PI3K's two heavens of ice and fire: delisting in Europe and the United States, and listing in China

On November 9, 2022, according to the official website of NMPA, the State Medical Products Administration (NMPA) conditionally approved the marketing of Linplisset tablets, a Class 1 innovative drug declared by Shanghai Yingli Pharmaceutical Co.
, Ltd.
, through the priority review and approval process, which is suitable for adult patients
with relapsed or refractory follicular lymphoma who have received at least two systemic treatments in the past.

As a highly selective PI3Kδ inhibitor, Linplisset has undergone nearly a decade of research and development
.

The study data showed that the high selectivity of Linplisset was reflected in the selection of PI3Kδ compared with the other three subtypes (PI3Kα, PI3Kβ, PI3Kγ) selection multiples were greater than 30, which helped to reduce the adverse reactions
such as hyperglycemia, hypertension and diarrhea that are prone to occur due to the inhibition of other subunits.

As one of the most frequently activated signaling pathways in human cancer, the PI3K pathway mediates almost 50% of malignancies
.

Whether used in combination or as a single pipeline development, PI3K target inhibitors have been attracting the attention
of major pharmaceutical companies.

However, in recent years, drugs targeting PI3K have exposed more and more safety problems, and a limited number of approved drugs have encountered delisting or abandonment of marketing applications caused by safety issues, casting a shadow
on the development prospects of this target.

In July 2014, Gilead's Zydelig was approved for marketing, becoming the world's first successful PI3Kδ inhibitor, but the drug was launched with four boxed warnings, indicating that there are risks
including fatal liver problems.

In March 2016, Zydelig suffered serious adverse events such as infection-related deaths in clinical studies, and was successively warned and investigated
by the EMA and FDA.

Gilead then announced that it was suspending all clinical studies of Zydelig, saying it would no longer seek to develop Zydelig as a first-line therapy
for hematological tumors.

On January 14, 2022, Gilead voluntarily withdrew Zydelig's indication for the treatment of FL and SLL in the treatment of FL and SLL in a drug that is basically equivalent to withdrawal from the market
.

Bayer's Copanlisib is a PI3Kα/δ inhibitor that received accelerated approval
from the US FDA in September 2017.

In 2022, Bayer withdrew Copanlisib's two indications in the EU and China
.

In 2018, Secura's PI3K inhibitor, Duvelisib, was fully approved by the FDA for the treatment of adult patients with relapsed/refractory CLL/SLL who have received at least two upfront therapies, and also received accelerated approval
for the third-line treatment of follicular lymphoma.

To assess the long-term safety of Duvelisib, the FDA asked the manufacturer Secura to submit survival results for the last five years of the clinical trial, known as the DUO trial
.

The results of the DUO experiment were surprising: Among patients in the DUO experiment who underwent third-line or second-line therapy, 13 patients (14%) in the Duvelisib group died of side effects
.

In September 2022, the FDA's Oncology Drug Advisory Committee voted 8:4 against approving the indication
of Duvelisib for the third-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

This is almost equivalent to recommending Duvelisib's exit from the US market
.

Due to the long-term side effects and safety implications of PI3K target drugs, in April 2022, the FDA's Oncology Drug Advisory Committee (ODAC) agreed to redesign
the development approval framework for PI3K drugs with 16 votes in favor, 0 votes against and 1 abstention.

The so-called "reprogramming" is essentially an enhancement of the regulation of PI3K drugs, which mainly includes three changes: first, advocating careful dose selection (including approved drugs) preferably through robust dose exploration in early randomized trials; Second, avoid single-arm trials as a regulatory strategy in favor of randomized trials; Finally, OS data are comprehensively collected and analyzed to assess the drug's impact
on this "ultimate safety endpoint.
"

The tightening of the regulatory environment has also caused setbacks
for a number of PI3K drugs that are ready to be marketed.

In 2022 alone, there are Incyte, MEI Pharma, TG Therapeutics and other three companies' PI3K drugs were rejected by the FDA or voluntarily abandoned their marketing applications
.

Linplisac, which was approved in China, is most likely the only PI3K inhibitor drug
on the market in the world in the near future.

According to publicly reported data, Linplisept showed a good safety profile, most of its adverse reactions were grade 1 or 2 (83.
9%), the most common hematological toxicity associated with ≥ and 3 treatment (>5%) was conventional hematological toxicity of chemotherapy, and the incidence of common gastrointestinal adverse reactions and side effects such as hepatotoxicity of particular concern was lower than that reported
in the literature of drugs with the same target.

In February 2021, Hengrui Pharmaceutical and Yingli Pharmaceutical reached an agreement to grant Hengrui Pharmaceutical joint development rights and exclusive commercialization rights
for Linplisset in the Greater China region.