Although domestic pharmaceutical companies have not started early in the field of global innovative drugs and are still in the catch-up stage, it is an undeniable fact that they are becoming more and more at the forefront.
This has been fully proven in many fields. Typically, under the wave of ADC, domestic pharmaceutical companies rely on comprehensive advantages such as engineers to gain the upper hand.
Not only ADC, but also domestic pharmaceutical companies are also in a leading position in the field of cell **. For example, in the exploration of the indication of car-t** lupus erythematosus, the R&D progress of many domestic players has run ahead of overseas big pharmaceutical companies.
So, in this disease field that has not been overcome for a long time, will it be Chinese pharmaceutical companies that will be the first to break through?
01 There is no *** dilemma
As a disease brought about by the autoimmune system, lupus erythematosus is a real area of "huge unmet clinical need".
From the perspective of pathogenesis, the cause is the presence of a variety of autoantibodies in the serum of patients, and the combination of autoantigens to form antigen-antibody immune complexes, which are deposited in different tissues and cause corresponding immune responses, resulting in multisystem damage.
The most characteristic symptom of lupus erythematosus is the appearance of butterfly erythema on the cheeks, and the name "lupus" is due to the fact that in the past, people thought that the facial erythema of the disease was caused by a wolf bite. In addition to the ** damage, the lesions of lupus erythematosus can also affect multiple organs and systems.
As a result, patients are in a situation where their condition deteriorates faster as the duration of the disease increases. At present, the 10-year survival rate of patients has risen to 97% at present, but the survival rate after 25-30 years has dropped off a cliff to only 30%. Therefore, there is a strong need and an urgent desire for lupus erythematosus.
However, unfortunately, the existing first-class drugs cannot have the best effect, and can only play a short-term role in controlling disease activity.
In the absence of lupus, glucocorticoids, antimalarials, immunosuppressants and biological agents are commonly used for lupus erythematosus. And these ** without exception, the effect is not good and there are *** high bugs.
As shown in the figure below, glucocorticoids are the basic drugs for lupus erythematosus, and the traditional hormone-based drug still has problems such as insufficient response rate, high risk, and obvious results.
In general, the direction of drug development for lupus erythematosus is very certain.
Among them, the short-term goal of ** is to control disease activity, improve clinical symptoms, achieve clinical remission, or achieve the lowest possible disease activity;
The long-term goal is to prevent and reduce, reduce adverse drug reactions, prevent and control organ damage caused by diseases, achieve long-term sustainable remission, reduce the mortality rate of patients, and improve the quality of life of patients.
Despite the clear direction, the development of lupus erythematosus drugs is not easy.
02 Two mountains to climb
For the development of lupus erythematosus drugs, the core dilemma is that two mountains are difficult to overcome: pathogenesis and clinical design.
In terms of pathogenesis, the pathogenesis of the disease has not yet been determined.
Although we were able to find that the overactivation of the autoimmune system led to the presence of lupus erythematosus. However, it is still inconclusive what causes the overactivation of the autoimmune system.
At present, it is generally believed that genetic, endocrine, infectious, and environmental factors are all involved in the pathogenesis. Research continues, and there are even people studying the relationship between dental caries and lupus erythematosus.
Therefore, it is still unrealistic to identify the driving factors of immune system activation, so as to achieve symptomatic disease and prevent the occurrence of clinical diseases.
In addition to the unknown mechanism, the clinical difficulty of the "purgatory" level is also one of the factors hindering the launch of the new **.
Because of the particularity of the disease, different populations, indications, and the setting of drug dosage will directly affect the success or failure of clinical practice.
Because lupus erythematosus is highly "variable", different patients will have different symptoms. In the previous research and development process of new drugs for lupus erythematosus, the clinical evaluation process has become a mountain that is difficult for many drug candidates to overcome.
In addition, because the condition of lupus erythematosus is often unstable and changes rapidly, doctors are especially cautious when it comes to **. For safety reasons, what dosage to use and how often to administer the drug are all difficult questions to be solved.
As a result of many factors, lupus erythematosus can be called a black hole in the research and development of innovative drugs. Up to now, there are very few effective drugs on the market.
03 Accelerate the battle ahead
Of course, our battle against lupus erythematosus is not for nothing.
Even though the factors that ultimately drive immune system overactivation are not yet known, the understanding of the pathogenesis of lupus based on immune system cells, mediators, and pathways has led to the emergence of targeted biologics.
Up to now, a number of macromolecule drugs have been marketed around the world, including glaxoSmithKline's belimumab, Remegen's tetanercept, AstraZeneca's avolumab, etc.
Compared with traditional drugs, targeted drugs can reduce the occurrence of systemic drugs due to their high specificity to bind to targets.
High ** window for improved efficacy and safety. Therefore, the long-listed belimumab has long entered the blockbuster ranks, and the volumumab launched in 2021 has also increased rapidly, with sales of nearly $200 million in the first three quarters of this year.
At the same time, many innovations**, including JAK inhibitors and CD20 monoclonal antibodies, have entered the registration and clinical stage. In the near future, we will have more new lupus erythematosus**.
Of course, none of these drugs are the end of the victory.
At present, the targeted drugs that have been marketed are mainly clinically positioned as supplements to the previous ones, and the main application scenarios are to improve the standard for patients with refractory (poor conventional lupus effect) or lupus erythematosus.
The same is true from a clinical design point of view. According to the existing marketed macromolecule drugs, the main clinical inclusion of patients is patients with moderate to severe SLE, and **combined with standards**.
In addition, most efficacy measures were SRI-4 or BICLA, which only reflected the improvement in disease activity after treatment compared to baseline, and did not measure "** or near**" indicators, such as the proportion of patients achieving DORIS (Systemic Lupus Erythematosus Mitigation Definition Working Group) remission or LLDAS (low disease activity).
This is because the primary endpoint is easier to meet in the current clinical setting than with DoRIS remission or LLDAS. Taking belimumab as an example, retrospective analysis results showed that in the two clinical trials of BLISS-52 and BLISS-76, the proportion of DORIS response was only 5-6%, and the LLDAS compliance rate was only 12-15%.
In fact, many of the biologics or targeted small molecule drugs mentioned above in the late-stage development are also positioned to alleviate disease activity, rather than a state of "complete drug response".
Obviously, this battle can continue to move forward.
04 Will car-t** be the final answer?
Perhaps, car-t** can bring us even more surprises.
From the perspective of mechanism, the pathogenesis and progression of systemic lupus erythematosus are closely related to B cells, so targeting B cells has always been an important direction of research and development.
Previously, it was difficult to achieve ** results due to factors such as the inability to completely eliminate B cells or completely inhibit the activity of B cells, while CAR-T ** has this possibility.
CAR-T** can be differentiated from plasma cells by expressing CD19 CAR-specific killer B cells, or by expressing BCMA CAR-specific killer B cells, which is expected to achieve the effect of deep clearance of lupus erythematosus pathogenic B cells, trigger immune "reset", and completely alleviate lupus erythematosus disease.
After scientists at the University of Tennessee Health Science Center in the United States validated this possibility in a mouse model in 2019, research on the application of CAR-T** in lupus erythematosus** is on the fast track.
At the ASH 2023 Annual Meeting, the Georg Schett team updated research data showing good results. Eight patients with lupus erythematosus achieved complete remission after 3 months of treatment, after which SLEDAI maintained a score of 0. Five patients with lupus erythematosus who were followed up for 14-24 months had reconstitution of B cells and remained in remission.
Not only overseas studies, but also the research team of Zhongshan People's Hospital has carried out similar studies, and the conclusion is also the same: CAR-T*** lupus erythematosus is expected to be safe and efficient to achieve one-time **.
This is undoubtedly a new hope for lupus erythematosus patients. Of course, whether the conclusion is correct or not remains to be tackled by pharmaceutical companies. Up to now, many companies around the world, including Novartis, have entered the exploration of CAR-T** in the field of lupus erythematosus.
Among them, domestic pharmaceutical companies are the backbone. As shown in the figure above, including IASO Biotech, Baiji Gene, JW Therapeutics, Heyuan Biotech, etc., all have layouts, and domestic pharmaceutical companies are in a leading position in terms of both the number of layouts and the progress.
So, will domestic pharmaceutical companies be the first to stand out?Let's wait and see.