There is hope that a rich biotech pipeline will produce a second generation of PI3K drugs after issues with the first generation from the class had brought up concerns.
Phosphoinositide 3-kinases (PI3K) drugs work by inhibiting a pathway that plays a role in cell metabolism, growth, proliferation and survival that has become dysregulated in almost all human cancers.
PI3K inhibitors work by blocking the action of the enzyme in the PI3K/AKT/mTOR pathway, with some working on different subunits on the enzyme, denoted by alpha, beta, gamma, or delta suffixes.
But accelerated approvals in hematological cancers based on single-arm trial data have been withdrawn, affecting some big pharma companies who have marketed drugs from the class. Although these first-generation drugs showed initial progression-free survival (PFS) advantages, long-term, they didn’t show a benefit to overall survival.
But despite this, they remain on the market as options in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
A landmark vote in April 2022 by the U.S. Food and Drug Administration’s (FDA’s) Oncologic Drugs Advisory Committee (ODAC) means future approvals of drugs from the class for hematological cancers should be supported by randomized data.
With this in mind, pharma and biotech firms continue with research into the class, although the bar is now higher as, following the vote, the FDA is looking for randomized studies that focus on overall survival as an endpoint rather than PFS, at least for hematological cancers. It is widely believed that toxicity of the first-generation PI3Kd inhibitors played a role in the lack of overall survival benefit. For this reason, the FDA is also requesting more dose-finding studies early on in drug development.
At the September 2023 meeting of the UK Biochemical Society in Barcelona, key opinion leaders discussed the pathway, and argued that understanding of PI3K biology and signaling brings this field to the cusp of a new era of PI3K targeting drugs, with mechanisms of action that modify these molecular signals.
Prof Bart Vanhaesebroeck, professor of Cell Signalling at the University College London (UCL) Cancer Institute in the U.K., pointed to research that suggests PI3K inhibitors shouldn’t be thought of as chemotherapies that cause cancer cell death.
Vanhaesebroeck told the conference, titled “The PI3K-AKT-mTOR-PTEN pathway: a new era in basic research and clinical translation,” that all evidence indicates that PI3K inhibitors are cytostatic, preventing cancer cells from growing and multiplying.
“It’s time people stopped thinking they kill cancer cells, they don’t – it’s time to take this knowledge into account for clinical development of PI3K pathway inhibitors by combining them intelligently, with other drugs that complement and add to their action,” he added. “For example, PI3Ka inhibitors, through their growth-inhibitory effect on breast cancer, make these cells more responsive to an estrogen receptor degrader. In other words, a PI3Ka inhibitor can be used to make an existing cancer therapy work again in the case of resistance, or make it work better.”
He also stressed that some PI3K inhibitors that are against PI3Kd have important effects on the immune system. These are exemplified by inhibitors of PI3Kd, which show promising impact in immunotherapy of both solid and hematological tumors. These could be used as an approach to reawaken the immune system for subsequent immunotherapy using approved check-point inhibitors.
This makes PI3K inhibitors good candidates for combination therapies, as long as toxicities are manageable. Any side-effects will likely be added to those of other drugs in the combination, meaning a next generation PI3K drug will have to be as tolerable as possible.
An important development is the focus on solid tumors. While the first approved drugs focusing on PI3K were limited to hematological cancer, it’s hoped that improving the therapeutic window, with better tolerability and efficacy could open up opportunities in new indications. A first success is Novartis’ PI3Ka inhibitor Piqray (alpelisib), which was approved in 2019 for breast cancer in combination with Faslodex (fulvestrant).
New strategies to target the pathway include AstraZeneca who filed capivasertib in combination with Faslodex with the FDA in June, which granted a Priority Review for patients with advanced HR-positive breast cancer.
Capivasertib is an adenosine triphosphate (ATP) inhibitor of all three AKR isoforms and is being evaluated in tumors harboring alterations in the AKT pathway (PI3KCA, AKT1 or PTEN genes).
AstraZeneca is also investigating it in combination with a range of other doublet and triplet combinations.
Other biotechs are following suit. Scorpion Therapeutics is developing STX-478 in phase 1/2 , and has noted that the drug is an allosteric and central nervous system penetrant inhibitor of mutant PI3K alpha. Allosteric kinase inhibitors offer the possibility for greater selectivity and lower dosing as these inhibitors do not bind to the highly conserved ATP pocket and not compete with cellular ATP.
The phase 1 /2 trial will evaluate STX-478 as a monotherapy in a variety of solid tumors including breast and gynecological tumors.
Loxo Oncology, which is now part of Eli Lilly after a merger in 2019, has another allosteric PI3K-alpha inhibitor LOX0783 in phase 1 clinical development in solid tumors with mutations that make them susceptible to this drug class.
Also in development is iOnctura’s roginolisib, a novel PI3kd inhibitor with a differentiated non-ATP-competitive binding mechanism.
Data announced earlier this year, showed roginolisib has a favorable toxicity profile with less than 5% grade 3/4 toxicities at the biologically effective dose. Importantly, these toxicities were transient in nature without the need for dose reductions.
iOnctura’s head of Research Giusy di Conza, said that much had been learned from the first generation of PI3K drugs.
Improved practices during drug development are translating into better results in the clinic, as issues with the first generation drugs are corrected.
“First generation drugs have been transformative and life-saving in CLL, and it’s great to see that pharma and biotech companies are investing in research in this area. These data from the conference showed that drugs targeting this pathway have potential in solid tumors, thanks to their improved safety and efficacy.”
Inhibition of PI3Kb could also prevent tumor development, according to mouse pancreatic cancer data presented at the event.
Experts pointed out that exploiting the PI3K signaling pathway also opens opportunities in other diseases – activating it instead of shutting it down could have potential in cardiology and regenerative medicine.
For example, mouse model data presented at the event showed PI3Ka activation during a reperfusion procedure after a stent operation prevents infarctions.
Activation of PI3Ka also led to regeneration of nerves in a mouse model of peripheral nerve injury.
Aside from these uses outside of cancer, and potential new cancer indications, there has been work to improve how already approved PI3K inhibitors are used in the clinic.
As an example, Yin Yanping, a postdoc at Oslo University, presented research suggesting that it could be possible to profile which patients are likely to respond to PI3K inhibitors by analyzing blood samples before treatment.
After a shaky start, there’s real hope that PI3K inhibitors could become increasingly important for patients, in diseases including cancer and beyond.
Next generation PI3K inhibitors
|iOnctura||IOA-244||Phase 1b/2||PI3Kd inhibitor||Solid tumors/hematological malignancies|
|Scorpion Therapeutics||STX-478||Phase 1/ 2||Mut-Sel PI3Ka inhibitor||Breast cancer/solid tumors|
|Eli Lilly/Loxo||LOXO-783||Phase 1||PI3Ka inhibitor||Cancer|
|AstraZeneca||Capiversatib||Registration||AKT inhibitor||Breast cancer, also phase 3 in prostate cancer|