Small molecule drugs have been around for a long time.
Taking prostate cancer and breast cancer, which are the most common cancers in American men and women, respectively, the HR+/HER2-type first-line treatment drug “Duba Jianghu”, which accounts for nearly 70% of breast cancer, the three similar drugs have created a 10 billion dollar market, and the market size is growing steadily; this is even more true for prostate cancer. AR antagonists and CYP17 inhibitors for antiandrogen treatment have firmly grasped the first-line treatment market, spawning major bombs such as enzalutamide and alonbite.
Today, both CDK4/6 inhibitors and AR antagonists are still active on the current stage. Among them, the best-selling drugs pibasilil and enzalutamide have been on the market for more than 9 and 12 years, respectively.
Why not say, “Those who get the two major indications of prostate cancer and breast cancer win the world?” Very few of the drugs that have been commercialized so far can cross these two major indications; even if they do, they are blockbusters with a very broad spectrum. Among the new small-molecule drugs, there is one “treasure molecule” that spans the two major indications of prostate cancer and breast cancer, and that is an AKT inhibitor.
Looking at the global R&D landscape, AKT inhibitor development is a promising and uncrowded blue ocean racetrack. Currently, only AstraZeneca's Capivasertib has been approved for marketing, while Laikai Pharmaceuticals (02105)'s LAE002 (Afuresertib) progress is second in the world. China and the US have already entered phase III clinical trials. The progress of the two leading companies has far outpaced other companies.
Corevian predicts that AstraZeneca's AKT inhibitor capivasertib will have sales of at least 1 billion US dollars in the G7 market by 2031; some overseas analysts also predict that Capivasertib will reach a sales peak of 3.8 billion US dollars in the future, all of which highlights the broad market prospects for AKT inhibitors.
01 AKT Inhibitor Eighteen Martial Arts and Lai Kai Pharmaceutical's “Me Better”
AKT is a serine/threonine protein kinase and is a key node in the PI3K/Akt/mTOR signal cascade. AKT can activate downstream effector molecules (mainly mTOR proteins), thereby stimulating metabolic growth and proliferation of tumor cells, immune escape, and angiogenesis. Among them, the activation process of AKT can be inhibited by PTEN, and loss of PTEN function will cause excessive activation of AKT and cause tumors to occur. Thus, by inhibiting the activation of AKT, the effect of treating cancer can be achieved.
The broad spectrum of AKT targets and the “eighteen martial arts” stem from the PI3K/AKT/mTOR pathway, which is the most commonly altered signaling pathway in human cancer. 38% of cancer patients found changes in the PI3K/AKT/mTOR pathway; at the same time, overactivation of this pathway is widespread in various types of cancer, including breast cancer, lung cancer, head and neck tumors, endometrial cancer, prostate cancer, and colorectal cancer.
Notably, AKT is at the core of the PI3K/Akt/mTOR signaling pathway. This position allows Akti to benefit patients with changes in Pik3ca, AKT, and PTEN, while PI3Ki is only effective for patients with Pik3ca mutations. On the one hand, AKT inhibition can inhibit tumor cell growth. On the other hand, activation of the PI3K/AKT signaling pathway may cause resistance to various small molecule inhibitors and worsen the condition of many types of cancer. AKT inhibitors are expected to solve the drug resistance problem of many types of small molecule anticancer drugs.
Currently, AstraZeneca's AKT inhibitor capivasertib has been approved for second-line HR+/HER2- breast cancer, and cancers such as castration-resistant prostate cancer, triple-negative breast cancer, non-Hodgkin lymphoma, endometrial cancer, and meningioma are in middle to late clinical trials.
Among the approved second-line HR+/HER2- breast cancer indications, capivasertib was successful with the overwhelming data advantage of the Phase III Capitello-291 study. In patients with advanced HR+/HER2-advanced breast cancer who had previously been treated with CDK4/6 inhibitors and those with changes in the PIK3CA/AKT1/PTEN pathway, the comparison between the “Capivasertib+ flunavisin” treatment group and the “placebo+fluvirizine” control group was 7.3 months vs. 3.1 months (HR=0.50). Based on the huge unmet clinical need after resistance to CDK4/6 inhibitors, the FDA granted priority review of capivasertib for this indication and approved its marketing in the US in November 2023.
Despite the excellent efficacy of Capivasertib, its safety signals have also attracted market attention. In the CapiTello-291 study, the adverse reaction rate in the treatment group was as high as 96.6% (82.3% of the control group), the serious adverse reaction rate was 16.1% (only 8.0% in the control group), and 13.0% (2.3% of the control group) were discontinued due to adverse events, which also left an excellent opportunity for latecomers.
Following Capivasertib, Laikai Pharmaceutical LAE002 is a potentially “best-in-class” AKT inhibitor, and its benefits are reflected in several major aspects:
1) Preclinical data support: Compared with similar competitors, LAE002 has a stronger inhibitory effect on AKT and has a lower off-target effect, which means that the efficacy and safety potential of this molecule are stronger;
2) Frequency of administration: The administration method of Capivasertib is continuous administration for four days and discontinuation for three days. Continuous administration may not be possible due to drug tolerability; however, Laikai Pharmaceutical LAE002 can maintain daily administration, and there are no restrictions on interval dosing;
3) Existing clinical data: Under non-head-to-head data comparison, LAE002 has advantages in efficacy, tumor suppression exposure and toxicity, and is safer.
As an AKT inhibitor with better potential efficacy and safety, and a wider treatment window, Laikai Pharmaceutical LAE002 can undoubtedly amplify the value of the AKT inhibitor cancer treatment market.
Lai Kai Pharmaceutical is promoting LAE002 to make great strides in clinical exploration of the two major types of cancer, prostate cancer and breast cancer.
02 The big market for drug resistance in advanced breast cancer
On May 30, Laikai Pharmaceutical announced that the first patient was enrolled in the domestic LAE002 clinical phase III clinical trial of HR+/HER2- locally advanced or metastatic breast cancer. It is reported that the company cooperated with 47 clinical centers in China. The enrollment of the first patient meant that the company's phase III clinical trial started at an accelerated pace.
There is huge market potential behind the breast cancer indications targeted by LAE002. According to data from the WHO International Agency for Research on Cancer (IARC), the estimated number of new cases of breast cancer worldwide in 2022 will reach 2.29 million, and about 666,000 patients will die as a result, while the number of new cases in China is estimated to be 357,000; of all types of breast cancer patients in the US, about 69% are HR+/HER2-, and the proportion of this subtype among breast cancer patients in China is 62%.
HR+/HER2-advanced breast cancer. Currently, the first-line treatment is endocrine therapy combined with CDK4/6 inhibitors. 15% to 20% of patients develop primary resistance to treatment, and 30-40% of patients will develop resistance to treatment over time; although the basic ER degrading agent fluvizine for second-line standard therapy has limited efficacy, it still dominates the SERD targeted drug market for the past 20 years, with sales peaking at US$1,028 million.
CDK4/6 drug resistance in HR+/HER2-breast cancer patients has always been a major pain point in second-line treatment, but the mechanisms of drug resistance are diverse, mainly including ESR1 gene mutation (ESR1m), elevated PI3K/Akt/mTOR signaling pathway expression, and BRCA2 gene mutation (BRCA2m). The data shows that these types account for 30%, 50%, and 12% of patients, respectively.
People with elevated PI3K/AKT/mTOR signaling pathway expression accounted for half of CDK4/6 resistant post-line breast cancer patients. Compared with the peak sales value of fluvirizine of US$1,028 billion in 2018, the AKT inhibitor and combination therapy market in this field is at least 2 to 3 billion US dollars.
As mentioned earlier, the pioneer of the AKT inhibitor capivasertib was successful with impressive benefit data in phase III clinical trials and achieved double PFS benefits in HR+/HER2-advanced breast cancer. Among them, 69.1% of patients were treated with CDK4/6 inhibitors.
Laikai Pharmaceutical LAE002 saw positive signals superior to Capivasertib in early clinical data. At the 2023 SABCS conference, Laikai Pharmaceutical announced clinical data for LAE002 combined with fluvirizin for second-line treatment of HR+/HER2 breast cancer: among 20 subjects, ORR was 30%, DCR was 80%, and mPFS was 7.3 months; in 11 patients with PIK3CA/AKT1/PTEN mutation, ORR was 45.4%, DCR was 82%, and mPFS was 7.3 months.
In terms of non-head-to-head data comparison, LAE002 small sample clinical data obtained a better ORR compared to Capivasertib phase III data. In particular, in patients with PIK3CA/AKT1/PTEN mutations, the benefits of ORR were more prominent. This is also in line with LAE002's data on the stronger inhibitory effect of AKT before clinical trials. It is worth noting that the ratio of patients resistant to CDK4/6 treatment was not much different between the two clinical trials, which basically verified the potential of AKT inhibitors as a post-line treatment standard for CDK4/6 resistance.
Perhaps more impressive is the safety shown by LAE002. Highlights include no drug withdrawal events due to adverse effects (Capivasertib 13.0%), most observed adverse events as grade 1 (no safety events of grade 4 or above), and no clinical dose adjustments (Capivasertib adjusted about 20% of patients).
Safety is likely to be a sharp sword in LAE002's post-treatment patients. Patients treated for breast cancer generally have weak immunity after multiple treatments. With its safety advantages, LAE002 is expected not only to expand the number of beneficiaries with different indications, but also to increase clinicians' acceptance of medication, laying a solid foundation for future commercialization of the drug.
03 Nuggets Metastatic Castration Resistant Prostate Cancer Blue Ocean
Also, on May 23 of last week, Laikai Pharmaceutical announced that LAE002 and LAE001 were approved by the FDA for the phase III clinical trial plan for patients with metastatic castration resistant prostate cancer (mCRPC). This approval means that LAE002 leads AstraZeneca's capivasertib (limited prostate cancer stage 3) in the differentiated layout of mCRPC indications.
Obviously, LAE002 chose a harder path, but once successful, it paid off handsomely.
The progression path of prostate cancer is generally “limited prostate cancer → metastatic prostate cancer sensitive to androgen deprivation treatment (ADT treatment) → non-metastatic prostate cancer resistant to ADT therapy (nmCRPC) → mCRPC”.
mCRPC is a type of cancer with a high degree of malignancy. Patients have a short survival time, and the 5-year survival rate is less than 30%. At the same time, prostate cancer has a high population base and new incidence rate, forming a promising therapeutic drug market. According to 2020 data, there are 1.41 million new cases of prostate cancer and 375,000 deaths every year.
Currently, first-line treatment for mCRPC is chemotherapy, CYP17A1 or AR inhibitors, ADT treatment, and combination therapy with PARP and CYP17A1 inhibitors; looking at second-line mCRPC treatment, patients with PSMA expression and HRRM gene mutations can be individually treated with Novartis nuclear drugs PluVicto and PARP inhibitors. Generally speaking, patients with this type of baseline patient have a median survival time of less than two years and are extremely resistant to drugs. This indicates that second-line mCRPC treatment has greatly failed to meet clinical needs.
Researchers found that about 50% to 70% of mCRPCs had loss of PTEN function, leading to excessive activation of the PI3K/Akt/mTOR pathway, leading to poor prognosis and drug resistance in prostate cancer patients. Therefore, the combination therapy of AKT inhibitors and CYP17a1 inhibitors is regarded by the market as a second-line mCRPC treatment that has the potential to solve drug resistance problems.
The approval of Laikai Pharmaceutical's overseas phase III clinical trial comes from the backing of early drug efficacy data, which is not only based on LAE002, but also includes LAE001, another molecule in combination therapy.
LAE001 is the world's first CYP17A1/CYP11B2 dual-target inhibitor. Compared with the previous generation drug Abiraterone, increasing the targeting of CYP11B2 can reduce the effects of excessive salicocorticoid. At the same time, the drug is highly selective for CYP enzymes, further improving the efficacy and safety of the drug.
Phase 1 clinical data for mCRPC revealed in LAE001 showed that among the 20 evaluable patients, 80% of patients had a decrease in PSA response of more than 50%, and the PSA response of 60% of patients decreased by more than 90%. The initial data was far superior to the combination therapy of abiraterone and dexamethasone or prednisolone.
The LAE002+LAE001 combination therapy data is even more impressive. As of November 21, 2023, its phase 2 clinical data showed that in 40 second-line mCRPC patients (abiraterone and/or androgen receptor antagonist treatment), rPFS was as high as 8.1 months; in reference third-line mCRPC treatment, RPFS was 2-4 months, which can be determined that the LAE002+LAE001 combination has significant core competitiveness.
What is also surprising is the safety data. The adverse effects of the above tests above grade 3 were mainly thrombocytopenia (7.5%), anemia (5.0%), hyperglycemia (5.0%), hyponatremia (5.0%), and hypertension (5.0%). Compared with other similar tests, which tend to be greater than 50% of grade 3 adverse events, it can be determined that LAE002+LAE001 combination therapy has broad prospects.
Many investors see Novartis Pluvicto as a strong rival for many developing mCRPC therapeutics, and it is also the world's fastest nuclide conjugation drug to reach $1 billion in revenue. It is worth noting that the proportion of patients with mCRPC with PSMA mutations is about 80-90%, and patients without PSMA mutations have limited efficacy; however, the LAE002+LAE001 combination is a strong competitor with clear mechanism, excellent efficacy, and excellent safety in second-line mCRPC treatment. If successfully implemented in overseas phase III clinical trials, the potential is imaginable.
For Laikai Pharmaceutical, the promotion and implementation of the LAE002+LAE001 combination will be an important component in determining the double impact of the company's value.
Conclusion: The success of AstraZeneca Capivasertib has verified the efficacy and potential market space for AKT inhibitors. For Laikai Pharmaceuticals, which has already entered the third phase of major indications such as prostate cancer and breast cancer, we have reason to look forward even more to its future development, not to mention the potential highly catalytic GLP-1 weight loss partner — self-developed LAE102 (ActRIa monoclonal antibody). Incidentally, LAE102 has received IND approval from both China and the US, and will soon launch the recruitment of obesity subjects.
This article is reprinted from the WeChat account of “Gazelle Club”; Author: Kris; Zhitong Finance Editor: Chen Xiaoyi.