Duvelisib

Last updated
Duvelisib
Duvelisib.svg
Clinical data
Pronunciation doo-VE-li-SIB
Trade names Copiktra
AHFS/Drugs.com Monograph
MedlinePlus a618056
License data
Routes of
administration 		By mouth (capsules)
Drug class PI3-Kinase inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism mainly metabolized by CYP3A4 [1]
Onset of action 1-2 hours after initial administration
Elimination half-life 5.2 to 10.9 hours
Excretion Feces (79%), urine (14%)
Identifiers
  • 8-Chloro-2-phenyl-3-[(1S)-1-(3H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.245.560 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H17ClN6O
Molar mass 416.87 g·mol−1
3D model (JSmol)
  • C[C@@H](C1=CC2=C(C(=CC=C2)Cl)C(=O)N1C3=CC=CC=C3)NC4=NC=NC5=C4NC=N5

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. [4] It is taken by mouth. [4] It is a PI3 kinase inhibitor. [5]

Contents

Common side effects include diarrhea, low white blood cells, rash, feeling tired, fever, and muscle pains. [4] Other serious side effects include inflammation of the lungs and infections. [4] It is a dual inhibitor of PI3Kδ and PI3Kγ. [6]

Medical uses

Duvelisib is indicated to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior therapies that did not work or stopped working. [1] [4] [5] CLL is a type of cancer that begins in the white blood cells, and SLL is a type of cancer that begins mostly in the lymph nodes. [5]

Adverse effects

Duvelisib may cause infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood. [5]

Duvelisib may have a higher risk of death. [5]

Pharmacology

Mechanism of action

Duvelisib is a Phosphoinositide 3-kinase inhibitor, specifically of the delta and gamma isoforms of PI3K. [7] This class of compounds works by preventing PI3K from playing its role in transducing signals from outside of cells into various intracellular pathways involved in cell cycle regulation, apoptosis, DNA repair, senescence, angiogenesis and cell metabolism, including the PI3K/AKT/mTOR pathway. [7]

History

Duvelisib, also known as IPI-145, was discovered by Intellikine, [8] a company founded in September 2007 based on biochemistry research from the lab of Kevan Shokat at the University of California San Francisco. [9]

In mid-June 2016, Infinity announced results of Phase II clinical trial of duvelisib. [7]

In November 2016, Infinity exclusively licensed the worldwide rights to duvelisib to Verastem Oncology for little money compared to earlier deals; the deal included no upfront payment, a $6 million milestone for success in a Phase 3 trial in chronic lymphocytic leukemia, a $22 million payment for an FDA approval, and royalties. [10]

Duvelisib received orphan drug designation in the United States for the treatment of peripheral T-cell lymphoma (PTCL) in 2019, [11] [12] the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma in 2013, [13] and the treatment of follicular lymphoma in 2013. [14]

In September 2020, duvelisib was sold by Verastem to Secura Bio, Inc. for $70 million and additional payments based on milestones and royalties. [15]

The US Food and Drug Administration (FDA) required the drug manufacturer, Secura Bio, to submit the final 5-year survival results from the clinical trial, called DUO trial, a phase III, randomized, open-label trial. [5] It was conducted in 319 participants with CLL or SLL who received a previous therapy that did not work or stopped working. [5] These final results showed a possible increased risk of death with duvelisib compared to the monoclonal antibody ofatumumab. [5] The rate of serious side effects, dose modifications, and deaths resulting from these side effects were also higher among participants who received duvelisib. [5] The serious side effects included infections, diarrhea, inflammation of the intestine and lungs, skin reactions, and elevated liver enzyme levels in the blood. [5] These safety findings were similar for other medicines in the same PI3 kinase inhibitor class. [5]

Society and culture

In April 2018, Verastem filed a New Drug Application (NDA) for duvelisib for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval for relapsed or refractory follicular lymphoma (FL). The FDA approved the application in September 2018. [16] [17] In April 2022, the FDA withdrew the approval of duvelisib for relapsed or refractory follicular lymphoma on request of its then owner, Secura Bio. [18]

Duvelisib is intended to be used in people who have received at least two prior systemic therapies, and carries a black box warning due to the risk of fatal/serious toxicities: infections, diarrhea or colitis, cutaneous reactions and pneumonitis. [19]

On 25 March 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Copiktra, intended for the treatment of adults with relapsed or refractory chronic lymphocytic leukaemia (CLL) and refractory follicular lymphoma (FL). [20] The applicant for this medicinal product is Verastem Europe GmbH. [20] Duvelisib was approved for medical use in the European Union in May 2021. [3]

Related Research Articles

Chronic lymphocytic leukemia 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.

Rituximab Pharmaceutical 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 injection into a vein. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.

Ofatumumab

Ofatumumab is a fully human monoclonal antibody to CD20, which appears to inhibit early-stage B lymphocyte activation. Under the brand name Arzerra, it is approved for the treatment of certain types of chronic lymphocytic leukemia (CLL) in the United States. Under the brand name Kesimpta, it is approved for the treatment of multiple sclerosis in the United States as well as in the EU and other regions.

Bendamustine

Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein.

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

Phosphoinositide 3-kinase inhibitor

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.

Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti-CD22 immunotoxin medication for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Moxetumomab pasudotox is a CD22-directed cytotoxin and is the first of this type of treatment for adults with HCL. The drug consists of the binding fragment (Fv) of an anti-CD22 antibody fused to a toxin called PE38. This toxin is a 38 kDa fragment of Pseudomonas exotoxin A.

Ibrutinib Medication used in cancer treatment

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Idelalisib Chemical compound

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

Copanlisib

Copanlisib is a drug which is approved by US FDA for the treatment of adult patients experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies.

Venetoclax 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).

Acalabrutinib Chemical compound

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Umbralisib

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Loncastuximab tesirine

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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.

Selinexor Anti-cancer drug

Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.

Indolent lymphoma Medical condition

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Brexucabtagene autoleucel, sold under the brand name Tecartus, is a cell-based gene therapy medication for the treatment of mantle cell lymphoma (MCL) and acute lymphoblastic leukemia (ALL).

Tafasitamab, sold under the brand name Monjuvi, is a medication used in combination with lenalidomide for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

References

  1. 1 2 3 "Copiktra- duvelisib capsule". DailyMed. Archived from the original on 11 November 2021. Retrieved 11 November 2021.
  2. ↑ "Copiktra- duvelisib capsule". DailyMed. 11 February 2022. Archived from the original on 24 June 2021. Retrieved 30 June 2022.
  3. 1 2 "Copiktra EPAR". European Medicines Agency (EMA). 24 March 2021. Archived from the original on 16 December 2021. Retrieved 11 November 2021.
  4. 1 2 3 4 5 "Duvelisib Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 28 February 2019. Retrieved 28 February 2019.
  5. 1 2 3 4 5 6 7 8 9 10 11 "FDA warns possible increased risk of death and serious side effects". U.S. Food and Drug Administration (FDA). 30 June 2022. Archived from the original on 30 June 2022. Retrieved 30 June 2022.PD-icon.svgThis article incorporates text from this source, which is in the public domain .
  6. ↑ "duvelisib (Rx)". Medscape. Archived from the original on 21 February 2019. Retrieved 24 September 2018.
  7. 1 2 3 Anastasia A, Rossi G (1 November 2016). "Novel Drugs in Follicular Lymphoma". Mediterranean Journal of Hematology and Infectious Diseases. 8 (1): e2016061. doi:10.4084/MJHID.2016.061. PMC   5111511 . PMID   27872741.
  8. ↑ "Duvelisib". AdisInsight. Archived from the original on 13 January 2017. Retrieved 11 January 2017.
  9. ↑ Timmerman L (20 December 2011). "Millennium: Takeda Acquires San Diego's Intellikine for $190M Upfront". Xconomy. Archived from the original on 20 April 2021. Retrieved 11 January 2017.
  10. ↑ Fidler B (2 November 2016). "Verastem Takes a Low-Cost Flier on Infinity's Blood Cancer Drug". Xconomy. Archived from the original on 21 April 2021. Retrieved 11 January 2017.
  11. ↑ "Duvelisib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 2 October 2019. Archived from the original on 23 November 2020. Retrieved 30 June 2022.
  12. ↑ "Copiktra Receives FDA's Orphan Drug Status for T-cell Lymphoma Treatment". Lymphoma News Today. Archived from the original on 6 November 2019. Retrieved 5 November 2019.
  13. ↑ "Duvelisib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 15 April 2013. Archived from the original on 24 October 2020. Retrieved 30 June 2022.
  14. ↑ "Duvelisib Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 1 August 2013. Archived from the original on 24 October 2020. Retrieved 30 June 2022.
  15. ↑ "Verastem Oncology Announces Closing of Copiktra (duvelisib) Sale to Secura Bio". Archived from the original on 2021-04-24. Retrieved 2021-02-19.
  16. ↑ "Duvelisib (Copiktra, Verastem, Inc.) for adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)". FDA. 24 September 2018. Archived from the original on 23 April 2019. Retrieved 1 February 2019.
  17. ↑ "FDA Accepts New Drug Application for Duvelisib and Grants Priority Review" (Press release). Verastem. 2018-07-07. Archived from the original on 2021-04-19. Retrieved 2019-02-01– via Business Wire.
  18. ↑ "Secura Bio, Inc.; Withdrawal of Approval of Relapsed or Refractory Follicular Lymphoma Indication for Copiktra". 2022-04-13. Archived from the original on 2022-04-13. Retrieved 2022-05-03.
  19. ↑ Carroll J (24 September 2018). "Unwanted by AbbVie and Infinity, battered Verastem gets an OK for duvelisib and a second shot at success". Endpoints News. Archived from the original on 20 April 2021. Retrieved 1 February 2019.
  20. 1 2 "Copiktra: Pending EC decision". European Medicines Agency (EMA). 26 March 2021. Archived from the original on 26 March 2021. Retrieved 26 March 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
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