Tiziana Life Sciences PLC   | AIM:TILS

Overview


Tiziana Life Sciences (TILS) acquired milciclib from Nerviano Medical Sciences.  Milciclib (a.k.a PHA-848125 or PHA-848125AC) is a small molecular inhibitor of cyclin-dependent kinases (CDKs) and Src family of kinases, and a limited number of additional kinases.

The compound is an oral drug candidate that inhibits cyclin-dependent kinase 2 (CDK2) and also exhibits inhibitory activity against other CDKs including CDK1 and CDK4 to produce potent anti-cancer activity (1-5). Preclinical studies conducted by scientists in Nerviano indicate that milciclib is a potent anti-cancer drug candidate for treatment of a variety of cancers including cancers of thymic, liver and breast cancer (6). 


THERAPEUTIC APPROACH


Milciclib was found to be well tolerated in over 263 patients in phase I and II clinical trials and the drug candidate has been granted orphan designation by the European Commission and by the U.S. Food and Drug Administration ("FDA") for the treatment of malignant thymoma / thymic epithelial tumours. The interim analysis of the data from the ongoing phase II clinical study in patients with thymic cancer showed potential of this compound for treatment of thymic cancer. To date, 43 pts have been treated (male/female 18/25; median age 55, range 21-80, TC/B3T 26/9). Out of 30 pts whose data are available and mature, 14 are successes (PFS-3 rate = 46.7%; 95%CI 28.3-65.7%) including a RECIST 1.1 PR. Toxicity was generally moderate. The most common Grade 3-4 AE are nausea and asthenia (8.3%), vomiting, myasthenic syndrome, dehydration, hypophosphatemia, cytolytic hepatitis, plantar fascitis (4.2%). The most common Grade 3-4 hematological and biochemical toxicities are neutropenia (8.4%), creatinine, amylase and lipase increase (5.6%). Thus, milciclib has already met its predefined primary endpoint in treated patients (6). The second stage of the trial is ongoing. Subject to successful completion of the ongoing phase II trials, Tiziana is committed to initiate a phase III study in this indication in 2016.

TILS is also planning to conduct additional preclinical studies to further explore therapeutic potentials of milciclib for treatment of liver (hepatocellular carcinoma; HCC) and triple negative breast cancer (TNBC). Objectives of these preclinical studies are to evaluate synergistic effect of milciclib with other FDA approved chemotherapeutic drugs that are commonly used for cancer treatment. Selection of a suitable partner for combination therapy will be useful developing treatment strategies for treatment of aggressive metastatic cancers HCC and TNBC.


MECHANISM


Disruption of cell-cycle regulation in cancer cells is very common observed. In addition, CDKs have been found to be overexpressed in a variety of human diseases with abnormal cell growth such as cancers, viral infections, neurodegenerative disorders and other proliferative diseases. These findings led to a rigorous search for small-molecule CDK inhibitors for the therapeutic purposes.

Schematic representation of possible mechanisms underlying cell cycle control and anti-cancer activities of milciclib.

Progression of cell cycle involves a control on expression, activation and inactivation of CDKs in each of the phases of cell cycle to achieve balance in cell growth. The transition from G1 to S phase of cell cycle is thought to be controlled by CDKs such as CDKs 2, 4, 6. Milciclib is potent inhibitor of CDK 2 but it also inhibits CDK 4. This unique profile of milciclib to inhibit CDKs is important for its anti-cancer activities.


REFERENCES


  1. 1.Asghar U, Witkiewicz AK, Turner NC, Knudsen ES, The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015 Feb;14(2):130-46.

  2. 2.Haider C, Grubinger M, Řezníčková E, Weiss TS, Rotheneder H, Miklos W, Berger W, Jorda R, Zatloukal M, Gucky T, Strnad M, Kryštof V, Mikulits W. Novel inhibitors of cyclin-dependent kinases combat hepatocellular carcinoma without inducing chemoresistance. Mol Cancer Ther. 2013 Oct;12(10):1947-57

  3. 3.Mayer EL. Targeting breast cancer with CDK inhibitors, Curr Oncol Rep. 2015 May;17(5):443

  4. 4.Dickson MA. Molecular pathways: CDK4 inhibitors for cancer therapy, Clin Cancer Res. 2014 Jul 1;20(13):3379-83

  5. 5.Mikhail S, Albanese C, Pishvaian MJ, Cyclin-dependent kinase inhibitors and the treatment of gastrointestinal cancers, Am J Pathol. 2015 May;185(5):1185-97

  6. 6.Benjamin Besse, Marina Chiara Garassino, Arun Rajan, Silvia Novello, Julien Mazieres, Glen J. Weiss, Marina Ciomei, Marcella Martignoni, Anna Petroccione, Cristina Davite, Giuseppe Giaccone; Gustave Roussy, Villejuif, France. A phase II study of milciclib (PHA-848125AC) in patients (pts) with thymic carcinoma (TC)

 

UNDERSTANDING THE UNMET NEED


  1. Cancer is primarily due to uncontrolled cell cycle eventually resulting in transformation of normal cells to rapidly growing cancer cells.

  2. Therapeutic intervention to control cell cycle has long been anticipated as effective cancer therapies. 

  3. Cyclin-dependent kinases (CDKs) are the specific enzymes that promote transition through the cell cycle ultimately drive cell proliferation.

 

Thymic & Liver Cancer

MILCICLIB   |   ORPHAN DRUG STATUS

We are particularly focusing on late stage CDK inhibitor, milciclib for thymoma cancer which has orphan drug status. This drug candidate is currently in late Phase II study for thymoma. This drug may have potential in other cancer, such as hepatocellular carcinoma and breast cancer.

We anticipate filing an IND in 2016.

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