Duvelisib

Duvelisib
Clinical data
ATC code None
Identifiers
Synonyms IPI-145
CAS Number 1201438-56-3
PubChem (CID) 50905713
ChemSpider 28637766
KEGG D10555
Chemical and physical data
Formula C22H17ClN6O
Molar mass 416.86 g/mol
3D model (Jmol) Interactive image

Duvelisib (INN,[1] previously known as IPI-145) is an inhibitor of PI3Kδ and PI3Kγ,[2] researched as a treatment for hematologic malignancies as well as a broad range of inflammatory conditions.[3] The phosphoinositide 3-kinases are involved in cell proliferation and differentiation and have significant potential in hematology fields and inflammatory disease treatments.[2] Ibrutinib and acalabrutinib are other inhibitors that are being used or researched for similar treatments.

Mechanism of action

It is a Phosphoinositide 3-kinase inhibitor, specifically of the delta and gamma isoforms.[2] By inhibiting the PI3K/AKT/mTOR pathway cancer cell growth/proliferation (dependant on this pathway) may be reduced.

These inhibitors also show promise in the rheumatoid arthritis and asthma fields of treatments as the kinases that are inhibited play a role in joint or airway inflammation.

Society and culture

Cost

Duvelisib, also known as IPI-145, is currently being researched by Infinity Pharmaceuticals (INFI). This public company largely pursues drugs for difficult to treat disorders and diseases such as immuno-suppressives and hematological malignancies.[4] Their main focus at the current moment are PI3K-gamma inhibitors such as IPI-549.

During 2012 and 2013, INFI experienced financial difficulties after clinical data for their drug Saridegib showed results demonstrating little effectiveness in treating bone marrow malignancies.[5] As a result, the company stated they would be focusing efforts on two drugs, one of which being Duvelisib.[5]

As of March 2015, INFI stated that it would pay $52.5 million to buy out future royalty obligations from Takeda Pharmaceuticals (TKPYY), an option that was initially bought by INFI for $5 million in 2014.[6] The decision was made based on the success demonstrated by several phase II studies, showing promise in treating multiple classes hematological malignancies. Millennium Pharmaceuticals, an affiliate of Takeda, will not longer be able to receive royalties on any of the sales of duvelisib should it complete trials and gain approval.[6]

In October, Infinity was able to license duvelisib to Verastem Inc., a drug being investigated as an oral dual inhibitor for PI3Kδ and PI3Kγ.[4] Under the agreement, officially announced in November, INFI is eligible to receive up to $28 million upon positive results from phase III trials in treating relapsed/refractory chronic lymphocytic leukemia and from regulatory approval inside or outside the U.S.[4] INFI is also eligible to receive mid-to-high royalties from Verastem on potential net sales.

Verastem's licensing of duvelisib aligns with the company's focus on targeting tumor micro-environments.[7] A similar kinase inhibitor that Verastem is also currently evaluating VS-6063, or defactinib.[7] Both INFI and Verastem's cash and investment outlooks have been significantly improved by the results and potential behind duvelisib and it's trials.[4][7] INFI is predicting $70 to $80 million in year-end cash, in comparison to their original estimation of $45 to $55 million.[4]

Ibrutinib, a drug duvelisib is being compared to, is sold in the U.S. for approximately $116,600 per year. The comparative drug is also predicted to reach global net sales of $1 billion in 2016, and $5 billion by 2020. Another drug duvelisib is being compared to, rituximab, costs anywhere from $159 to $2,480 per vial or treatment. Rituxmab is a monoclonal antibody and not a kinase inhibitor. However, duvelisib is being researched to treat similar malignancies.

Clinical trials

It was announced in 2011, that two phase I clinical trials would be started to explore duvelisib's effect on hematologic cancers.[3] The first phase I trial for IPI-145 was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of various dosage levels in healthy adult subjects.[3] The trial was randomized, placebo-controlled, and double-blinded. Phase I results in patients with relapsed/refractory hematologic malignancies who had been previously treated with ibrutinib showed "clinical activity and a tolerable safety profile".[8] In July 2012 the phase I trial was expanded and two phase II trials were planned.[9][10]

A phase II trial for refractory indolent non-Hodgkin lymphoma has been registered and as of November 2106, is still ongoing.[11] A phase IIA study in asthma has reported preliminary results indicating improvement in lung function.[12] The ASPIRA trial, a Phase 2 study of duvelisib with methotrexate in patients with moderate-to-severe rheumatoid arthritis, was expected to report by end 2014.[12] Both of these trials indicate a potential of PI3K-delta,gamma inhibitors in the anti-inflammatory industry. Data strongly supports a significant decrease in mediator levels causing airway inflammation when the inhibitors are used.[12]

As of December 2015 there are four active phase III trials.[13] Since, the trial involving a combination treatment of duvelisib with rituximab and bendamustive for previously-treated indolent non-hogkin lymphoma has been withdrawn. The three trials still in progress involve the combination and comparison of duvelisib with rituximab or ofatumumab in the treatment of diseases such as follicular lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma.[13] A phase III trial for chronic lymphocytic leukemia/small lymphocytic lymphoma previously treated with a BTK inhibitor (Obinutuzumab) became active in December 2015.[14]

Patents

There are 33 patents granted that are related to the drug Duvelisib. The most recent 5 are displayed in the table below:[15]

Patent ID Patent Title Submitted Date Granted Date
US2016068601 TREATMENT OF CANCER USING A CD123 CHIMERIC ANTIGEN RECEPTOR 2015-08-19 2016-03-10
US2016051651 TREATMENT OF CANCER USING A CLL-1 CHIMERIC ANTIGEN RECEPTOR 2015-07-21 2016-02-25
US2016046724 TREATMENT OF CANCER USING HUMANIZED ANTI-BCMA CHIMERIC ANTIGEN RECEPTOR 2015-07-21 2016-02-18
US2016031886 CERTAIN CHEMICAL ENTITIES, COMPOSITIONS AND METHODS 2015-10-15 2016-02-04
US2016016957 CHEMICAL COMPOUNDS, COMPOSITIONS AND METHODS FOR KINASE MODULATION 2015-09-29 2016-01-21

These patents belong to various pharmaceutical companies including Infinity, Novartis, and Intellikine.[15]

See also

References

  1. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 72" (PDF). World Health Organization. p. 393. Retrieved 16 April 2016.
  2. 1 2 3 "Infinity Initiates Two Phase 1 Trials of IPI-145, a Potent Inhibitor of PI3K Delta and Gamma". finanznachrichten.de. 31 October 2011.
  3. 1 2 3 "Infinity commences two IPI-145 Phase 1 clinical trials for hematologic malignancies". Retrieved November 28, 2011.
  4. 1 2 3 4 5 "Press Releases - Infinity Pharmaceuticals, Inc". Infinity Pharmaceuticals, Inc. Retrieved 2016-11-21.
  5. 1 2 Jones, Kristin (2012-06-18). "Market Watch". Retrieved 2016-11-19.
  6. 1 2 McDermid, Riley (2015-03-31). "Breaking News Sr. Editor". DHI. BioSpace.com. Retrieved 2016-11-19.
  7. 1 2 3 Interactive, Blackfly (2016-11-21). "News Release - Novel Drugs Targeting Cancer Stem Cells". phx.corporate-ir.net. Retrieved 2016-11-21.
  8. ↑ Clinical Activity of Duvelisib (IPI-145), a Phosphoinositide-3-Kinase-δ,γ Inhibitor, in Patients Previously Treated with Ibrutinib. Dec 2014
  9. ↑ "Infinity Regains Worldwide Rights to PI3K, FAAH and Early Discovery Programs". 18 July 2012.
  10. ↑ Infinity Reports IPI-145 Phase 1 Data Showing Clinical Activity in B-Cell and T-Cell Malignancies at ASH Annual Meeting. Dec 2012
  11. ↑ A Phase 2 Study of Duvelisib in Subjects With Refractory Indolent Non-Hodgkin Lymphoma (DYNAMO)
  12. 1 2 3 Infinity Reports Topline Data from Phase 2a Exploratory Study of Duvelisib in Patients with Mild, Allergic Asthma. Oct 2014
  13. 1 2 Phase 3 trials
  14. ↑ Duvelisib With Obinutuzumab in Patients With CLL/SLL Previously Treated With a BTKi (SYNCHRONY)
  15. 1 2 Pubchem. "Duvelisib | C22H17ClN6O - PubChem". pubchem.ncbi.nlm.nih.gov. Retrieved 2016-11-22.
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