Copanlisib (trade name Aliqopa ; codenamed BAY 80-6946) is a drug which is approved by US

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

for the treatment of adult patients experiencing relapsed

follicular lymphoma Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normal ...

who have received at least two prior systemic therapies. Copanlisib has been shown to have an effect against survival and spread of cancerous

B-cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...

. Efficacy resulting in the approval of copanlisib was based on the subgroup of 104 patients with follicular lymphoma from a Phase 2

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

. Of these, 59 percent had a complete or partial shrinkage of their tumors that lasted about 12 months. To assess the safety of the drug, data from 168 adults with follicular lymphoma and other hematologic malignancies treated with copanlisib were evaluated. Copanlisib is administered as

intravenous infusion Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

on a weekly but intermittent schedule (three weeks on and one week off). Copanlisib is currently approved only in the United States.

Adverse effects

Data for safety and efficacy of copanlisib are described in the consumer-targeted FDA Drug Trial Snapshot. Copanlisib can cause serious side effects including

infections An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmiss ...

hyperglycemia Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

pneumonitis Pneumonitis describes general inflammation of lung tissue. Possible causative agents include radiation therapy of the chest, exposure to medications used during chemo-therapy, the inhalation of debris (e.g., animal dander), aspiration, herbicides ...

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

and

skin rashes A rash is a change of the human skin which affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cr ...

. The most common side effects of copanlisib are hyperglycemia,

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

, decreased general strength and energy, hypertension,

leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...

, neutropenia,

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

, lower respiratory tract infections and

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...

. Copanlisib can cause harm to unborn babies. Patients with reproductive potential are thus advised to use effective contraception. Lactating patients are advised to not breastfeed.

Mechanism of action

Copanlisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3K-α and PI3K-δ isoforms expressed in malignant B-cells. It has been shown to induce tumor cell death by

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

and inhibition of proliferation of primary malignant B cell lines.

Regulatory history

Follicular lymphoma

For follicular lymphoma, the

awarded copanlisib

orphan drug status An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment o ...

in February 2015 and

fast track designation Fast track is a designation by the United States Food and Drug Administration (FDA) of an investigational drug for expedited review to facilitate development of drugs that treat a serious or life-threatening condition and fill an unmet medical ...

in February 2016. The

NDA NDA may stand for: Military * National Defence Academy (India), a military academy in India * National Defence Act, legislation for organizing and funding Canada's military * National Defense Academy of Japan, a military academy in Japan * Nig ...

for follicular lymphoma was granted

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

in May 2017. In September 2017, it received

accelerated approval The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endp ...

(FDA regulation 21 CFR Part 314 subpart H) for the treatment of adult patients experiencing relapsed follicular lymphoma who have received at least two prior systemic therapies. Further clinical trials are to be performed as a post-marketing requirement to verify the clinical benefit.

Other

Copanlisib was granted orphan drug status for the treatment of splenic, nodal and extranodal subtypes of

marginal zone lymphoma Marginal zone B-cell lymphomas, also known as marginal zone lymphomas (MZLs), are a heterogeneous group of lymphomas that derive from the malignant transformation of marginal zone B-cells. Marginal zone B cells are innate lymphoid cells that norma ...

Clinical trials

Phase II clinical trials are in progress for treatment of

endometrial cancer Endometrial cancer is a cancer that arises from the endometrium (the lining of the uterus or womb). It is the result of the abnormal growth of cells that have the ability to invade or spread to other parts of the body. The first sign is most o ...

diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibody, antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual Incidence (epidemiology), in ...

cholangiocarcinoma Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool ...

, and

non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. ...

. Copanlisib in combination with R-CHOP or R-B (

rituximab 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 (in non-geriatric p ...

and

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. Common s ...

) is in a phase III trial for relapsed indolent non-Hodgkin lymphoma (NHL). Two separate phase III trials are investigating the use of copanlisib in combination with rituximab for indolent NHL and the other using copanlisib alone in cases of rituximab-refractory indolent NHL. In a preclinical study, copanlisib was effective in inhibiting HER2+ breast cancer cells with acquired resistance to the HER2-inhibitors

trastuzumab Trastuzumab, sold under the brand name Herceptin among others, is a monoclonal antibody used to treat breast cancer and stomach cancer. It is specifically used for cancer that is HER2 receptor positive. It may be used by itself or together wit ...

and/or

lapatinib Lapatinib ( INN), used in the form of lapatinib ditosylate (USAN) (trade names Tykerb and Tyverb marketed by Novartis) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts ...

. This effect was increased when copanlisib was administered along with the aforementioned HER2-inhibitors. Consequently, treatments of copanlisib with trastuzumab are being clinically trialled in HER2-positive breast cancer patients.

References

{{reflist Antineoplastic drugs Phosphoinositide 3-kinase inhibitors 4-Morpholinyl compunds Bayer brands Pyrimidines