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The most frequent adverse events such as diarrhea, ascites,
nausea, fatigue, asthenia, fever, ataxia, headache, and rash were manageable. No drug-related deaths
were recorded.
Notice of Tiziana Life Sciences plc General Meeting 2020 8
4144-6060-7011.2
? 9 out of 14 patients (64.2%) were approved by their respective ethical committees to continue the
treatment.
? 15 of the 9 patients on compassionate use had received Milciclib for a total of 9, 9, 11, 13 and 16
months.
? As of January 17, 2020, the remaining 2 patients continuing the compassionate use treatment are
in their 15th month.
? Both median TTP and PFS were 5.9 months (95% Confidence Interval ("CI") 1.5-6.7 months) out
of the 6-months duration of the trial.
? 17 of 28 (60.7%) evaluable patients showed "Stable Disease" (SD; met at least once in an 8-week
interval).
? One patient (3.6%) showed "Partial Response" (PR, unconfirmed).
? 18 of 28 (64.3%) evaluable patients showed "Clinical Benefit Rate" defined as CBR=CR+PR+SD
(with CR representing Complete Remission).
Since overexpression of CDKs and dysregulation in pRB pathway (regulates transcription factors critical
for cell cycle progression) are prominently associated with tumor cell resistance to certain
chemotherapeutic drugs, inhibition of multiple CDKs is an appealing approach to improve clinical
responses in cancer patient’s refractory to existing treatment options.
The Company's lead product candidate in oncology is Milciclib (TZLS-201), which is an orally bioavailable,
small molecule broad spectrum inhibitor of cyclin-dependent kinases, or CDKs, and Sarcoma, or Src,
family kinases. CDKs are a highly conserved family of enzymes that phosphorylate a specific group of
proteins that are involved in regulating the cell cycle. The cell cycle is a series of events that takes place
in cells leading to division and duplication of its DNA to produce two daughter cells. Src family kinases are
non-receptor tyrosine kinase proteins encoded by the Src gene also involved in regulating cell growth and
potential transformation of normal cells to cancer cells. The Company now has a drug discovery pipeline
of small molecule new chemical entities, or NCEs, and biologics. Milciclib has Orphan Drug Designation
(ODD) in the U.S. and EU for thymic cancer (thymic epithelial tumor or TET) such as thymic carcinoma
and thymoma.
The Company is developing Milciclib, for which the intellectual property was in-licensed from Nerviano
Medical Sciences S.r.l., or Nerviano, in January 2015, as a potential treatment for hepatocellular
carcinoma, or HCC. A novel feature of Milciclib is its ability to reduce levels of microRNAs, miR-221 and
miR-222. MicroRNAs are small RNA molecules that play a significant role in the regulation of gene
expression. miR-221 and miR-222 are believed to be linked to the development of blood supply
(angiogenesis) in cancer tumors. Levels of these microRNAs are consistently elevated in HCC patients
and may contribute towards resistance to treatment with Sorafenib, a multikinase inhibitor (a drug which
may inhibit the cellular division and proliferation associated with certain cancers) often prescribed to HCC
patients as the Standard of Care (SOC). To date, Milciclib has been studied in a total of eight Phase 1 and
Phase 2 clinical trials in 316 patients. In these trials, Milciclib was well-tolerated with minimal adverse
events. We initiated a Phase 2a trial for Milciclib as a monotherapy in patients with HCC in the third quarter
of 2017. This trial is a single-arm, repeated-dose (100 mg once daily; 4 days on/3 days off every 4 weeks
defining each cycle), 6-month duration study to evaluate the safety, tolerability and anti-tumor activity of
Milciclib in Sorafenib-refractory or intolerant patients with unresectable or metastatic advanced HCC, the
most common form of liver cancer. Enrollment of 31 patients in Italy, Greece, and Israel was completed in
November 2018
In March 2019, the Independent Monitoring Committee, or IDMC, reviewed safety data from patients as of
February 26, 2019 and concluded that the administration of Milciclib to patients with advanced HCC was
not associated with unexpected signs or signals of toxicity. 28 out of 31 treated patients were evaluable,
14 completed the 6-month duration study.