Tiziana Life Sciences plc (NASDAQ: TLSA), a biotechnology
company focusing on the discovery and development of innovative
therapeutics for inflammation and oncology indications, today
announced additional positive Phase 2a clinical data exhibiting
impressive clinical activity of Milciclib monotherapy in patients
with advanced Sorafenib-resistant or -intolerant patients with
unresectable or metastatic hepatocellular carcinoma (HCC).
This Phase 2a multi-center, single-arm, repeated-dose (100 mg
once daily; 4 days on/3 days off for 4 weeks; defining each cycle)
and 6-month duration study was conducted to evaluate the safety,
tolerability and anti-tumor activity of Milciclib in
Sorafenib-resistant patients with unresectable or metastatic
advanced HCC. The trial enrolled 31 patients in Italy, Greece and
Israel, of which 28 patients were evaluable. While the primary
endpoint of this study was overall safety, secondary endpoints were
also evaluated.
As previously announced on 22 July 2019, the clinical data from
the Phase 2a trial indicated that Milciclib was well tolerated with
manageable toxicities and no recorded drug related deaths, thereby
meeting the trial’s primary endpoint. The Company now announces all
the major highlights of the clinical data from the trial, which
also indicate positive clinical activity relating to the secondary
endpoints including progression-free survival (“PFS”) and time to
progression (“TTP”).
MAJOR HIGHLIGHTS OF THE CLINICAL DATA
As per the study protocol, data collection was limited to
6-months. Thus, clinical data were not collected from patients
under compassionate use treatment. The clinical activity assessment
in evaluable patients was based on the investigators’ review using
the modified Response Evaluation Criteria in Solid Tumors
(mRECIST).
- 14 out of 28 (50%) evaluable patients completed 6-month
duration of the trial.
- 9 out of 14 patients (64.2%) were approved by their respective
ethical committees to continue the treatment.
- 5 of the 9 patients on compassionate use had received Milciclib
for a total of 9, 9, 11, 13 and 16 months.
- As of 1 September 2019, the remaining 4 patients continuing the
treatment are in their 10th, 11th, 11th and 12th months.
- 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).
- 18 of 28 (64.3%) evaluable patients showed ‘Clinical Benefit
Rate’ defined as CBR=CR+PR+SD (with CR representing Complete
Remission).
Sorafenib® (Bayer) was approved, based on the clinical data from
the pivotal Phase 3 (SHARP) clinical trial1, as the first line
therapy for naive HCC patients. The clinical data from that study
showed median TTP of 5.5 months (95% CI 4.1-6.9 months), CBR of 43%
and 71% SD by RECIST criteria1. Conversely, the clinical data from
a phase 2 trial with Sorafenib in patients with advanced HCC,
showed SD (33.6%), TTP of 4.2 months and median OS of 9.2
months2.
Regorafenib was approved, based on the clinical data from the
pivotal Phase 3 (RESORCE) clinical trial3, as the second line
therapy for sorafenib-resistant HCC patients. In this study,
Regorafenib showed median PFS of 3.1 months (95% CI 2.8-4.2
months), median TTP of 3.2 months (95% CI 2.9-4.2 months) and
disease control rate (DCR, similar to CBR) of 65% by mRECIST. On
the other hand, the clinical data from a Phase 2 study in patients
with intermediate and advanced HCC, Regorafenib showed median TTP
of 4.3 months (95% CI 2.9-13.1 months), SD (69%) and PR was
3%4.
“The current therapies for HCC are often associated with severe
toxicities, resulting in poor patient compliance. Hence, there is
an immediate need for efficacious therapies that will not
compromise patients’ quality of life. We believe that the overall
safety profile of Milciclib is an important competitive advantage
over existing therapies currently used for treating HCC” said
Gabriele Cerrone, Chairman and founder of Tiziana Life
Sciences.
"The positive clinical activity and tolerability data of
Milciclib in Sorafenib-resistant and advanced HCC patients are very
encouraging and provides affirmation for continued development of
Milciclib, either as monotherapy or combination therapy" said Dr.
Kunwar Shailubhai, CEO & CSO of Tiziana. “We reported last year
at AASLD that Milciclib produced pronounced synergistic anti-HCC
activity in combination with any one of the FDA approved tyrosine
kinase inhibitor (TKI) class of drugs, including Sorafenib
(Nexavar®), Regorafenib (Stivarga®), and Lenvatinib (Lenvima®)5.
Thus, we believe that Milciclib in combination with any one of the
TKI drugs has good potential to expand the Clinical Benefit Rate in
HCC patients.”
Cited References
1. Llovet, J., Ricci, S., Mazzaferro, V.,
Hilgard, P., Gane, E., Blanc, J-F., de Oliveira, A., Santoro, A.,
Raoul, J-L, Forner, A., Schwartz, M., Porta, C., Zeuzem, S.,
Bolondi, L., Greten, T., Galle, P., Seitz, J-F., Borbatch, I.,
Haussinger, D., Giannaris, T., Shan, M., Moscovici, M., Voliotiz,
D., and J. Bruix. (2008) Sorafenib in Advance Hepatocellular
Carcinoma. N Engl. J Med. 359:378.
2. Abou-Alfa, G., Schwartz, L., Ricci., S.,
Amadori, D., Santoro, A., Figer, A. De Greve, J., Douillard, J-Y.,
Lathia, C., Schwartz, B., Taylor, I., Moscovici, M. and L. Saltz.
(2006). Phase II Study of Sorafenib in Patients with Advanced
Hepatocellular Carcinoma. J. Clin. Oncol. 24:4293.
3. Bruix, J, Qin, S., Merle, P., Granito, A.,
Huang, Y-H, Bodoky, G., Pracht, M., Yokosuka, O., Rosmorduc, O.,
Breder, V., Gerolami, R., Masi, G., Ross, P., Song, T., Bronowicki,
J-P., Ollivier-Hourmand, I., Kudo, M., Cheng, A-L., Llovet, J.M.,
Finn, R., LeBerre, M-A., Baumhauer, A., Meinhardt, G. and Han, G.
(2017) Regorafenib for patients with hepatocellular carcinoma who
progressed on sorafenib treatment (RESORCE): a randomized,
double-blind, placebo-controlled, phase 3 trial. Lancet 389:
56.
4. Bruix, J., Tak, W-Y., Gasbarrini, A.,
Santoro, A., Colombo, M., Lim, H-Y., Mazzaferro, V., Wiest, R.,
Reig, M., Wagner, A., and Bolondi, L.(2013) Regorafenib as
Second-Line Therapy for Intermediate or Advanced Hepatocellular
Carcinoma: Multicentre, Open-Label Phase II Safety Study. Eur.J.
Cancer 49:3412.
5. Jindal, A., Palejwala, V. and Shailubhai,
K. (2018). Oral treatment with milciclib either alone or in
combination with sorafenib inhibited tumor growth in an orthotopic
model of hepatocellular carcinoma. Hepatology 68 Number 1 (Suppl):
879A (Abstract 1543)
The person who arranged for the release of this announcement on
behalf of the Company was Dr Kunwar Shailubhai, CEO & CSO of
Tiziana.
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Forward-Looking Statements
Certain statements made in this announcement are forward-looking
statements. These forward-looking statements are not historical
facts but rather are based on the Company's current expectations,
estimates, and projections about its industry; its beliefs; and
assumptions. Words such as 'anticipates,' 'expects,' 'intends,'
'plans,' 'believes,' 'seeks,' 'estimates,' and similar expressions
are intended to identify forward-looking statements. These
statements are not guarantees of future performance and are subject
to known and unknown risks, uncertainties, and other factors, some
of which are beyond the Company's control, are difficult to
predict, and could cause actual results to differ materially from
those expressed or forecasted in the forward-looking statements.
The Company cautions security holders and prospective security
holders not to place undue reliance on these forward-looking
statements, which reflect the view of the Company only as of the
date of this announcement. The forward-looking statements made in
this announcement relate only to events as of the date on which the
statements are made. The Company will not undertake any obligation
to release publicly any revisions or updates to these
forward-looking statements to reflect events, circumstances, or
unanticipated events occurring after the date of this announcement
except as required by law or by any appropriate regulatory
authority.
About HCC
HCC is the fifth most common cancer and the third highest cause
of cancer mortality worldwide. The primary risk factor for HCC is
hepatic cirrhosis. Between 2003 to 2012, rates of new liver cancer
cases went up 38% according to the Centers for Disease Control and
Prevention. Most HCC patients present with advanced disease and do
not benefit from transplantation, surgical resection, or
locoregional therapies. Sorafenib (standard of care) and Lenvatinib
are approved in the United States and EU as first line-treatment
for advanced HCC patients.
Regorafenib (Stivarga®) and Nivolumab (Opdivo®) are both
approved by the FDA for second line treatment of advanced HCC. The
complex multi-factorial etiology of HCC warrants a need for
systemic therapies that target different signaling cascades to
provide improved efficacy and safety for both naive patients
presenting with unresectable, advanced stage and those who suffer
recurrence after curative treatments (resection, ablation and
transplantation).
About Milciclib
Milciclib (PHA-848125AC) is a small molecule inhibitor of
several cyclin dependent kinases such as CDK1, CDK2, CDK4, CDK5 and
CDK7. CDKs are serine threonine kinases that play crucial roles in
progression of the cell cycle from G1 to S phase. Overexpression of
CDKs and other downstream signaling pathways that regulate cell
cycles have been frequently associated with development of
resistance towards chemotherapies. In a Phase 1 study, oral
treatment with Milciclib was well-tolerated and the drug showed
promising clinical responses in patients with advanced solid
malignancies such as in NSCLC, pancreatic and colon cancer, thymic
carcinoma and thymoma. Additionally, milciclib met its primary
endpoint in two separate Phase 2 multi-center clinical trials
(CDKO-125A-006: 72 patients and CDKO-125A-007: 30 patients) in
thymic carcinoma and thymoma patients.
About Tiziana Life Sciences
Tiziana Life Sciences plc is a biotechnology company that
focuses on the discovery and development of novel molecules to
treat human disease in oncology and immunology. In addition to
Milciclib, the Company is also developing Foralumab for liver
diseases. Foralumab is the only fully human anti-CD3 monoclonal
antibody in clinical development in the world. This Phase 2
compound has potential application in a wide range of autoimmune
and inflammatory diseases, such as nonalcoholic steatohepatitis
(NASH), primary biliary cholangitis (PBS), ulcerative colitis,
multiple sclerosis, type-1 diabetes (T1D), inflammatory bowel
disease (IBD), psoriasis and rheumatoid arthritis, where modulation
of a T-cell response is desirable.
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version on businesswire.com: https://www.businesswire.com/news/home/20190904005447/en/
Tiziana Life Sciences plc Gabriele Cerrone, Chairman and founder
+44 (0)20 7495 2379 Cairn Financial Advisers LLP (Nominated
adviser) Liam Murray / Jo Turner +44 (0)20 7213 0883 Shore Capital
(Broker) Andy Crossley / Antonio Bossi +44 (0)20 7601 6125
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