Swiss-based Lonza a contract development and manufacturing organization and global manufacturing partner to the pharma and biotech industries, has signed a large-scale manufacturing agreement with Swedish-based Vivesto, previous known as Oasmia Pharmaceuticals, for the ongoing development and production of the company’s main drug intermediate in the supply of clinical material for Cantrixil ― a first-in-class investigational drug candidate targeting late-stage ovarian cancer, one of the most aggressive cancers which is difficult to treat in advanced stages.

Cantrixil consists of the active molecule, a potent and selective third generation benzopyran SMETI inhibitor named TRXE-002-01, encapsulated in a cyclodextrin. It is believed that this intraperitoneally administered drug targets a wide spectrum of cancer cells, including chemotherapy-resistant tumor-initiating cells that are thought to be responsible for disease relapse.

Manufacturing
The manufacture of Cantrixil is planned to be performed in three steps, the first of which is this agreement.

“The first step in manufacturing clinical drug supply for the ongoing development of Cantrixil is the most crucial step in securing the clinical drug supply chain,” said Kai Wilkinson, Chief Technical Officer at Vivesto.

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“Our team has extensive experience with supporting the development and manufacture of challenging molecules,” noted Christian Dowdeswell, VP and Global Head, Commercial Development – Small Molecules, Lonza, suggesting that the collaboration means that Vivesto will be able to tap into Lonza’s experience and expertise in manufacturing HPAPIs.

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Licensing
In 2021 Vivesto licensed Cantrixil from the Australian pharmaceutical company Kazia Therapeutics (formerly Novogen) after it successfully completed a Phase I clinical trial.

The top-line results this Phase I open-label study were presented in December 2020 when researchers at Kazia confirmed that the trial had met its primary endpoints, establishing clinical proof of concept, subject to further clinical evaluation and confirmation.[1]

The the trial, conducted at sites in the USA and Australia, was designed to determine the safety and feasibility of weekly intra-peritoneal administration of Cantrixil to women with persistent or recurrent ovarian cancer, Fallopian tube cancer or primary peritoneal cancer. The results demonstrated the drug’s potential to provide prolonged survival in advanced ovarian cancer by inducing the death of ovarian cancer stem cells and sensitising cancer cells to standard chemotherapy. The study also to helped determine the maximum tolerated dose of Cantrixil in these patients when administered as a monotherapy or a combination therapy.[1]

Early development
Cantrixil was original created by Kazia Therapeutics’ subsidiary CanTx (a joint venture between Kazia Therapeutics and Yale University).  The initial drug concept was based on a believe by long-term ovarian cancer researchers in the Yale Medical School that this investigational drug represented a potential breakthrough in the treatment of ovarian cancer. Early in vitro studies demonstrated that Cantrixil had potent cytotoxic activity against human cancer cells including CD44+/MyD88+ ovarian cancer stem cells. The result of these studies confirmed that the investigational agent increased phosphorylated c-Jun levels in these cancer cells resulting in caspase-mediated apoptosis.[2]

In addition, early In vivo studies further demonstrated that Cantrixil was active in a model of disseminated ovarian cancer as a monotherapy and in combination with cisplatin. The researchers observed that Cantrixil was active as maintenance therapy in a model of drug-resistant, recurrent ovarian cancer and in an orthotopic model of pancreatic cancer.[1][2]

Overall, in animals studies, this novel clinical formulation and route of administration demonstrated acceptable activity, safety pharmacology, genotoxicity and toxicology profile, which, according to the initial researchers, warranted further development of the investigational drug. [3]

Furthermore, based on pre-clinical data presented by Yale researchers at the 2015 annual meeting of the American Association of Cancer Research (AACR), which included data related to an animal model believed to be highly representative of late-stage chemo-resistant ovarian cancer (leading to a > 95% tumor reduction), the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation in the treatment of ovarian cancer.

Complementing treatmenmt
The investigational drug has the potential to complement Vivesto’s lead product for ovarian cancer, Apealea®, through treatment protocols to be developed. Apealea is approved by the European Medicines Agency (EMA) in combination with carboplatin, for the treatment of adult patients with first relapse of platinum-sensitive epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer. Vivesto also expects that Cantrixil may offer synergies with the compamy’s XR-17™ technology platform, which could enhance solubility in various routes of administration.

Vivesto is now preparing for the initiation of a Phase II trial of Cantrixil in advanced ovarian cancer.

In April 2021 Kazia Therapeutics out-licensed Cantrixil to Vivesto in a deal worth up to $46 million. Vivesto paid $4 million up front, and development milestones worth up to $42 million and double-digit sales royalties.  In exchange, the company received exclusive global development rights to Cantrixil in all indications, starting with ovarian cancer.

Following the signing of the manufacturing agreement, Lonza will start providing kilogram-scale synthesis, purification and stability testing of Cantrixil, and deliver cGMP batches of this drug substance for clinical supply from its laboratory and highly-potent active pharmaceutical ingredients (HPAPI) manufacturing site at Nansha, China, where the company owns and operates a 250 m2 state-of-the-art analytical and manufacturing facility.

Clinical trials
Phase I Study of Cantrixil in Patients With Ovarian Cancer, Fallopian Tube Cancer or Primary Peritoneal Cancer – NCT02903771

Summary of Product Characteristics
Apealea 60 mg powder for solution for infusion (Product Information)

Highlights of Prescribing Information
Cisplatin (Prescription Information)

Reference
[1 Coward JI, Barve MA, Kichenadasse G, Moore KN, Harnett PR, Berg D, Garner JS, Dizon DS. Maximum Tolerated Dose and Anti-Tumor Activity of Intraperitoneal Cantrixil (TRX-E-002-1) in Patients with Persistent or Recurrent Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer: Phase I Study Results. Cancers (Basel). 2021 Jun 26;13(13):3196. doi: 10.3390/cancers13133196. PMID: 34206826; PMCID: PMC8268018.
[2]Alvero AB, Heaton A, Lima E, Pitruzzello M, Sumi N, Yang-Hartwich Y, Cardenas C, Steinmacher S, Silasi DA, Brown D, Mor G. TRX-E-002-1 Induces c-Jun-Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo. Mol Cancer Ther. 2016 Jun;15(6):1279-90. doi: 10.1158/1535-7163.MCT-16-0005. Epub 2016 Apr 8. PMID: 27196760.
[3] Saif MW, Heaton A, Lilischkis K, Garner J, Brown DM. Pharmacology and toxicology of the novel investigational agent Cantrixil (TRX-E-002-1). Cancer Chemother Pharmacol. 2017 Feb;79(2):303-314. doi: 10.1007/s00280-016-3224-2. Epub 2016 Dec 24. PMID: 28013349; PMCID: PMC5306062.

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