PI3K (Phosphoinositide 3-kinase) is an enzyme which is responsible for helping cells receive and respond to signals from their environment. It essentially acts as a messenger, transmitting information from the outside of the cell to the inside. It might be prudent to think of PI3K as a key that unlocks various cellular processes. It is involved in various cellular signaling pathways. 

PI3K Functioning

It phosphorylates the 3-position hydroxyl group of the inositol ring in phosphatidylinositol lipids, leading to the production of second messengers, particularly phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 plays a crucial role in intracellular signaling by recruiting and activating downstream effector proteins.

When certain signals, like growth factors or hormones, bind to receptors on the cell surface, PI3K gets activated. Once activated, PI3K modifies certain lipids (specific types of fats) in the cell membrane, creating a signal that triggers various cellular responses. It is involved in signal transduction pathways activated by growth factors, cytokines, and other extracellular signals. PI3K is activated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), among other receptors. It then produces a molecule called PIP3. PIP3 then triggers a series of reactions that control important cellular functions.

PI3K is involved in a number of biological processes like cell growth, survival, and metabolism. It helps cells grow, divide, and stay alive. It also plays a role in regulating the uptake of glucose into cells. Additionally, PI3K is involved in immune responses and the functioning of the nervous system.

When PI3K is not working properly, it can lead to various diseases. For example, if PI3K is overactive, it can contribute to the development of cancer by promoting excessive cell growth and survival. Research is thus now geared towards studying ways to target and inhibit PI3K in certain diseases, including cancer, in order to restore normal cellular function.

PI3K Classes

There are different classes of PI3K, classified based on their structure and substrate specificity. Class I PI3Ks are the most well-studied and are further divided into class IA and class IB. Class IA PI3Ks are heterodimers composed of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85α, p55α, or p50α). Class IB PI3Ks consist of the catalytic subunit p110γ and the regulatory subunits p101 or p87.

PI3K can be effectively utilized for a number of biological processes such as cell growth and proliferation. Its signaling is involved in promoting cell growth and proliferation. It stimulates the activation of downstream targets, such as protein kinases like AKT (also known as protein kinase B), which regulate cell cycle progression and promote cell division. PI3K signaling is essential for cell survival. Activation of PI3K leads to the production of PIP3 which recruits and activates AKT. AKT, in turn, promotes cell survival by inhibiting apoptosis (programmed cell death) and promoting cell survival pathways.

PI3K plays a critical role in insulin signaling. When insulin binds to its receptor on the cell surface, it activates PI3K, leading to the translocation of glucose transporter proteins (GLUT4) to the cell membrane. This process facilitates the uptake of glucose from the bloodstream into the cells, regulating blood sugar levels.

PI3K signalling is involved in regulating immune responses. It plays a role in the activation, migration, and survival of immune cells such as T cells, B cells, and macrophages. PI3K is important for the development and functioning of the immune system.

Dysregulation of the PI3K pathway is commonly observed in cancer. Mutations or aberrant activation of PI3K can lead to increased cell proliferation, survival, and migration, contributing to tumour growth and metastasis. Therefore, PI3K inhibitors are being developed as potential targeted therapies for various types of cancer.

PI3K is implicated in inflammatory processes. It is involved in the activation of immune cells and the production of inflammatory mediators. Inhibiting PI3K can help modulate excessive immune responses and inflammation associated with autoimmune disorders and inflammatory diseases.

PI3K signaling is also important in the nervous system. It plays a role in neuronal development, synaptic plasticity, and neuronal survival. Dysregulation of PI3K signalling has been implicated in neurological disorders such as Alzheimer’s disease and Parkinson’s disease.

P13K Market Potential

P13K’s potential contribution in cancer treatment cannot be undermined. Given that the PI3K cell-signalling network’s significance in promoting various cancer types was first understood over 40 years ago, it has been a crucial therapeutic target in oncology research. When idelalisib (Zydelig), the first PI3K inhibitor to receive FDA clearance, it was used to treat recurrent follicular lymphoma , small lymphocytic lymphoma, and chronic lymphocytic leukemia, these efforts started to bear fruit in 2014. Four other PI3K inhibitors were subsequently given FDA approval for cancer applications.

However, due to worries regarding efficacy and safety, the use of PI3K inhibitors in hematologic malignancies has come under investigation over the past year. Pharmaceutical firms have voluntarily removed the indications for idelalisib in FL and SLL as well as duvelisib (Copiktra) in FL since December 2021; umbralisib (Ukoniq), which was approved in which had been approved for FL and marginal zone lymphoma (MZL) was fully taken off the market.4,5

Additionally, in September 2022, the FDA’s Oncologic Drugs Advisory Committee (ODAC) decided against maintaining duvelisib’s indications for patients with relapsed or refractory (R/R) CLL or SLL following at least two prior regimens. Copanlisib (Aliqopa), however, has withdrew a supplemental new drug application for the combination of copanlisib and rituximab (Rituxan) in patients with relapsed indolent non-Hodgkin lymphoma (iNHL) pending analysis. Copanlisib is still indicated as monotherapy for the treatment of adults with relapsed FL after at least two prior therapies. 

Market Players

Alpelisib (Piqray), which is approved in conjunction with fulvestrant (Faslodex) for patients with hematologic malignancies, is notable in that no concerns regarding PI3K inhibitors in hematologic malignancies have been noted.

The FDA authorised Alpelisib, marketed as Vijoice, in April 2022 for use in treating adult and paediatric patients with PIK3CA-related overgrowth spectrum, a group of uncommon genetic illnesses brought on by PIK3CA mutations. 

PI3K inhibitors are still being researched in hematopoietic situations. Additionally, a search of ClinicalTrials.gov revealed that PI3K inhibitor development in breast cancer and other solid tumours is still ongoing. 

In order to increase the effectiveness of PI3K inhibitors, researchers have been concentrating on a number of tactics, with a particular focus on lowering toxicities, creating combination regimens, and overcoming resistance.

According to some professionals, experimenting with different scheduling and dosing regimens would lead to fewer toxicities and a better therapeutic index. To test intermittent dosing, as opposed to continuous dosing at the maximum tolerated dose established in phase 1 trials, certain studies of new PI3K inhibitors have been conducted in this way. Although it has been difficult to combine PI3K inhibitors with other targeted therapy, there might be room for logical combinations in patients with PIK3CA-mutant tumours. 

With over, 22+ major companies working on PI3K inhibitor treatments. Celcuity, Inc. is one of the businesses whose inhibitor medication candidates are in the most advanced stage, or phase III.  According to Technavio, the market for phosphoinositide 3-kinase (PI3K) inhibitors would increase by USD 71.29 million between 2021 and 2026. During the forecast period, the market is anticipated to develop at a CAGR of 5.09%. Phosphoinositide 3-kinase (PI3K) inhibitor demand is driven by elements including new approvals, strategic alliances, and unique therapeutic designations, while problems like low drug uptake limit market expansion. 

Only four approved PI3K inhibitors currently make up the majority of the market for these products worldwide. The leading companies in the market are Bayer AG, Celon Pharma SA, Curis Inc., Exelixis Inc., Gilead Sciences Inc., Merck KGaA, Molecular Depot LLC., Novartis AG, Secura Bio Inc., and TG Therapeutics Inc. Copanlisib, a phosphoinositide 3 kinase inhibitor, is provided by Bayer AG. Kichai is one of the phosphoinositide 3 kinase inhibitors offered by Celon Pharma SA. Fimepinostat, a phosphoinositide 3 kinase inhibitor, is provided by Curis Inc.

During the projection period, North America is anticipated to contribute 37% of the market growth for phosphoinositide 3-kinase (pi3k) inhibitors worldwide. The primary markets in the area for phosphoinositide 3-kinase (PI3K) inhibitors are the US and Canada.

Conclusion

One of the key factors promoting the market growth for PI3K inhibitors is the recent approvals to some of its treatments for blood cancer yet a few were withdrawn. There is a significant unmet demand in the market for the treatment of different forms of blood cancer, despite the availability of numerous authorized medicines. Many chemotherapeutic medications, including those for lymphomas, currently rule the field of cancer treatment. Chemotherapies have various drawbacks that make it harder for patients to follow their treatment regimens. As a result, tailored medicines are replacing conventional chemotherapy agents in the treatment of cancer. PI3K offers an alternative treatment yet we would have to wait for trials to finish, data to be published etc to gauge its effectiveness. It won’t be wrong however to say that companies will continue explore various treatments for cancer.