Sapacitabine

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Sapacitabine
Sapacitabine.png
Clinical data
Other namesN-[1-[(2R,3S,4S,5R)-3-Cyano-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-oxopyrimidin-4-yl]hexadecanamide
ATC code
  • none
Identifiers
  • 1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-4-(palmitoylamino)pyrimidin-2(1H)-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
Formula C26H42N4O5
Molar mass 490.645 g·mol−1
3D model (JSmol)
  • CCCCCCCCCCCCCCCC(=O)NC1=NC(=O)N(C=C1)[C@H]2[C@H]([C@@H]([C@H](O2)CO)O)C#N
  • InChI=1S/C26H42N4O5/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-23(32)28-22-16-17-30(26(34)29-22)25-20(18-27)24(33)21(19-31)35-25/h16-17,20-21,24-25,31,33H,2-15,19H2,1H3,(H,28,29,32,34)/t20-,21+,24-,25+/m0/s1 X mark.svgN
  • Key:LBGFKUUHOPIEMA-PEARBKPGSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Sapacitabine is a chemotherapeutic drug developed by US biotechnology firm Cyclacel currently undergoing clinical trials against leukemia. [1] [2]

Contents

Sapacitabine is an orally available nucleoside analog prodrug of 2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosyl-cytosine (CNDAC) that acts through a dual mechanism. CNDAC lasts longer in the bloodstream by being metabolized from sapacitibine than it would do so by being directly administered. [3]

The compound interferes with DNA synthesis by causing single-strand DNA breaks due to CNDAC being incorporated into DNA during replication or repair, [3] then inducing arrest of the cell division cycle at G2 phase.

Both sapacitabine and its major metabolite, CNDAC, have demonstrated potent anti-tumor activity in both blood and solid tumors in preclinical studies. In a liver metastatic mouse model, sapacitabine was shown to be superior to gemcitabine or 5-FU, two widely used nucleoside analogs, in delaying the onset and growth of liver metastasis.

Clinical trials

Cyclacel has initiated a number of clinical trials to evaluate sapacitabine in both solid and hematological tumors laying the foundation for future Phase II studies and combination studies with other anti-cancer agents. Three Phase I clinical trial studies have been completed, which evaluated safety and pharmacokinetics of a variety of dosing schedules in approximately 120 patients with solid tumors. [4]

Sapacitabine is being evaluated as of March 2016 in three different studies; a Phase III trial for elderly patients with AML (acute myeloid leukemia), a Phase II trial for MDS (myelodysplastic syndromes), and a Phase I trial in combination with seliciclib for cancer treatment including hereditary ovarian and breast cancers. [3] Thus far approximately 1,000 patients have received sapacitibine treatment in all phases of trials. [3]

An ongoing Phase III clinical trial, SEAMLESS, has 485 enrolled members and is open to elderly (70+ years of age) AML (acute myeloid leukemia) patients with good renal and liver function and who are not viable candidates for or have refused intensive induction chemotherapy. [5] SEAMLESS is a global study with 118 different sites in the United States, Austria, Belgium, France, Germany, Hungary, Italy, Poland, Spain, Sweden, Switzerland, and the United Kingdom. [6] In the trial an arm of oral sapacitibine is given in alternating cycles with IV decitabine, which is compared to the control arm of IV decitabine alone. [3] The SEAMLESS study was constructed based on the promising results of a Phase II one-year survival study for patients with AML. The efficacy goal of the treatment is overall survival; the average survival of an elderly person diagnosed with AML is approximately three to six months. [7] The Data Safety Monitoring Board has communicated the unlikelihood that this Phase III study will reach a statistically significant survival improvement due to the planned futility boundary of 247 patient deaths already being crossed, but the trial is ongoing. During a poster session at the 2012 American Society of Hematology, results from a Phase I/II clinical trial studying the safety and efficacy of the oral sapacitibine along with IV decitabine were presented, selected data highlights are as follows: median overall survival was approximately 8 months, patients still alive at 3 months was 83%, 35% of patients survived a year or longer, 2 dose-limiting toxicities in the form of lung infection and typhlitis were observed. [3]

For the Phase II trial for MDS patients so far, median survival overall was about 9.7 months, with the average median survival overall for patients receiving classic azacitidine or decitabine is approximately 4.3-5.9 months. [3] More data will be arriving from the second half of this trial meant to allow better dosing regimens. [3]

The Phase II study for sapacitibine with seliciclib in advanced cancer patients is ongoing; so far, "durable partial responses" [8] and "prolonged stable disease" [8] have been seen particularly for patients with the BRCA mutations. [8] In a group of 45 patients including those with breast, ovarian, and pancreatic cancers, a "35.6% disease control rate was observed." [8]

Commercial Aspects and Intellectual Property

As of August 2016, Cyclacel had a 19.5 million dollar market capitalization and shares of the company have declined in value recently due to research and development costs of 2.6 million dollars and general and administrative expense costs of 1.3 million dollars. [9] Cyclacel ended the last quarter in 2016 with 15.9 million dollars in cash and equivalents. [9] An earnings report from H.C. Wainwright & Co. acknowledged how Cyclacel may at first seem like an unattractive investment but the ultimate risk/reward opportunity may be positive; [9] sapacitibine has indeed shown very positive anti-tumor activity and has progressed to Phase III clinical trials for elderly patients with AML.[ citation needed ]

Cyclacel holds worldwide right to commercialize sapacitibine, except in Japan for which Daiichi Sankyo "has a right of first negotiation". [3] They currently have essentially all marketing rights globally for the compounds in association with their drug development programs. [3] Numerous patents from Cyclacel are found related to sapacitibine and sapacitibine dosing regimes along with other drugs such as decitibine. [10] There are patents and applications that no longer apply to current use of sapacitibine, some involving administration of sapacitibine and seliciclib. [3]

Cyclacel currently has no sales or marketing capability and so will rely on alliances to distribute and commercialize the various drugs they hope to bring through the development pipeline. [3] These compounds particularly target control of the cell cycle for treating cancer and other diseases. [11]

Cyclacel says current funds and generated money from items such as R&D tax credits and "recent financing activities" [3] will carry them through 2017. [3] The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to sapacitibine for the treatment of AML and MDS; [3] this designation assists in funding and provides various benefits for the drug's development such as market exclusivity for a period of several years, grant funding, tax credits, and potential fee waivers. [3]

Related Research Articles

<span class="mw-page-title-main">Leukemia</span> Blood cancers forming in the bone marrow

Leukemia is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Azacitidine</span> Chemical compound

Azacitidine, sold under the brand name Vidaza among others, is a medication used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacitidine and its deoxy derivative, decitabine were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.

<span class="mw-page-title-main">Acute myeloid leukemia</span> Cancer of the myeloid line of blood cells

Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. Occasionally, spread may occur to the brain, skin, or gums. As an acute leukemia, AML progresses rapidly, and is typically fatal within weeks or months if left untreated.

<span class="mw-page-title-main">Decitabine</span> Medication for the treatment of conditions where certain blood cells are dysfunctional,

Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for acute myeloid leukemia (AML). Chemically, it is a cytidine analog.

Lintuzumab (SGN-33) is a humanized monoclonal antibody used in the treatment of cancer. The drug had been developed by Seattle Genetics as a treatment for acute myeloid leukemia (AML), a condition which results in the deaths of 9,000 people a year in the United States. Lintuzumab targets the CD33 protein, which is expressed in AML and other myeloproliferative diseases, but does not appear in abundance on normal cells.

<span class="mw-page-title-main">Acute myeloblastic leukemia with maturation</span> Medical condition

Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).

Demethylating agents are chemical substances that can inhibit methylation, resulting in the expression of the previously hypermethylated silenced genes. Cytidine analogs such as 5-azacytidine (azacitidine) and 5-azadeoxycytidine (decitabine) are the most commonly used demethylating agents. They work by inhibiting DNA methyltransferases. Both compounds have been approved in the treatment of myelodysplastic syndrome (MDS) by Food and Drug Administration (FDA) in United States. Azacitidine and decitabine are marketed as Vidaza and Dacogen respectively. Azacitidine is the first drug to be approved by FDA for treating MDS and has been given orphan drug status. Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. There are many other demethylating agents that can be used to inhibit the growth of other diseases.

A hypomethylating agent is a drug that inhibits DNA methylation: the modification of DNA nucleotides by addition of a methyl group. Because DNA methylation affects cellular function through successive generations of cells without changing the underlying DNA sequence, treatment with a hypomethylating agent is considered a type of epigenetic therapy.

<span class="mw-page-title-main">Crenolanib</span> Chemical compound

Crenolanib besylate is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable benzimidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor tyrosine kinases (RTK) FLT3, PDGFR α, and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to phosphorylated active kinases with the ‘DFG in’ conformation motif.

<span class="mw-page-title-main">Midostaurin</span> Chemical compound

Midostaurin, sold under the brand name Rydapt & Tauritmo both by Novartis, is a multi-targeted protein kinase inhibitor that has been investigated for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and advanced systemic mastocytosis. It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus.

<span class="mw-page-title-main">Volasertib</span> Chemical compound

Volasertib is an experimental small molecule inhibitor of the PLK1 protein being developed by Boehringer Ingelheim for use as an anti-cancer agent. Volasertib is the second in a novel class of drugs called dihydropteridinone derivatives.

<span class="mw-page-title-main">Vadastuximab talirine</span> Chemical compound

Vadastuximab talirine is an antibody-drug conjugate (ADC) directed to CD33 (siglec-3) which is a transmembrane receptor expressed on cells of myeloid lineage. The experimental drug, being developed by Seattle Genetics, was in clinical trials for the treatment of acute myeloid leukemia (AML).

<span class="mw-page-title-main">Filanesib</span> Chemical compound

Filanesib is a kinesin spindle protein (KIF11) inhibitor which has recently been proposed as a cancer treatment, specifically for multiple myeloma.

Microtransplantation (MST) is an advanced technology to treat malignant hematological diseases and tumors by infusing patients with granulocyte colony-stimulating factor (G-CSF) mobilized human leukocyte antigen (HLA)-mismatched allogeneic peripheral blood stem cells following a reduced-intensity chemotherapy or targeted therapy. The term "microtransplantation" comes from its mechanism of reaching donor cell microchimerism.

<span class="mw-page-title-main">Venetoclax</span> 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).

<span class="mw-page-title-main">Gedatolisib</span> Chemical compound

Gedatolisib (PF-05212384) is an experimental drug for treatment of cancer in development by Celcuity, Inc. The mechanism of action is accomplished by binding the different p110 catalytic subunit isoforms of PI3K and the kinase site of mTOR.

Camidanlumab tesirine is an antibody-drug conjugate (ADC) composed of a human antibody that binds to the protein CD25, conjugated to a pyrrolobenzodiazepine dimer toxin. The experimental drug, developed by ADC Therapeutics is being tested in clinical trials for the treatment of B-cell Hodgkin's lymphoma (HL) and non-Hodgkin lymphoma (NHL), and for the treatment of B-cell acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

<span class="mw-page-title-main">Devimistat</span> Chemical compound

Devimistat is an experimental anti-mitochondrial drug being developed by Cornerstone Pharmaceuticals. It is being studied for the treatment of patients with metastatic pancreatic cancer and relapsed or refractory acute myeloid leukemia (AML).

<span class="mw-page-title-main">Decitabine/cedazuridine</span> Medication

Decitabine/cedazuridine, sold under the brand name Inqovi among others, is a fixed-dose combination anticancer medication used for the treatment of adults with myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML). It is a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a cytidine deaminase inhibitor.

References

  1. ↑ Faderl S, Gandhi V, Kantarjian HM (March 2008). "Potential role of novel nucleoside analogs in the treatment of acute myeloid leukemia". Current Opinion in Hematology. 15 (2): 101–107. doi:10.1097/MOH.0b013e3282f46e94. PMID   18300755. S2CID   10744649.
  2. ↑ Serova M, Galmarini CM, Ghoul A, Benhadji K, Green SR, Chiao J, et al. (September 2007). "Antiproliferative effects of sapacitabine (CYC682), a novel 2'-deoxycytidine-derivative, in human cancer cells". British Journal of Cancer. 97 (5): 628–636. doi:10.1038/sj.bjc.6603896. PMC   2360357 . PMID   17637678.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Cyclacel Pharmaceuticals, Inc. - Annual Report". investor.cyclacel.com. Retrieved 2016-11-17.
  4. ↑ Liu XJ, Nowak B, Wang YQ, Plunkett W (August 2012). "Sapacitabine, the prodrug of CNDAC, is a nucleoside analog with a unique action mechanism of inducing DNA strand breaks". Chinese Journal of Cancer. 31 (8): 373–380. doi:10.5732/cjc.012.10077. PMC   3777512 . PMID   22739266.
  5. ↑ "The SEAMLESS Study". www.seamlessstudy.com. Retrieved 2016-11-09.
  6. ↑ Clinical trial number NCT01303796 for "A Study of Oral Sapacitabine in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia" at ClinicalTrials.gov
  7. ↑ "Cyclacel: Innovative Medicines for Cancer and other proliferative diseases using cell cycle biology" (PDF). 2015-06-24. Retrieved 2016-11-17.
  8. 1 2 3 4 "Sapacitibine" (PDF). Cyclacel. Summer 2016. Retrieved 2016-11-20.
  9. 1 2 3 Fein, Andrew S., Emile Yu, and Rachel F. Lane. H.C.Wainwright & Co. Cyclacel Pharmaceuticals, Inc. 12 August 2016. Web. 5 November 2016.
  10. ↑ "sapacitabine - Google Search". www.google.com. Retrieved 2016-11-20.
  11. ↑ "Cyclin Dependent Kinase (CDK) and Aurora Kinase (AK) inhibitors | Cyclacel R&D for anticancer drugs acting on cell cycle". www.cyclacel.com. Retrieved 2016-11-17.
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