Baiji, Cinda, Tianqing... More than 10 domestic companies are deployed, PI3K inhibitors are about to face the FDA exam tonight

On April 21, this evening, the FDA will convene a meeting of the Oncology Advisory Committee (ODAC) on PI3K Inhibitors to discuss the toxicity of PI3K inhibitors and whether randomized controlled trial data can be useful in assessing overall survival (OS), which in turn serves as substantive evidence to support the risk-benefit assessment of this class of drugs in the field of hematological malignancies

(* FDA has released the conference-related materials in advance, and the official account can reply to "PI3K" to get the direct link)

This meeting is not for a specific drug, but for all new drugs in the class of PI3K inhibitors for hematological tumors, and the results will largely affect the fate of future PI3K inhibitors

Questions to be discussed and voted on at this meeting

From: FDA official document

According tothe Insight database, the research and development of PI3K inhibitors in China has been active in recent years, and so far, 34 corresponding projects have entered clinical development in China

Trends of domestic PI3K inhibitor new drug projects at various stages (Insight)

Screenshot from: Insight databaseproject progress visualization (http://db.

* The visualization function of the Insight database can easily view the progress trend of specific targets/indications/component categories in China and even in the world at each stage, and clearly grasp the research and development status of new drug projects in the field of interest.

Opportunities and challenges coexist

PI3K is phosphatidylinositol 3-kinase, the most widely studied type I PI3K is a heterodimer composed of regulatory subunit p85 and catalytic subunit p110, and the catalytic subunit is divided into α, β, δ, γ four

However, safety issues have become one of the important factors hindering the development of such drugs

Among the approved PI3Kδ inhibitors, Gilead announced earlier this year that it had withdrawn the PI3Kδ inhibitor idelalisib (trade name: Zydelig) for both follicular lymphoma (FL) and small lymphocytic lymphoma (SLL).
item indications
.
Gilead said the withdrawal was due to changes in current clinical practice, making it difficult for FDA-required confirmatory clinical trials to complete enrollment
.

Zydelig received accelerated FDA approval in 2011 and is a first-in-class product in the same field, with cumulative sales exceeding $800 million
.
Following the withdrawal of the indication, Zydelig will remain in the US for CLL patients and will continue to be marketed in the EU, UK, Canada, Australia, New Zealand and Switzerland for CLL, SLL and FL markets, although sales are expected to decline
.

There is a view that the safety problem of PI3K inhibitors stems from the selectivity of each isoform of PI3K
.
Therefore, one of the development directions of next-generation PI3K inhibitors is to improve selectivity
.
MEI Pharma/Concord Kirin's Zandelisib and TG Therapeutics' Umbralisib are highly selective PI3Kδ inhibitors, and have shown safety advantages compared to previous-generation PI3Kδ inhibitors, but both are earlier than setbacks recently
.

On March 25, MEI Pharma and Xiehe Kirin received a complete response letter (CRL) from the FDA and were asked to supplement clinical trial data to support the approval of Zandelisib.
As soon as the news came out, the former’s stock price plummeted by 60%
.
Zandelisib, once considered a potential best-in-class, was introduced in 2020 by Kyowa Kirin for a total of $682.
5 million
.

TG Therapeutics, on the other hand, chose to withdraw Umbralisib's new indication marketing application for CLL and SLL and voluntarily stopped selling the drug
.
The FDA was scheduled to discuss whether its accelerated approval application should be approved at this ODAC meeting, but this agenda has been canceled due to the company's voluntary withdrawal
.
Incyte also withdrew its NDA applications for the PI3Kδ inhibitor Parsaclisib for follicular lymphoma (FL), marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL), saying the decision was a commercial decision and not because of The efficacy and safety of the drug itself
.

The FDA presented in this ODAC meeting briefing that 6 randomized controlled trials of PI3K inhibitors for hematologic malignancies showed consistent results: overall survival increased in the context of a PFS advantage or potential advantage A downward trend, possibly due to toxicity
.
The FDA said it considered the possibility of exploring lower dose regimens through early randomized trials, avoiding single-arm trials for marketing applications, and wanted a comprehensive analysis of overall survival data to reflect the drug's ultimate clinical benefit
.

Status of approved PI3K inhibitors

Safety and overall survival benefit have become a bottleneck for PI3K inhibitors , which not only presents challenges for companies, but also represents new opportunities
.
If companies can develop new drugs with real clinical advantages, they will surely occupy an important place in the market and lead similar drugs to take off again in the fiery competitive landscape
.


The competition is hot and the potential can be expected.

According to the  Insight database , there are currently 34 PI3K inhibitor projects in China, of which 23 are domestic
.
Specific to the frequency of target occurrence, α and δ are divided into half; if the indication search scope is narrowed to hematological tumors, 10 domestic projects and 4 imported projects are left
.
Last year, CDE granted breakthrough therapy designation to 7 PI3Kδ inhibitors in China, which also showed optimism for this type of therapy from the side
.
As mentioned above, CSPC's PI3Kδ/γ inhibitor duvelise capsule (previously known as duensibu) was just approved for marketing in March for follicular lymphoma .
Two other similar new drugs are in the stage of marketing application, namely Yingli Pharmaceutical/Hengrui Medicine's PI3Kδ inhibitor Limpres and Bayer Pharma's PI3Kα/δ inhibitor Kupanisib , which are expected to be approved this year .
Screenshot of the domestic progress distribution of PI3K inhibitors for hematological tumors from: Insight database project progress visualization (http://db.
dxy.
cn/v5/home/) Duvelisib  (Copiktra)  is a company launched by CSPC in  2018 Introduced from Verastem Oncology in September, CSPC has the license to develop and commercialize the drug in China (including Hong Kong, Macau and Taiwan) .
In April 2021 , Velise was reported for domestic production, and was subsequently included in the priority review by CDE, and it took less than a year to be approved for marketing .
Limplis



 


 

(YY-20394) is a new generation of PI3Kδ highly selective inhibitors developed by Yingli Pharmaceutical, and it is also the only project independently developed by domestic companies among the first-tier PI3K inhibitors in China
.
In February 2021, Hengrui Medicine and Yingli Pharmaceutical signed a strategic cooperation agreement to obtain the joint development rights and exclusive commercialization rights of the drug in Greater China
.
In May, the indication application of Limplix for the  treatment of relapsed/refractory follicular lymphoma was accepted by the CDE and included in the priority review process
.
Among the new clinical stage drugs, in addition to Parsaclisib introduced by Innovent, six clinical phase II products have progressed the fastest, including TQ-B3525 (PI3Kα/δ) of Chia Tai Tianqing, Cybolisai of Shenghe Pharmaceuticals ( R&D code: SHC014748M , PI3Kδ) , Hutchison Whampoa’s amdizalisib (R&D code : HMPL-689, PI3Kδ) and BeiGene’s BGB-10188 (PI3Kδ ) , etc.
The domestic competition pattern of PI3Kδ targets  Click here to query from: Insight database (http://db.
dxy.
cn/v5/home/)