Almost unanimously passed!

This is an ODAC meeting that looks inconspicuous, but has great significance

PI3K (phosphoinositide 3-kinase), an important secondary messenger involved in cell signaling and function, was discovered more than 30 years ago

The signal transduction pathway mediated by it is also believed to play a key role in cell proliferation, differentiation, apoptosis and other processes, and also has a great impact on tumor drug resistance

It seems to be a very promising target: the mechanism is well defined, and it is widely distributed in multiple cancer types

So large and small pharmaceutical companies have followed suit.

Subsequently, PI3K inhibitor products from Infinity, Bayer, Novartis and TG Therapetics were approved one after another

Among them, except Novartis' Alpelisib, which is approved for the treatment of advanced metastatic breast cancer with PIK3CA mutation, the indications of the other four products are all hematological tumors

It can also be seen that hematological tumors are relatively easy to break through by PI3K, but unfortunately the good times are not long

One of the main troubles with PI3K during development is that either the adverse effects are too strong or the effects are too weak, it is difficult to find the right subtype and dose selection

In 2016, 2 years after the approval of Gilead's Zydelig, serious adverse events occurred in clinical trials, and were warned and investigated by the FDA and EMA, and then Gilead no longer invested in Zydelig, and on January 14 this year.

Half a month later, TG Therapetics suspended the clinical trials of its PI3K product Umbralisib for the treatment of CLL and SLL, possibly because Umbralisib was investigated by the FDA for whether it would increase the risk of patient death

Another day later, Bayer withdrew its PI3K product Copanlisib's marketing application in the EU for the treatment of MZL

As early as last December, Infinity had voluntarily withdrawn its PI3K product for the treatment of FL

There is also an even more unfortunate product, MEI Pharma's PI3K inhibitor zandelisib, which was directly rejected by the FDA last month , and the company's stock price plummeted nearly 60% that day

None of the other four PI3K inhibitors in the field of hematological tumors were spared, and all of them encountered major safety problems.

Changes in FDA Attitude

Before such "regular" safety problems were found, the FDA's attitude towards PI3K inhibitors was still very welcome.
Novartis, Infinity, and Bayer's products have all received accelerated approvals
.

However, the continuous emergence of safety problems led the FDA to conduct a retrospective analysis and released it in yesterday's ODAC meeting materials.
The data stated that 6 randomized clinical trials showed that 4 marketed PI3K inhibitors may cause toxicity and shorten the time.
Life expectancy of patients with hematological malignancies
.

What do you mean? After taking the medicine, the tumor was shrunk, and the patient died prematurely due to side effects
.

Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence, called the observation "unprecedented
.
"

This prompted the convening of this ODAC meeting, and the FDA is also reflecting on whether there is a problem with its previous strategy of granting accelerated approval of PI3K products for hematological tumors based on a single-arm trial
.

After all, there is no control group in the single-arm trial, and there is no safety issue.
It is difficult to directly prove the ultimate meaning of the drug for the treatment of patients with the surrogate endpoint as the primary endpoint - the effect of prolonging life
.

That's why, OS is always the hard end
.

The FDA put forward three ideas before the meeting: 1.
Advocate a more secure dose ramping and dose selection, preferably through early randomized controlled trials
.
2.
The use of "single-arm trials" as a regulatory strategy should be avoided, and more randomized controlled trials should be used
.
3.
Comprehensive collection and analysis of OS data should take this most important clinical outcome into consideration
.

At last night's meeting, despite the intense discussions on the agenda, the results were largely unanimous
.
The only expert who abstained from voting, his reason is also very intriguing: "No one can predict the future.
If there is a 'very explosive' one-arm test result in the future, will we approve it?"

Epilogue

The issue of PI3K inhibitors may become a thorn in the heart when the FDA approves oncology drugs in the future.
Although this meeting only discussed PI3K inhibitor products, no one can guarantee whether other products will be applied for accelerated approval.
Affected by this, I was asked to do one more randomized controlled trial, or wait another year and a half, and wait for the OS data to come out
.
From the perspective of PI3K inhibitors, currently, the license for use in hematological tumors is still an important problem on a global scale
.
Perhaps China's companies in this layout, such as Hengrui, Baekje, Cinda, Arnold, and Hutchison, have a chance to overtake in a corner
.
Coexisting with a crisis is usually an opportunity
.

Attachment: full video of the ODAC meeting

References:

https://endpts.
com/when-os-is-the-ultimate-safety-endpoint-fda-leaders-question-single-arm-trials-amid-scrutiny-of-pi3k-drugs-for-blood-cancer/

https://endpts.
com/fdas-oncology-adcomm-to-review-pi3k-inhibitors-in-blood-cancers-in-april/

https://endpts.
com/fdas-odac-votes-unanimously-that-future-pi3k-inhibitors-should-include-randomized-data-for-blood-cancers/

https://endpts.
com/crowded-rheumatoid-arthritis-category-gets-jak-reality-check-while-tnf-stalwarts-continue-to-dominate-study/

Although it is a mature target, drug indications are frequently withdrawn.
What is the difficulty in developing PI3K inhibitors?

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