Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti-
CD22
CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule that ...
immunotoxin
An immunotoxin is an artificial protein consisting of a targeting portion linked to a toxin. When the protein binds to that cell, it is taken in through endocytosis, and the toxin kills the cell. They are used for the treatment of some kinds of c ...
medication for the treatment of adults with relapsed or refractory
hairy cell leukemia
Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a subtype of chronic lymphocytic leukemia (CLL). Hairy cell leukemia makes up about 2% of all le ...
(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
The Pseudomonas exotoxin (or exotoxin A) is an exotoxin produced by ''Pseudomonas aeruginosa''. ''Vibrio cholerae'' produces a similar protein called the Cholix toxin ().
It inhibits elongation factor-2. It does so by ADP-ribosylation of EF ...
A.
Hairy cell leukemia (HCL) is a rare, slow-growing cancer of the blood in which the bone marrow makes too many
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 ...
(lymphocytes), a type of white blood cell that fights infection.
HCL is named after these extra B cells which look “hairy” when viewed under a microscope.
As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.
Medical uses
Moxetumomab pasudotox as monotherapy is indicated for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) after receiving at least two prior systemic therapies, including treatment with a purine nucleoside analogue (PNA).
Adverse effects
Common side effects include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.
The prescribing information for moxetumomab pasudotox includes a boxed warning about the risk of developing
capillary leak syndrome
Capillary leak syndrome, or vascular leak syndrome, is characterized by the escape of blood plasma through capillary walls, from the blood circulatory system to surrounding tissues, muscle compartments, organs or body cavities. It is a phenomenon ...
, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues.
Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face.
The boxed warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells.
Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities.
Women who are breastfeeding should not be given moxetumomab pasudotox.
Discovery and ownership background
On 1 November 2005,
Cambridge Antibody Technology
Cambridge Antibody Technology (officially Cambridge Antibody Technology Group Plc, informally CAT) was a biotechnology company headquartered in Cambridge, England, United Kingdom. Its core focus was on antibody therapeutics, primarily using Ph ...
(CAT) announced it was acquiring two
anti-CD22 immunotoxin products from
Genencor
Genencor is a biotechnology company based in Palo Alto, CA and a subsidiary of IFF. Genencor is a producer of Industrial enzymes and low-priced bulk protein. The name Genencor originates with Genencor, Inc., the original joint venture between Ge ...
, namely GCR-3888 and GCR-8015.
Genencor is the
biotechnology
Biotechnology is the integration of natural sciences and engineering sciences in order to achieve the application of organisms, cells, parts thereof and molecular analogues for products and services. The term ''biotechnology'' was first used b ...
division of
Danisco
Danisco A/S is a Danish bio-based company with activities in food production, enzymes and other bioproducts as well as a wide variety of pharmaceutical grade excipients. It was formed in 1989 from the largest Danish industrial merger ever of t ...
and the acquisition meant CAT would hire certain former Genencor key employees to be responsible for the development of the programmes.
GCR-3888 and GCR-8015 were discovered and initially developed by the
National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
, which is part of the U.S.
National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
. Genencor licensed the candidates for
hematological malignancies
Tumors of the hematopoietic and lymphoid tissues (American English) or tumours of the haematopoietic and lymphoid tissues (British English) are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all ...
and entered into a
Cooperative Research and Development Agreement
In the United States, a cooperative research and development agreement (CRADA or CRDA) is an agreement between a government agency and another government agency, a private company, non-profit, or university to work together on research and develop ...
(CRADA) with the NIH, which will now be continued by CAT. Under the original
license agreement with the NIH, CAT gained the rights to a portfolio of intellectual property associated with the programs and would pay future royalties to the NIH.
CAT intended to file an
Investigational New Drug (IND) application for GCR-8015 in various CD22 positive B-cell malignancies, including
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. ...
and
chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
, following a period of manufacturing development which is expected to be complete by the end of 2006 and to support the NCI's ongoing development of GCR-3888 in
Hairy cell leukemia
Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a subtype of chronic lymphocytic leukemia (CLL). Hairy cell leukemia makes up about 2% of all le ...
(HCL) and pediatric
acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...
(pALL).
CAT-8015 exhibited a greater affinity for CD22 than its predecessor, CAT-3888 and CAT's language such as "CAT will support the NCI's ongoing development of CAT-3888..." suggested at the time that their focus was on the second generation candidate.
CAT was acquired by
AstraZeneca
AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includin ...
, who also acquired MedImmune, combining the two into a biologics division. MedImmune renamed CAT-8015 to moxetumomab pasudotox.
On 16 May 2013, AstraZeneca announced that CAT-8015 had started Phase III clinical trials.
History
On 5 December 2008, orphan designation (EU/3/08/592) was granted by the European Commission to Medimmune Limited, United Kingdom, for murine anti-CD22 antibody variable region fused to truncated Pseudomonas exotoxin 38 for the treatment of hairy cell leukaemia.
[ Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] It was renamed to Moxetumomab pasudotox.
The sponsorship was transferred to AstraZeneca AB, Sweden, in January 2019.
On 17 July 2013, orphan designation (EU/3/13/1150) was granted by the European Commission to MedImmune Ltd, United Kingdom, for moxetumomab pasudotox for the treatment of B-lymphoblastic leukaemia / lymphoma.
[ Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] The sponsorship was transferred to AstraZeneca AB, Sweden, in January 2019.
Moxetumomab pasudotox was approved for use in the United States in September 2018.
[ ]
The efficacy of moxetumomab pasudotox was studied in a single-arm, open-label clinical trial of 80 subjects who had received prior treatment for hairy cell leukemia with at least two systemic therapies, including a purine nucleoside analog.
The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR.
Thirty percent of subjects in the trial achieved durable CR, and the overall response rate (number of subjects with partial or complete response to therapy) was 75 percent.
The US
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) granted the application for moxetumomab pasudotox
fast track
The fast track is an informal English term meaning "the quickest and most direct route to achievement of a goal, as in competing for professional advancement". By definition, it implies that a less direct, slower route also exists.
Fast track or F ...
,
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 ...
, and
orphan drug
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 of ...
designations.
The FDA granted the approval of a Biologics License Application for Lumoxiti to AstraZeneca Pharmaceuticals.
This was subsequently transferred to Innate Pharma in March 2020.
On 10 December 2020, the
Committee for Medicinal Products for Human Use
The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding ...
(CHMP) of the
European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
(EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Lumoxiti, intended for the treatment of relapsed or refractory hairy cell leukemia after two prior systemic therapies including a purine nucleoside analog. The orphan designation for Lumoxiti for treatment of hairy cell leukaemia was also maintained.
[ Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] The applicant for this medicinal product is AstraZeneca AB. Moxetumomab pasudotox was approved for medical use in the European Union in February 2021.
[ Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.] The EU marketing authorization was withdrawn in July 2021.
References
External links
*
*
*
{{Portal bar , Medicine
AstraZeneca brands
Monoclonal antibodies for tumors
Orphan drugs
Antibody-drug conjugates
Withdrawn drugs