On April 09, 2018, Verastem, a biopharmaceutical company focused on developing and commercializing medicines to improve the survival and quality of life of cancer patients, announced that the United States Food and Drug Administration (USFDA) has accepted for filing, with Priority Review, its New Drug Application (NDA) for its lead product candidate Duvelisib13. Duvelisib is a first-in-class oral dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, for which Verastem is seeking full approval for the treatment of relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and accelerated approval for the treatment of relapsed or refractory follicular lymphoma (FL). Priority Review is granted by the FDA to drugs which, if approved, would provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition. Duvelisib has received Fast Track Designation from the FDA for patients with CLL who have received at least one prior therapy and for patients with FL who have received at least two prior therapies. In addition, Duvelisib received orphan drug designation in the United States and the European Union for patients with CLL, SLL and FL14.
About Duvelisib
Duvelisib is a first-in-class investigational, dual inhibitor of phosphoinositide 3-kinase (PI3K)-delta and PI3Kgamma, two enzymes known to help support the growth and survival of malignant B-cells and T-cells. PI3K signaling may lead to the proliferation of malignant B- and T-cells and is thought to play a role in the formation and maintenance of the supportive tumor microenvironment.
Clinical Development
Duvelisib was evaluated in late- and mid-stage extension trials, including the DUO" trial, and the DYNAMO" trial. DUO" was a randomized, Phase 3 monotherapy study in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). DUO", evaluated safety and efficacy of Duvelisib vs. Ofatumumab in 319 patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL). The DUO" trial has been completed and has successfully met its primary endpoint (with some patients still in long term followup).
DYNAMO" - The DYNAMO study was a Phase 2, open-label, single–arm monotherapy study evaluating the safety and efficacy of Duvelisib dosed at 25 mg BID in 129 patients with Indolent Non-Hodgkin Lymphoma (iNHL). Patients in DYNAMO who continue to derive benefit remain on treatment. DYNAMO enrollment criteria included patients with FL, the most common subtype of iNHL, Marginal zone lymphoma (MZL) and SLL, whose disease is refractory to rituximab, a monoclonal antibody treatment, and to either chemotherapy or radio-immunotherapy and who have progressed within six months of receiving their final dose of a previous therapy. The primary endpoint of the study was an Overall Response Rate (ORR) according to the International Working Group Criteria, which includes change in target nodal lesion in combination with other measurements to determine response to treatment.
The results from the DYNAMO study showed that the trial achieved the primary endpoint in a heavily pre-treated, double refractory to chemotherapy and rituximab, patient population with an ORR of 46% (p=0.0001) in the ITT population, as assessed by an IRC with a median duration of response of 10 months. The breakdown of ORR in the three subtypes of iNHL for the overall study population was 41% in FL (n=83), 68% in SLL (n=28) and 33% in MZL (n=18). 83% of patients had a reduction in target lymph nodes.
Now the FDA is reviewing New Drug Application (NDA) requesting the full approval of Duvelisib for the treatment of patients with relapsed or refractory CLL/SLL, and accelerated approval for the treatment of patients with relapsed or refractory follicular lymphoma (FL). Duvelisib is also being developed for the treatment of peripheral T-cell lymphoma (PTCL), which has Fast Track status, and is being investigated in combination with other agents through investigator-sponsored studies.
US FDA Priority Review
A Priority Review designation from USFDA means that the agency's goal is to act on an application within 6 months (compared to 10 months under standard review) of filing. A Priority Review designation directs overall attention and resources to the evaluation of applications for drugs which, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications15.
Significant improvement may be demonstrated by the following examples:
- Evidence of increased effectiveness in treatment, prevention, or diagnosis of condition;
- Elimination or substantial reduction of a treatment-limiting drug reaction;
- Documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes; or
- Evidence of safety and effectiveness in a new subpopulation.
Orphan Drug Designation
The Orphan Drug Act (ODA) of the United States provides for granting special status to a drug or biological product (drug) to treat a rare disease or condition upon request from a sponsor. This status is referred to as orphan designation16. For a drug to qualify for orphan designation, both the drug and the disease or condition must meet certain criteria specified in the ODA and FDA's implementing regulations at 21 CFR Part 31617. Orphan designation qualifies the sponsor of the drug for various development incentives of the ODA, including tax credits for qualified clinical testing. A marketing application for a prescription drug product that has received orphan designation is not subject to a prescription drug user fee unless the application includes an indication for other than the rare disease or condition for which the drug was designated.
Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are cancers that affect lymphocytes. Lymphocytes, a type of white blood cell, carried along by the lymph fluid, are a part of the immune system and fight infections. CLL and SLL are essentially the same disease, with the only difference being the location where the cancer primarily occurs. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL18.
Follicular Lymphoma
Follicular lymphoma is a cancer of the lymphatic system. It occurs when a lymphocyte (a type of white blood cell that fights infection) grows out of control. There are two main groups of lymphomas: Hodgkin lymphomas and non-Hodgkin lymphomas. Non-Hodgkin lymphomas are further grouped into:
- Low-grade (slow-growing) or high-grade (fast-growing)
- T-cell lymphoma (develops from abnormal T-lymphocytes or T-cells) or B-cell lymphoma (develops from abnormal B-lymphocytes or B-cells).
Follicular lymphoma is the most common type of low-grade NHL and develops from B-cells. The abnormal B-cells often collect in lymph nodes (glands) as follicles (clumps)19.
Conclusion:
Duvelisib presents itself as an important therapeutic option for patients with unmet need in relapsed/ refractory chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma (FL).
Footnotes
13. http://investor.verastem.com/phoenix.zhtml?c=250749&p=irol-newsArticle&ID=2341489
14. http://investor.verastem.com/phoenix.zhtml?c=250749&p=irol-newsArticle&ID=2330853
15. https://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm
18. https://www.lymphoma.org/wp-content/uploads/2017/06/LRF_FACTSHEET_CLL_SLL.pdf
19. https://www.lymphomas.org.uk/printpdf/5423
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