Recently, Ascentage Pharmaceuticals' APG-2449 has obtained CDE approval and will conduct two registered Phase III clinical studies for the treatment of non-small cell lung cancer. APG-2449 is a small molecule FAK inhibitor independently developed by Ascentage Pharmaceuticals with oral activity. It is a third-generation ALK/ROS1 TKI and the first FAK inhibitor in China to be approved by CDE for clinical trials. This may mean that the node for domestic drugs to disrupt the ALK target pattern is getting closer and closer, and it also indicates that the next blockbuster product of China's innovative drugs is on the way.

The saying "He who gets lung cancer gets the world" is widely circulated in the field of tumors. Lung cancer is the leading cause of morbidity and mortality of malignant tumors in China. The large number of lung cancer patients has always been a must-fight place for pharmaceutical companies. This is also the core reason why ALK targets have become a hot spot for pharmaceutical companies to pursue.

On the one hand, in the field of non-small cell lung cancer, the scale of ALK rearrangement patients is not small. According to a research report by Huachuang Securities, ALK-positive non-small cell lung cancer accounts for about 3%-7% of all non-small cell lung cancer. Lung cancer is the most common type of cancer in the world. According to a research report released by the National Cancer Center, the number of new lung cancer patients in my country in 2022 will reach 1.06 million. Based on this, it is estimated that the number of newly diagnosed ALK-rearranged non-small cell lung cancer patients in China may exceed 60,000 each year. If we look at the world, the number of new patients will be even larger. On the other hand, there is a significant "cumulative effect" in the treatment of ALK-rearranged patients. Due to the significant efficacy of targeted drugs, ALK rearrangement is called "diamond mutation", and the medication cycle has tended to chronic disease management: at this year's ASCO conference, the 5-year follow-up results of the CROWN study of lorlatinib as a first-line treatment for ALK-positive non-small cell lung cancer showed that the 5-year progression-free survival rate of patients in the lorlatinib treatment group reached 60%, and the median progression-free survival period has not yet been reached.

This means that over time, the cumulative number of ALK-positive non-small cell lung cancer patients will gradually increase, and the corresponding medication population is also expanding. Therefore, the global ALK target market has never lacked blockbuster drugs. As shown in the figure below, the global ALK inhibitor market size will exceed US$2.5 billion in 2023, of which the leading Alectinib will have sales of US$1.7 billion, and Pfizer's Lorlatinib will also reach US$500 million.

At present, the treatment needs in the ALK field are far from being fully met. On the one hand, drug resistance is an inevitable challenge. About 50% of patients will develop drug-resistant mutations after receiving treatment with the first or second generation ALK TKI currently on the market. The resistance rate of the third-generation ALK TKI Lorlatinib is still unclear, but many studies have shown that multiple ALK gene mutations will gradually weaken the efficacy of Lorlatinib, resulting in limited drug effects.

On the other hand, existing drugs still have many shortcomings in first-line treatment. For example, according to the CROWN study, the incidence of CNS adverse events of Lorlatinib was 35%, and after 18.3 months of follow-up, 38% of patients still had unrelieved toxicity. It should be noted that there are many CNS reactions in the treatment of lorlatinib, including not only epileptic seizures, mental effects, speech, mental state and sleep changes, but also cognitive functions (such as consciousness, memory, time and space positioning, attention, etc.) and emotions (including suicidal thoughts), which will seriously affect the life and work of some patients. This also makes it difficult to continue the treatment. Due to the impact of the central nervous system, 1.5% of patients permanently stopped taking the drug, 9% of patients suspended taking the drug, and 8% of patients reduced the dose.

Nowadays, as tumor treatment gradually shifts to "chronic disease" management, the safety of ALK inhibitors has also received increasing attention. Although lorlatinib has significant efficacy, considering safety issues, its choice as a first-line treatment is still controversial. Therefore, in the field of ALK targets, the space for breakthrough is always open to powerful pharmaceutical companies.

In the field of ALK targets, domestic molecules are destined to be worthy of attention. The core reason is that domestic pharmaceutical companies have not only kept up with the pace at the research and development level, but also innovated in their thinking. For example, APG-2449, as a triple TKI of FAK/ALK/ROS1, has breakthrough linkage of FAK (focal adhesion kinase) signal. As an important signal transduction target, FAK has been shown to mediate resistance to a variety of anticancer drugs. In other words, APG-2449 adopts a more targeted "problem-solving approach" and is expected to bring better tumor suppression effects.

The data released at the ASCO conference this year also preliminarily showed the potential of APG-2449. On the one hand, the results of biomarker studies showed that for NSCLC patients with resistance to second-generation ALK TKI, the expression level of phosphorylated FAK (pFAK) in their baseline tumor tissue was positively correlated with progression-free survival after APG-2449 treatment, suggesting that elevated pFAK may be associated with resistance to second-generation ALK TKI. On the other hand, APG-2449 has shown extremely outstanding effects in NSCLC patients who are resistant to or first-line treatment with second-generation ALK TKI. Specifically, in ALK-positive NSCLC patients who had not been treated with TKI, the ORR reached 78.6%; in NSCLC patients who were resistant to second-generation ALK TKI treatment and had no targetable bypass gene mutations, 45.5% of patients achieved PR. As shown in the figure below, APG-2449 has a better potential effect than lorlatinib for both newly treated patients and resistant patients.

In addition, APG-2449 also has a strong inhibitory effect on brain metastases. Previous cerebrospinal fluid PK analysis confirmed that APG-2449 can penetrate the blood-brain barrier. In human trials, 12 patients who received RP2D treatment had brain metastases at baseline, of which 9 achieved PR of intracranial lesions, with an ORR of 75.0%. This is particularly critical. According to statistics, about 20-40% of ALK-positive patients have brain metastases before treatment, so ALK-TKI needs to have a stronger ability to penetrate the blood-brain barrier and have a better control effect on intracranial tumors.

In terms of safety, APG-2449 mainly has grade 1-2 TRAEs, which are clinically controllable and avoid TRK-related neurotoxicity. It not only maintains activity against ALK, but also has brain permeability and controllable safety. Whether it is a choice for drug-resistant patients or a first-line therapy for ALK rearrangement, APG-2449 has high potential. The clinical license obtained by APG-2449 this time is a "two-pronged approach", with both clinical exploration of drug resistance and the layout of first-line therapy: one is APG-2449 versus platinum-containing chemotherapy for the treatment of second-generation ALK resistant/intolerant advanced NSCLC patients; the other is APG-2449 versus crizotinib for the treatment of first-line advanced/localized NSCLC patients.

Based on the clinical design, APG-2449 has a great chance of winning. Crizotinib, as the first-generation ALK-TKI that was first launched on the market, has been unable to withstand the offensive of the new generation of molecules. The control group of the CROWN study mentioned above is crizotinib. When the median progression-free survival was not reached in the 5-year follow-up of lorlatinib, the mPFS of patients in the crizotinib group was only 9.1 months. Under this logic, APG-2449, which has a potential combat effectiveness that is even better than lorlatinib, will obviously have a greater chance of winning. Obviously, APG-2449 may become a disruptor in the field of ALK targets, and is expected to become the next blockbuster product of China's innovative drugs. From a global perspective, the upper limit of ALK-TKI, which takes into account both efficacy and safety advantages, is extremely high. At this year's ESMO conference, ALK-TKI NVL-655 announced potential data that was better than lorlatinib, and was highly expected by the market. Optimistic analysts predict that the potential market peak of NVL-655 in the future may exceed US$6 billion.

If the research and development goes smoothly, the upper limit of APG-2449 may actually be higher than NVL-655. If APG-2449 can be successfully launched, it will actually kill two birds with one stone: not only will it successfully gain a position in the ALK field, but it will also be expected to surpass the FAK target field and become the world's first batch of FAK inhibitors to be launched. At present, APG-2449 is the first FAK inhibitor in China to be approved by the CDE for clinical trials. In the field of anti-tumor, FAK inhibitors are expected to form a combination of drugs with many targeted drugs in the form of super sensitizers. In other words, if it can break through, APG-2449 is expected to become the preferred partner for the combined treatment of many emerging tumor therapies. With one clever move, APG-2449 is expected to unlock two major application scenarios at the same time and completely open up the market ceiling.

Looking back on the development history of Ascent Pharmaceuticals, the attack of APG-2449 may be just a routine operation. Prior to this, Ascent Pharmaceuticals had fully demonstrated its strength in the field of hematological tumors. In November 2021, Ascent Pharmaceuticals approved the marketing of Narica, the only third-generation BCR-ABL inhibitor in China, which provides better treatment options for patients in the chronic phase (CP) or accelerated phase (AP) of chronic myeloid leukemia (CML). Its foray into the field of hematological malignancies has thus begun. According to clinical exploration, Narica will not only be a solution for patients resistant to first- and second-generation BCR-ABL inhibitors, but will also remain effective for patients resistant to Ponatinib and Asciminib. In addition, Narica is also accelerating its expansion outside the CML field. Its pivotal registration Phase III clinical study of combined chemotherapy for the treatment of newly diagnosed Ph+ ALL patients has entered the patient enrollment stage, and is expected to become the first TKI drug approved in China for the first-line treatment of Ph+ ALL. At the same time, the new pipeline Bcl-2 inhibitor APG-2575 is also moving towards first-line treatment in the field of hematological malignancies. In 2023, the global Phase III clinical trial of APG-2575 combined with acotinib for the first-line treatment of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was approved.

According to the company's financial report, APG-2575 will submit an application for listing in 2024. If nothing unexpected happens, APG-2575 will become the first domestically produced BCL-2 inhibitor to be listed. With the synergy of Nelic and the Bcl-2 inhibitor APG-2575, Ascent Pharmaceuticals' map in the field of hematological tumors has gradually expanded from "C to A to M". The so-called C refers to CML (chronic myeloid leukemia) and CLL (chronic lymphocytic leukemia); A refers to ALL (acute lymphocytic leukemia) and AML (acute myeloid leukemia); M refers to MDS (myelodysplastic syndrome) and MM (multiple myeloma).

Ascentage Pharmaceuticals' layout in the field of oncology is like a relay race: from blood tumors to solid tumors, potential molecules and indications will always be launched at the right time. The reason why Ascentage Pharmaceuticals can do this is essentially the fission of its capabilities: it has extremely outstanding global foresight, a broad vision, and strong enough R&D and clinical strength to continuously produce products with international competitiveness. In other words, Ascentage Pharmaceuticals' success will not be limited to pipelines such as Narica and APG-2449. There will be more surprising molecules in the future, which will surprise the market at the right time. At present, the market has also seen this. In Hong Kong stocks, the trend of the innovative drug industry has shown a clear polarization. Since the beginning of this year, although the market sentiment is not good, Ascentage Pharmaceuticals' increase is still close to 50%. This also tells us more and more that in the tide of China's innovative drug industry, reshuffles will become the norm, but companies that are truly competitive in the long run will definitely not be eliminated, and their value will not be ignored.

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