, Hengrui Medicine's HRS-5635 is currently the first to enter the clinical phase II among many domestic independently developed pipelines, but the specific data has not yet been disclosed. On the contrary, Zhengda Tianqing TQA3038 has disclosed some phase I data, with its highest dose climbing to 800mg and good safety (adverse events are all mild and alleviated before the end of the study). In addition, VIR-2218 introduced by Fosun Pharma and AB-729 introduced by Qilu Pharmaceutical in the cooperative development pipeline have made rapid overseas development progress and are in the clinical phase II.

In terms of nucleocapsid inhibitors, the most eye-catching one is GST-HG141 of Guangshengtang, which not only successfully completed the domestic phase II clinical trial, but also achieved relatively amazing data. The phase II clinical data of GST-HG141 in treating 90 patients with chronic hepatitis B with low viremia showed that after 24 weeks of continuous treatment with GST-HG141 combined with nucleoside analogs, the proportion of HBV DNA below the detection limit in the high and low dose groups reached 81.5% and 84.0%, far exceeding the nucleoside analog monotherapy (32.1%), and the decrease in HBV DNA and pgRNA in patients exceeded 1 log10, further verifying the role of GST-HG141 in blocking HBV viral replication and depleting cccDNA. In addition, Guangshengtang has also deployed HBsAg inhibitor GST-HG121 and surface antigen inhibitor GST-HG131, and the overall layout is relatively comprehensive.

Of course, there are a lot of new developers emerging in China, including first-tier companies such as Bowang Pharmaceutical, Haobo Pharmaceutical, and Xintong Pharmaceutical. They are using their own unique development routes to solve the problem that hepatitis B is difficult to cure or achieve functional cure.

Conclusion: Roche, Johnson & Johnson and other MNCs clearing out their hepatitis B pipelines does not mean that there is no hope for development in this field. It is more likely that, like the case of some MNCs returning Chinese assets, it is just a strategic adjustment made by their own resource reconfiguration. Against the background of record low success rates in new drug research and development and increasing drug research and development costs, it is understandable to make such a choice, and investors need to look at it rationally.

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