Idelalisib

Last updated
Idelalisib
Idelalisib.svg
Idelalisib structure
Clinical data
Pronunciation /aɪˈdɛləlɪsɪb/
eye-DEL-ə-li-sib
Trade names Zydelig
Other namesGS-1101, CAL-101
AHFS/Drugs.com Monograph
MedlinePlus a614040
License data
Pregnancy
category
  • AU:D
Routes of
administration 		Oral (tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • US: WARNING [2] Rx-only
  • EU:Rx-only [3]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding >84% [4]
Metabolism Aldehyde oxidase (~70%), CYP3A4 (~30%); [5] UGT1A4 (minor)
Metabolites GS-563117 (inactive in vitro)
Onset of action Tmax = 1.5 hours
Elimination half-life 8.2 hours
Excretion Feces (78%), urine (14%)
Identifiers
  • 5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.235.089 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H18FN7O
Molar mass 415.432 g·mol−1
3D model (JSmol)
  • CC[C@H](Nc1ncnc2nc[nH]c12)c4nc3cccc(F)c3c(=O)n4c5ccccc5
  • InChI=1S/C22H18FN7O/c1-2-15(28-20-18-19(25-11-24-18)26-12-27-20)21-29-16-10-6-9-14(23)17(16)22(31)30(21)13-7-4-3-5-8-13/h3-12,15H,2H2,1H3,(H2,24,25,26,27,28)/t15-/m0/s1
  • Key:IFSDAJWBUCMOAH-HNNXBMFYSA-N

Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers. [4] [3]

Contents

The substance acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase. [6] [7] It was developed by Gilead Sciences. Idelalisib had annual sales of $168 million (USD) during the year of 2016, up from $132 million (USD) in 2015. [8] It is taken orally (swallowed by mouth).

Medical uses

Idelalisib is a second-line drug for patients whose chronic lymphocytic leukemia (CLL) has relapsed. Used in combination with rituximab, [9] idelalisib is to be used in patients for whom rituximab alone would be considered appropriate therapy due to other existing medical conditions. [9] It appears to be effective and leads to improvement of lymphadenopathy and splenomegaly. However, the lymphocyte counts take longer to decrease to normal levels with idelalisib. It is not recommended as a first-line treatment. [4] Ac

Adverse effects

Clinical symptoms include diarrhea, fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills and rash. Laboratory abnormalities may include: neutropenia, hypertriglyceridemia, hyperglycemia and elevated levels of liver enzymes. Idelalisib's safety and effectiveness to treat relapsed FL and relapsed SLL were established in a clinical trial with 123 participants with slow-growing (indolent) non-Hodgkin lymphomas. All participants were treated with idelalisib and were evaluated for complete or partial disappearance of their cancer after treatment (objective response rate, or ORR). Results showed 54% of participants with relapsed FL and 58% of participants with SLL experienced ORR. [10]

The U.S. label for idelalisib has a boxed warning describing toxicities that can be serious and fatal, including liver toxicity, severe diarrhea, colon inflammation, lung tissue inflammation (pneumonitis) and intestinal perforation, and the manufacturer was required to put in place a Risk Evaluation and Mitigation Strategy (REMS) under which the risk of toxicities would be managed. [11]

In March 2016, as reports were made from three ongoing clinical trials of serious adverse events and deaths, mostly due to infections, the European Medicines Agency opened a review of the drug and its risks. [12] On March 21, 2016 Gilead Sciences (the manufacturer of idelalisib) alerted healthcare providers about decreased overall survival and increased risk of serious infections in patients with CLL and indolent non-Hodgkin lymphoma (iNHL) treated with idelalisib. [13] The company also disclosed that it stopped six clinical trials in patients with CLL, SLL and iNHL due to an increased rate of adverse events, including deaths. [14] In 2016, the EMA recommended that people on idelalisib should be given medication against the lung infection Pneumocystis jirovecii pneumonia and this should be continued for up to 6 months after idelalisib has stopped. In addition, people should be monitored for signs of infection. [15]

Pharmacology

Mechanism of action

PI3Kδ is expressed in normal and malignant B-cells. By inhibiting it, idelalisib induces apoptosis and prevents proliferation in cell lines derived from malignant B-cells and in primary tumor cells. It also inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in the trafficking and homing of B-cells to the lymph nodes and bone marrow. [4]

Binding profile

Idelalisib is a competitive inhibitor of the ATP binding site of the PI3Kδ catalytic domain. Its in vitro potency and selectivity relative to the other Class I PI3K isoforms is the following: [16]

PI3K isoform IC50 (nM)IC50-based PI3Kδ-fold selectivity
PI3Kα 8,600453
PI3Kβ 4,000211
PI3Kγ 2,100110
PI3Kδ 191

History

Regulatory

In July 2014, the FDA and EMA granted idelalisib approval to treat chronic lymphocytic leukemia. [10] [17]

It was also approved by the FDA for the treatment of relapsed follicular lymphoma (FL) and small lymphocytic lymphoma (SLL), both in patients who had received at least two prior systemic therapies. [4] This approval was voluntarily withdrawn by the manufacturer in May 2022 after they failed to complete post-marketing confirmatory studies required by the FDA. [18] This has coincided with the withdrawal of every other PI3K inhibitor for follicular lymphoma: duvelisib in December 2021, umbralisib in January 2022, and copanlisib in November 2023. [19] [20] [21] These withdrawals are attributed to a possibly detrimental effect on survival seen in multiple studies of this drug class, likely due to toxic side effects. [22]

Related Research Articles

<span class="mw-page-title-main">Chronic lymphocytic leukemia</span> Medical condition

Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes. Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years.

<span class="mw-page-title-main">Rituximab</span> Biopharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.

<span class="mw-page-title-main">P110δ</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an enzyme that in humans is encoded by the PIK3CD gene.

<span class="mw-page-title-main">Bruton's tyrosine kinase</span> Kinase that plays a role in B cell development

Bruton's tyrosine kinase, also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.

<span class="mw-page-title-main">Ofatumumab</span> Medication

Ofatumumab is a fully human monoclonal antibody to CD20, which appears to provide rapid B-cell depletion. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the European Union and other regions. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. It is sold by Novartis under license from Genmab.

Richter's transformation (RT), also known as Richter's syndrome, is the conversion of chronic lymphocytic leukemia (CLL) or its variant, small lymphocytic lymphoma (SLL), into a new and more aggressively malignant disease. CLL is the circulation of malignant B lymphocytes with or without the infiltration of these cells into lymphatic or other tissues while SLL is the infiltration of these malignant B lymphocytes into lymphatic and/or other tissues with little or no circulation of these cells in the blood. CLL along with its SLL variant are grouped together in the term CLL/SLL.

Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody used as a treatment for cancer. It was originated by GlycArt Biotechnology AG and developed by Roche.

<span class="mw-page-title-main">Phosphoinositide 3-kinase inhibitor</span>

Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.

<span class="mw-page-title-main">Ibrutinib</span> Medication used in cancer treatment

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.

<span class="mw-page-title-main">Copanlisib</span> Chemical compound

Copanlisib, sold under the brand name Aliqopa, is a medication used for the treatment of adults experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies.

<span class="mw-page-title-main">Venetoclax</span> Medication

Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML).

<span class="mw-page-title-main">Acalabrutinib</span> Chemical compound

Acalabrutinib, sold under the brand name Calquence, is a medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic Lymphoma (CLL/SLL). It may be used both in relapsed as well as in treatment-naive settings.

<span class="mw-page-title-main">Duvelisib</span> PI3K inhibitor

Duvelisib, sold under the brand name Copiktra, is a medication used to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma after other treatments have failed. It is taken by mouth. It is a PI3 kinase inhibitor.

<span class="mw-page-title-main">Umbralisib</span> Chemical compound

Umbralisib, sold under the brand name Ukoniq, is an anti-cancer medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). It is taken by mouth.

Lisocabtagene maraleucel, sold under the brand name Breyanzi, is a cell-based gene therapy used to treat B-cell lymphoma.

Verastem Oncology is an American pharmaceutical company that develops medicines to treat certain cancers. Headquartered and founded in Boston, Massachusetts, the firm is a member of NASDAQ Biotechnology Index.

<span class="mw-page-title-main">Zanubrutinib</span> Chemical compound

Zanubrutinib, sold under the brand name Brukinsa, is an anticancer medication used for the treatment of mantle cell lymphoma (MCL), Waldenström's macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL). Zanubrutinib is classified as a Bruton's tyrosine kinase (BTK) inhibitor. It is given by mouth.

<span class="mw-page-title-main">Indolent lymphoma</span> Medical condition

Indolent lymphoma, also known as low-grade lymphoma, is a group of slow-growing non-Hodgkin lymphomas (NHLs). Because they spread slowly, they tend to have fewer signs and symptoms when first diagnosed and may not require immediate treatment. Symptoms can include swollen but painless lymph nodes, unexplained fever, and unintended weight loss.

BeiGene, Ltd. is a global oncology company that specializes in the development of drugs for cancer treatment. Founded in 2010 chief executive officer by John V. Oyler and Xiaodong Wang, the multinational company headquartered in Cambridge, Massachusetts has offices in North America, Europe, South America, Asia and Australia. BeiGene has a large presence in Chinese market. BeiGene has developed several pharmaceuticals, including tislelizumab, a checkpoint inhibitor, and zanubrutinib, a Bruton's tyrosine kinase inhibitor.

Mosunetuzumab, sold under the brand name Lunsumio, is a monoclonal antibody used for the treatment of follicular lymphoma. It bispecifically binds CD20 and CD3 to engage T-cells. It was developed by Genentech.

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  3. 1 2 "Zydelig EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 21 October 2020.
  4. 1 2 3 4 5 "Zydelig- idelalisib tablet, film coated". DailyMed. 22 October 2018. Retrieved 21 October 2020.
  5. ↑ "Clinical Pharmacology and Biopharmaceutics Review: Zydelig (idelalisib)" (PDF). U.S. Food and Drug Administration. p. 6. Retrieved 15 April 2016.
  6. ↑ Spreitzer H (13 May 2013). "Neue Wirkstoffe – Ibrutinib und Idelalisib". Österreichische Apothekerzeitung (in German) (10/2013): 34.
  7. ↑ Wu M, Akinleye A, Zhu X (May 2013). "Novel agents for chronic lymphocytic leukemia". Journal of Hematology & Oncology. 6: 36. doi: 10.1186/1756-8722-6-36 . PMC   3659027 . PMID   23680477.
  8. ↑ "Annual Sales of Idelalisib reported using PharmaCompass' compilation of Annual Reports of Global Pharmaceutical Companies". Pharmacompass. Retrieved January 21, 2019.
  9. 1 2 Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. (March 2014). "Idelalisib and rituximab in relapsed chronic lymphocytic leukemia". The New England Journal of Medicine. 370 (11): 997–1007. doi:10.1056/NEJMoa1315226. PMC   4161365 . PMID   24450857.
  10. 1 2 "FDA approves Zydelig for three types of blood cancers" (Press release). Food and Drug Administration. July 23, 2014. Archived from the original on January 12, 2017. Retrieved March 21, 2022.{{cite press release}}: CS1 maint: bot: original URL status unknown (link)
  11. ↑ "Press Announcements — FDA approves Zydelig for three types of blood cancers". www.fda.gov. Retrieved 2016-03-14.
  12. ↑ "European Medicines Agency — News and Events — EMA reviews cancer medicine Zydelig". www.ema.europa.eu. Archived from the original on 2016-03-15. Retrieved 2016-03-14.
  13. ↑ "Important Drug Warning: Decreased Overall Survival and Increased Risk of Serious Infections in Patients Receiving ZYDELIG (idelalisib)" (PDF). Gilead Sciences, Inc. March 21, 2016. Retrieved 19 April 2016.
  14. ↑ "Drug Safety and Availability — FDA Alerts Healthcare Professionals About Clinical Trials with Zydelig (idelalisib) in Combination with Other Cancer Medicines". FDA Center for Drug Evaluation and Research. Retrieved 19 April 2016.
  15. ↑ "CHMP confirms recommendations for use of Zydelig". European Medicines Agency (EMA). 15 September 2016.
  16. ↑ "Committee for Medicinal Products for Human Use Assessment Report: Zydelig (idelalisib)" (PDF). European Medicines Agency. p. 17. Archived from the original (PDF) on 2 April 2016. Retrieved 19 April 2016.
  17. ↑ "European Medicines Agency recommends approval of two new treatment options for rare cancers" (Press release). European Medicines Agency. July 25, 2014.
  18. ↑ "Gilead Sciences, Inc.; Withdrawal of Approval of Indications for Relapsed Follicular Lymphoma and Relapsed Small Lymphocytic Lymphoma for ZYDELIG (Idelalisib) Tablets" (Press release). Federal Register. May 26, 2022. Archived from the original on May 26, 2022. Retrieved November 15, 2023.{{cite press release}}: CS1 maint: bot: original URL status unknown (link)
  19. ↑ "Secura Bio Withdraws Duvelisib Relapsed/Refractory Follicular Lymphoma Indication in the United States". OncLive. Retrieved 15 November 2023.
  20. ↑ "FDA withdrew its approval for the cancer medicine Ukoniq (umbralisib) due to safety concerns". FDA Drug Safety Podcast. 7 July 2022. Retrieved 15 November 2023.
  21. ↑ "Bayer withdraws follicular lymphoma drug after further trial fails". Reuters. 13 November 2023. Retrieved 15 November 2023.
  22. ↑ Richardson NC, Kasamon Y, Pazdur R, Gormley N (May 2022). "The saga of PI3K inhibitors in haematological malignancies: survival is the ultimate safety endpoint". The Lancet. Oncology. 23 (5): 563–566. doi:10.1016/S1470-2045(22)00200-5. PMID   35429996.
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