An Open-Label, Single-Arm, Phase II Study to Evaluate the Efficacy, Safety and CNS Exposure of G-202 in Patients With PSMA Positive Recurrent or Progressive Glioblastoma

Glioblastoma (GBM) comprises about 16% of all malignancies of the nervous system and over 50% of all gliomas. Standard of care for newly-diagnosed GBM is a combination of surgical debulking followed by concurrent radiotherapy and chemotherapy with temozolomide. Efforts to improve second-line therapy in GBM have met with only marginal success and there is a large unmet medical need for new therapies. G-202 (mipsagargin) is an example of prodrug chemotherapy. It is activated by Prostate Specific Membrane Antigen (PSMA), which is expressed by some cancer cells and in the blood vessels of most solid tumors, including GBM, but not by normal cells or blood vessels in normal tissue. It is believed that activation of the prodrug G-202 will allow the drug to kill cancer cells. This study will evaluate the activity, safety and CNS exposure of G-202 in patients with PSMA-positive recurrent or progressive GMB receiving G-202 by intravenous infusion on three consecutive days of a 28-day cycle.

Start Date01 Sep 2016

Sponsor / Collaborator

Rebus Holdings, Inc.

[+1]

NCT02607553

/ CompletedPhase 2

G-202-006: An Open-Label, Single-Arm, Phase II Study to Evaluate the Safety and Activity of G-202 in Patients With Clear Cell Renal Cell Carcinoma That Expresses PSMA

An open-label, single-arm, single-center Phase II study to evaluate the safety and activity of G-202 in patients with clear cell renal cell carcinoma that expresses PSMA

Start Date01 Jun 2016

Sponsor / Collaborator

Rebus Holdings, Inc.

NCT02381236

/ CompletedPhase 2

G-202-005: An Open-Label, Single-Arm, Phase II Study to Evaluate the Safety and Activity of G-202 Administered in the Neoadjuvant Setting Followed by Radical Prostatectomy in Patients With Adenocarcinoma of the Prostate

A single-arm, open-label Phase II clinical trial to evaluate the effect of G-202 on the perfusion and volume of the prostate using non-invasive multiparametric prostate magnetic resonance imaging (mpMRI).

Start Date01 Feb 2016

Sponsor / Collaborator

Rebus Holdings, Inc.

100 Clinical Results associated with Mipsagargin

100 Translational Medicine associated with Mipsagargin

100 Patents (Medical) associated with Mipsagargin

Literatures (Medical) associated with Mipsagargin

04 Feb 2022·Organic lettersQ1 · CHEMISTRY

Rh(I)-Catalyzed Allenic Pauson–Khand Reaction to Access the Thapsigargin Core: Influence of Furan and Allenyl Chloroacetate Groups on Enantioselectivity

Q1 · CHEMISTRY

Article

Author: Brummond, Kay M. ; Liu, Peng ; Newman, Logan J. ; Jesikiewicz, Luke T. ; Deihl, Eric D.

Thapsigargin (Tg) is a potent SERCA pump inhibitor with the potential to treat cancer and COVID-19. We have extended the scope of the asymmetric allenic Pauson-Khand reaction to furan-tethered allene-ynes, a stereoconvergent transformation affording the 5,7,5-ring system of Tg in good yields and high enantioselectivity. Computational studies of the oxidative cyclization step show that the furan and chloroacetate groups contribute to this high selectivity.

01 Jan 2021·Progress in the chemistry of organic natural products

From Plant to Patient: Thapsigargin, a Tool for Understanding Natural Product Chemistry, Total Syntheses, Biosynthesis, Taxonomy, ATPases, Cell Death, and Drug Development

Article

Author: Denmeade, Samuel R ; Møller, Jesper Vuust ; Simonsen, Henrik Toft ; Isaacs, John T ; Christensen, Søren Brøgger ; Nissen, Poul ; Engedal, Nikolai

Thapsigargin, the first representative of the hexaoxygenated guaianolides, was isolated 40 years ago in order to understand the skin-irritant principles of the resin of the umbelliferous plant Thapsia garganica. The pronounced cytotoxicity of thapsigargin is caused by highly selective inhibition of the intracellular sarco-endoplasmic Ca²⁺-ATPase (SERCA) situated on the membrane of the endo- or sarcoplasmic reticulum. Thapsigargin is selective to the SERCA pump and to a minor extent the secretory pathway Ca²⁺/Mn²⁺ ATPase (SPCA) pump. Thapsigargin has become a tool for investigation of the importance of SERCA in intracellular calcium homeostasis. In addition, complex formation of thapsigargin with SERCA has enabled crystallization and structure determination of calcium-free states by X-ray crystallography. These results led to descriptions of the mechanism of action and kinetic properties of SERCA and other ATPases. Inhibition of SERCA depletes Ca²⁺ from the sarco- and endoplasmic reticulum provoking the unfolded protein response, and thereby has enabled new studies on the mechanism of cell death. Development of protocols for selective transformation of thapsigargin disclosed the chemistry and facilitated total synthesis of the molecule. Conversion of trilobolide into thapsigargin offered an economically feasible sustainable source of thapsigargin, which enables a future drug production. Principles for prodrug development were used by conjugating a payload derived from thapsigargin with a hydrophilic peptide selectively cleaved by proteases in the tumor. Mipsagargin was developed in order to obtain a drug for treatment of cancer diseases characterized by the presence of prostate specific membrane antigen (PSMA) in the neovascular tissue of the tumors. Even though mipsagargin showed interesting clinical effects the results did not encourage funding and consequently the attempt to register the drug has been abandoned. In spite of this disappointing fact, the research performed to develop the drug has resulted in important scientific discoveries concerning the chemistry, biosynthesis and biochemistry of sesquiterpene lactones, the mechanism of action of ATPases including SERCA, mechanisms for cell death caused by the unfolded protein response, and the use of prodrugs for cancer-targeting cytotoxins. The presence of toxins in only some species belonging to Thapsia also led to a major revision of the taxonomy of the genus.

14 May 2020·ACS medicinal chemistry letters

Missing Selectivity of Targeted 4β-Phorbol Prodrugs Expected to be Potential Chemotherapeutics

Article

Author: Christensen, Søren Brøgger ; Franzyk, Henrik ; Yli-Kauhaluoma, Jari ; Tarvainen, Ilari ; Heinonen, Pia ; Tuominen, Raimo K. ; Jäntti, Maria Helena ; Zimmermann, Tomáš ; Talman, Virpi

Targeting cytotoxic 4β-phorbol esters toward cancer tissue was attempted by conjugating a 4β-pborbol derivative with substrates for the proteases prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) expressed in cancer tissue. The hydrophilic peptide moiety was hypothesized to prevent penetration of the prodrugs into cells and prevent interaction with PKC. Cleavage of the peptide in cancer tumors was envisioned to release lipophilic cytotoxins, which subsequently penetrate into cancer cells. The 4β-phorbol esters were prepared from 4β-phorbol isolated from Croton tiglium seeds, while the peptides were prepared by solid-phase synthesis. Cellular assays revealed activation of PKC by the prodrugs and efficient killing of both peptidase positive as well as peptidase negative cells. Consequently no selectivity for enzyme expressing cells was found.

News (Medical) associated with Mipsagargin

14 Sep 2022

·www.globenewswire.com

MediciNova Receives Issue Notification for a New Patent Covering MN-166 (ibudilast) for the Treatment of Glioblastoma

LA JOLLA, Calif., Sept. 14, 2022 (GLOBE NEWSWIRE) -- MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the JASDAQ Market of the Tokyo Stock Exchange (Code Number: 4875), today announced that it has received an Issue Notification from the U.S. Patent and Trademark Office for a new patent which covers MN-166 (ibudilast) for the treatment of glioblastoma. This new patent is expected to expire no earlier than February 2039. The allowed claims cover a method of treating a patient diagnosed with glioblastoma or recurrent glioblastoma, wherein the patient expresses unmethylated MGMT, using MN-166 (ibudilast) in combination with one or more other therapeutic agents including temozolomide (TMZ), carmustine, bevacizumab, procarbazine, hydroxyurea, irinotecan, lomustine, nimotuzumab, sirolimus, mipsagargin, cabozantinib, onartuzumab, patupilone (epothilone B), and recombinant oncolytic poliovirus (PVS-RIPO). The allowed claims cover a wide range of doses of MN-166 (ibudilast) as well as the other therapeutic agents. The allowed claims also cover different types of glioblastoma including classical glioblastoma, proneural glioblastoma, mesenchymal glioblastoma, and neural glioblastoma. Kazuko Matsuda, MD, PhD, MPH, Chief Medical Officer of MediciNova, Inc. commented, “We are very pleased to receive the issue notification for this new patent as it offers additional coverage compared to our other two patents covering glioblastoma. We have an ongoing clinical trial of MN-166 in combination with temozolomide for the treatment of recurrent glioblastoma at the Dana-Farber Cancer Institute, Harvard Medical School. Results of our glioblastoma animal model study showed that median survival was longer in the group that received combination treatment with MN-166 plus temozolomide compared to the group that received the standard treatment of temozolomide alone, and this data was presented at the American Society of Clinical Oncology (ASCO) annual meeting. Encouragingly, the FDA granted orphan-drug designation to MN-166 as adjunctive therapy to temozolomide for the treatment of glioblastoma based on this data.” About Glioblastoma According to the American Association of Neurological Surgeons, glioblastoma is an aggressive brain cancer that often results in death during the first 15 months after diagnosis. Glioblastoma develops from glial cells (astrocytes and oligodendrocytes), grows rapidly, and commonly spreads into nearby brain tissue. Glioblastoma is classified as Grade IV, the highest grade, in the World Health Organization (WHO) brain tumor grading system. The American Brain Tumor Association reports that glioblastoma represents about 15% of all primary brain tumors and approximately 10,000 cases of glioblastoma are diagnosed each year in the U.S. Despite decades of advancements in neuroimaging, neurosurgery, chemotherapy and radiation therapy, only modest improvements have been achieved and the prognosis has not improved for individuals diagnosed with glioblastoma. Median survival is about 11-15 months for adults with more aggressive glioblastoma (IDH-wildtype) who receive standard treatment of surgery, temozolomide, and radiation therapy. About MN-166 (ibudilast) MN-166 (ibudilast) is a small molecule compound that inhibits phosphodiesterase type-4 (PDE4) and inflammatory cytokines, including macrophage migration inhibitory factor (MIF). It is in late-stage clinical development for the treatment of neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis), progressive MS (multiple sclerosis), and DCM (degenerative cervical myelopathy); and is also in development for glioblastoma, CIPN (chemotherapy-induced peripheral neuropathy), and substance use disorder. In addition, MN-166 (ibudilast) was evaluated in patients that are at risk for developing acute respiratory distress syndrome (ARDS). About MediciNova MediciNova, Inc. is a clinical-stage biopharmaceutical company developing a broad late-stage pipeline of novel small molecule therapies for inflammatory, fibrotic, and neurodegenerative diseases. Based on two compounds, MN-166 (ibudilast) and MN-001 (tipelukast), with multiple mechanisms of action and strong safety profiles, MediciNova has 11 programs in clinical development. MediciNova’s lead asset, MN-166 (ibudilast), is currently in Phase 3 for amyotrophic lateral sclerosis (ALS) and degenerative cervical myelopathy (DCM) and is Phase 3-ready for progressive multiple sclerosis (MS). MN-166 (ibudilast) is also being evaluated in Phase 2 trials in glioblastoma and substance dependence. MN-001 (tipelukast) was evaluated in a Phase 2 trial in idiopathic pulmonary fibrosis (IPF) and a second Phase 2 trial in non-alcoholic fatty liver disease (NAFLD) is ongoing. MediciNova has a strong track record of securing investigator-sponsored clinical trials funded through government grants. Statements in this press release that are not historical in nature constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding the future development and efficacy of MN-166, MN-001, MN-221, and MN-029. These forward-looking statements may be preceded by, followed by or otherwise include the words "believes," "expects," "anticipates," "intends," "estimates," "projects," "can," "could," "may," "will," "would," “considering,” “planning” or similar expressions. These forward-looking statements involve a number of risks and uncertainties that may cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Factors that may cause actual results or events to differ materially from those expressed or implied by these forward-looking statements include, but are not limited to, risks of obtaining future partner or grant funding for development of MN-166, MN-001, MN-221, and MN-029 and risks of raising sufficient capital when needed to fund MediciNova's operations and contribution to clinical development, risks and uncertainties inherent in clinical trials, including the potential cost, expected timing and risks associated with clinical trials designed to meet FDA guidance and the viability of further development considering these factors, product development and commercialization risks, the uncertainty of whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, risks associated with the reliance on third parties to sponsor and fund clinical trials, risks regarding intellectual property rights in product candidates and the ability to defend and enforce such intellectual property rights, the risk of failure of the third parties upon whom MediciNova relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials, and the timing of expected filings with the regulatory authorities, MediciNova's collaborations with third parties, the availability of funds to complete product development plans and MediciNova's ability to obtain third party funding for programs and raise sufficient capital when needed, and the other risks and uncertainties described in MediciNova's filings with the Securities and Exchange Commission, including its annual report on Form 10-K for the year ended December 31, 2021 and its subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Undue reliance should not be placed on these forward-looking statements, which speak only as of the date hereof. MediciNova disclaims any intent or obligation to revise or update these forward-looking statements. INVESTOR CONTACT:Geoff O'BrienVice PresidentMediciNova, Inc.info@medicinova.com

Radiation TherapySmall molecular drugASCOCollaborateIPO

02 Aug 2016

·www.biospace.com

GenSpera Announces Name Change To Inspyr Therapeutics

SAN ANTONIO--(BUSINESS WIRE)--GenSpera, Inc. (OTC/QB: GNSZ), a clinical-stage biotechnology company developing a novel prodrug therapeutic for the treatment of cancer, announces that it will change its corporate name to Inspyr Therapeutics, Inc. and will begin trading on OTC/QB under the ticker symbol NSPX effective August 2, 2016. The Company will also unveil a new corporate website at . “The changing of our corporate name is a first step in a number of upcoming actions that will define our path forward and our focus on building shareholder value” “The changing of our corporate name is a first step in a number of upcoming actions that will define our path forward and our focus on building shareholder value,” said Peter E. Grebow, Ph.D., Interim Chairman. “Our new corporate name, Inspyr Therapeutics, reflects the significant potential we see with the novel prodrug mipsagargin and our Company’s future potential.” About Inspyr Therapeutics Inspyr Therapeutics, Inc. (formerly known as GenSpera, Inc.) is developing a novel technology platform that combines a powerful cytotoxin (thapsigargin) with a patented prodrug delivery system that targets the release of drugs within solid tumors without the side effects of chemotherapeutic agents. Mipsagargin, its lead drug candidate, has been studied in a Phase 2 clinical trial in patients with hepatocellular carcinoma (liver cancer) and has been granted Orphan Drug designation by the U.S. Food and Drug Administration (FDA) in this indication. Mipsagargin is being evaluated in other therapeutic areas within oncology. For additional information on Inspyr Therapeutics, visit Cautionary Statement Regarding Forward-Looking Information This communication may contain forward-looking statements. Investors are cautioned that statements in this document regarding potential applications of GenSpera’s technologies or the future prospects of the company constitute forward-looking statements that involve risks and uncertainties, including, without limitation, risks inherent in the development and commercialization of potential products, uncertainty of clinical trial results or regulatory approvals or clearances, need for future capital, dependence upon collaborators and maintenance of our intellectual property rights and the acceptance of GenSpera’s proposed therapies by the health community. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties will be detailed from time to time in GenSpera's periodic reports filed with the Securities and Exchange Commission.

Small molecular drugOrphan Drug

28 Apr 2015

·www.biospace.com

GenSpera Granted New Patent For Prodrugs Activated By Prostate Specific Antigen

SAN ANTONIO, April 28, 2015 /PRNewswire/ -- GenSpera, Inc. (OTCQB: GNSZ) announced today that the U.S. Patent and Trademark Office has issued U.S. Patent No. 8,957,016. This patent expands GenSpera's intellectual property portfolio claiming numerous compositions for the company's prodrugs designed to be activated by Prostate Specific Antigen (PSA). GenSpera is developing a series of prodrugs that couple specific peptides with a powerful cytotoxin isolated from the poisonous plant, Thapsia garganica. The prostate-specific antigen-targeting agent is designed to minimize side effects commonly observed with other therapies, while maximizing activity against tumors. This most recent patent relates to GenSpera's platform technology, which targets activation of biologically active materials to cells that produce PSA and more specifically to a peptide that can be recognized and removed by PSA to activate therapeutic prodrugs. The patent extends coverage for GenSpera's series of PSA targeted prodrugs through 2026. "We see significant potential for our investigational agents in prostate cancer," said Craig Dionne, Ph.D., chief executive officer at GenSpera. "Prostate cancer treatments are currently dominated by hormonal agents and cytotoxic chemotherapies, all of which have significant side effects. This patent rounds out our portfolio, ensuring we are well-positioned to help bring new, innovative treatment optionswith minimal side effectsto men fighting prostate cancer." About GenSpera GenSpera, Inc. is a San Antonio-based biotech company that unlocks conventional thinking to conceive, design, and develop cancer therapies. GenSpera's technology platform combines a powerful, plant-derived cytotoxin (thapsigargin) with a patented prodrug delivery system that provides for targeted release of drug candidates within tumors. GenSpera's lead drug candidate, mipsagargin, was granted Orphan Drug designation by the U.S. Food and Drug Administration (FDA) in 2013 for evaluation in patients with hepatocellular carcinoma (liver cancer). For additional information on GenSpera, visit and connect on Twitter, LinkedIn, Facebook, YouTube and Google+. Cautionary Statement Regarding Forward Looking Information This communication may contain forward-looking statements. Investors are cautioned that statements in this document regarding potential applications of GenSpera's technologies or the future prospects of the company constitute forward-looking statements that involve risks and uncertainties, including, without limitation, risks inherent in the development and commercialization of potential products, uncertainty of clinical trial results or regulatory approvals or clearances, need for future capital, dependence upon collaborators and maintenance of our intellectual property rights and the acceptance of GenSpera's proposed therapies by the health community. Actual results may differ materially from the results anticipated in these forward-looking statements. Additional information on potential factors that could affect our results and other risks and uncertainties will be detailed from time to time in GenSpera's periodic reports filed with the Securities and Exchange Commission. To view the original version on PR Newswire, visit: SOURCE GenSpera, Inc. Help employers find you! Check out all the jobs and post your resume.

Orphan Drug

100 Deals associated with Mipsagargin

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KEGG	Wiki	ATC	Drug Bank
D10715	-	-	DB11813

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
PSMA-Positive Tumor	Phase 2	United States	Rebus Holdings, Inc.	01 Sep 2016
Metastatic Clear Cell Renal Cell Carcinoma	Phase 2	United States	Rebus Holdings, Inc.	01 Jun 2016
Adenocarcinoma of prostate	Phase 2	United States	Rebus Holdings, Inc.	01 Feb 2016
Glioblastoma Multiforme	Phase 2	United States	Rebus Holdings, Inc.	01 Feb 2014
Recurrent Glioblastoma	Phase 2	United States	Rebus Holdings, Inc.	01 Feb 2014
Metastatic castration-resistant prostate cancer	Phase 2	United States	Rebus Holdings, Inc.	01 May 2013
Advanced Hepatocellular Carcinoma	Phase 2	United States	Rebus Holdings, Inc.	01 Jan 2013
Advanced Malignant Solid Neoplasm	Phase 1	United States	Rebus Holdings, Inc.	01 Jan 2010
Neoplasms	Preclinical	United States	The Johns Hopkins University School of Medicine	27 Jun 2012
Neoplasms	Preclinical	United States	Inspyr Therapeutics, Inc.	27 Jun 2012

Clinical Result

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Phase

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02067156 (CTgov)	Phase 2	Glioblastoma Multiforme \| Recurrent Glioblastoma	26	G-202	uzmuubirxm = ghxunmwjhk lssmzgxokx (rrjmbtshfe, xdqezwkryv - ixthdsdgtk) View more	-	21 May 2024
NCT01777594 (Pubmed \| Cancers (Basel)) Manual	Phase 2	Advanced Hepatocellular Carcinoma Second line	19	Mipsagargin	qzqyejywzg(bcngqtysas) = gnxivsbejm toeetcmzpy (jyufbzbhmp ) View more	Positive	17 Jun 2019

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