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Tiziana CEO Kunwar Shailubhai discusses the company’s anti il6 technology to deliver drugs to lungs with Andrew Scott at Proactive Investors
Tiziana Life Sciences (LON:TILS)(NASDAQ:TLSA) CEO and chief scientific officer Kunwar Shailubhai discusses the recent excitement around inhalation and the direct delivery of drugs to lungs. ”It makes a lot of sense”, he says.
Shailubhai says he’s pleased he’s covered this approach in his recent patent and in fact was one of the first to do it . ”COVID-19 grows in lungs, that’s where it proliferates and produces inflammation .. that leads to what’s known as a Cytokine Storm and that’s the main reason for respiratory failure”, he says.
”Right now drugs are being delivered by intravenous … it works, but think about it this way, only a fraction of the drug reaches the lung so to give an effective treatment you have to give a higher dose”. Shailubhai also discusses why a vaccine isn’t the complete answer to the coronavirus crisis and why antibodies have a crucial role to play.
Tiziana Life Sciences #TILS – Files Patent on Combination of Nanoparticle-Actinomycin D with Anti-Interleukin-6 Receptor Monoclonal Antibody for Treatment of Coronavirus
Tiziana Life Sciences Files Patent on Combination of Nanoparticle-Actinomycin D with Anti-Interleukin-6 Receptor Monoclonal Antibody for Treatment of Coronaviruses
Combination of nanoparticle-Actinomycin D acting as an anti-viral treatment, with an anti-inflammatory agent may present a potential therapeutic option for COVID-19 patients.
New York/London – April 27, 2020 – Tiziana Life Sciences plc (Nasdaq: TLSA) (“Tiziana” or the “Company”), a biotechnology company focused on innovative therapeutics for inflammatory, autoimmune and infectious diseases, announced today that it has filed a provisional patent application on the combination of nanoparticle-Actinomycin D (NP-ACT D) with anti-interleukin-6 receptor monoclonal antibody (anti-IL-6R) as a potential therapy for management of COVID-19 disease. The underlying invention concepts are based on the hypothesis that a combination of an antiviral drug controlling proliferation of COVID-19, with an anti-inflammatory agent (e.g., anti-IL-6R) suppressing a possible ‘Cytokine Storm’ may provide immediate relief to severe cases of COVID-19 patients.
Actinomycin D (ACT D), an antibiotic drug approved initially for infectious diseases in the United States in 1964, is on 
the World Health Organization’s List of Essential Medicines as the most effective medicine needed in a health system (1). However, severe toxicities associated with the intravenous administration of ACT D limits its widespread therapeutic utility. The NP-ACT D formulation, effectively controlling slow and sustained release, may overcome the severe toxicities of ACT D. Side-by-side animal studies have compared NP-ACT D with free ACT D and demonstrated that the intravenous treatment with NP-ACT D was well-tolerated with minimal apparent toxicities in animal models. Importantly, results from another animal study comparing free ACT D side-by-side with an equivalent dose of NP-ACT D, showed 0% mortality in rats dosed with NP-ACT D as compared to > 90% mortality with free ACT D (2). Nonetheless, safety and tolerability of NP-ACT D needs to be evaluated in healthy volunteers prior to any clinical studies.
Patients infected with COVID-19 are known to develop an uncontrolled immune response (“cytokine storm”), which results in excessive production of pro-inflammatory cytokines such as IL-6 and TNF- a both of which are regarded as key drivers of chronic inflammation and are believed to be associated with severe lung damage commonly observed in patients with COVID-19 infections and acute respiratory distress syndrome (ARDS). Therefore, Tiziana believes it is possible to potentially combine TZLS-501 (anti-IL6R) with NP-Act D to inhibit viral proliferation and to suppress inflammation in lungs to halt progression of COVID-19-mediated lung damage and death.
Citations
1. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO
2. Shailubhai, K. Dactinomycin compositions and methods for the treatment of myelodysplastic syndrome and acute myeloid leukemia. US PCT: 2018/0092857 A1
It is important to note that the Company has not, at the current time, conducted any clinical or pre-clinical research into the use of NP-ACT D, either alone or in combination with anti-interleukin-6 receptor monoclonal antibody (anti-IL-6R) as a treatment for COVID-19, but is basing its assessment for the combination’s potential on research and anecdotal evidence involving NP-ACT D activity on other strains of coronavirus and established theoretical principles underlying combinations of drugs.
About TZLS-501
TZLS-501, a fully human mAb, was acquired from Novimmune, a Swiss biotechnology company, in 2017. The cytokine, IL-6, a major determinant in the priming of pathogenic T cells to produce an inflammatory response, binds to its receptor subunit IL-6Rα on the cell membrane. The receptor IL-6Rα can be shed as a soluble sIL6Rα, which binds to circulating IL-6 cytokine in the blood. The downstream signaling from this complex mediates pro-inflammatory effects underlying the inflammatory diseases such as rheumatoid arthritis (RA) and acute respiratory distress syndrome (ARDS). The Company believes that the novel features of TZLS-501 consisting of its dual mechanism of action to inhibit signaling by the membrane-bound and soluble IL-6 receptor and the rapid depletion of circulating IL-6 cytokines, a major cause of lung damage, suggests a potential role for this mAb in patient management and treatment of COVID-19.
About NP-Act D
Broad-spectrum antibiotics that have been deemed ‘safe-in-man’ through testing in early phase clinical trials have been touted as good drug repurposing candidates for treatment of emerging infectious diseases. Actinomycin D, an inhibitor of RNA-dependent RNA polymerase, is a potent antibiotic with therapeutic utility in infectious diseases and cancer. As intravenous administration of Actinomycin D is known to produce severe toxicities, its therapeutic utility has been limited. The nanoparticle-based Actinomycin D (NP-ACT D) is formulated to control a slow release of Act D such that the Cmax (maximum serum concentration) in blood can be adjusted to a desired level. In animal studies, NP-Act D was found to produce minimal toxicities and it was found to be safe and well-tolerated.
About Tiziana Life Sciences
Tiziana Life Sciences plc is a UK 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”), ulcerative colitis, multiple sclerosis, type-1 diabetes (“T1D”), Crohn’s disease, psoriasis and rheumatoid arthritis, where modulation of a T-cell response is desirable.
Receive news and updates from Tiziana Life Sciences plc by signing up to get email alerts straight to you on https://ir.tizianalifesciences.com
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.
THE PERSON WHO ARRANGED FOR THE RELEASE OF THIS INFORMATION IS DR KUNWAR SHAILUBHAI, THE COMPANY’S CHIEF EXECUTIVE AND CHIEF MEDICAL OFFICER.
Contacts :
Tiziana Life Sciences plc
United Kingdom:
|
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) Antonio Bossi / Fiona Conroy |
+44 (0)20 7601 6125
|
United States:
Investors
Scott Gordon
CORE IR
(516) 222-2560
scottg@coreir.com
Media
Jules Abraham
CORE IR
(917) 885-7378
julesa@coreir.com
Tiziana Life Sciences #TILS – Acquires Nanoparticle-Based Formulation Technology for Controlled Delivery of Actinomycin D for Treatment of Myelodysplastic syndrome and Acute Myeloid Leukemia
New York/London – April 24, 2020 – Tiziana Life Sciences plc (Nasdaq: TLSA) (“Tiziana” or the “Company”), a biotechnology company focused on innovative therapeutics for inflammatory, autoimmune and infectious diseases, announced today that it pursuant to an asset purchase agreement it has acquired all of the intellectual property relating to a nanoparticle-based formulation of Actinomycin D (Act D; a.k.a. Dactinomycin), from Rasna Therapeutics, Inc. (“Rasna”) to expand its pipeline for a consideration of an initial $120,000 upfront payment and milestone payments of up to an additional aggregate $630,000 .
This formulation technology was invented by Dr. Kunwar Shailubhai when he was previously an executive officer at Rasna, which he remains a director.
Act D, an antibiotic drug, was approved initially for infectious diseases in the United States in 1964. Subsequently, this antibiotic was shown to exhibit anti-cancer activity in 1974 (1). Since then the drug has been used to treat various types of cancer, including Wilms tumor, rhabdomyosarcoma, Ewing’s sarcoma, trophoblastic neoplasm, and testicular cancer. The drug is on the World Health Organization’s List of Essential Medicines as the most effective medicines needed in a health system (2). Falini et al., reported in New England Journal of Medicine that intravenous administration of Act D could be used for treatment of patients with Acute Myeloid Leukemia (AML) carrying NPM1 gene mutation (3). Recent studies have also suggested that Act D, being a potent inhibitor of RNA synthesis, may have potential for treatment of COVID-19 patients (4). Currently, the drug is intravenously (IV) administered, which produces severe toxicities possibly due to excessive Cmax in blood during the first couple of hours after administration.
The nanoparticle-based Act D (NP-ACT D) is formulated such that the release of Act D is slow and Cmax in blood may be pre-adjusted to a desired level. In pharmacokinetics (PK) and safety studies in rats, free Act D or an equivalent dose of NP-Act D were intravenously administered side-by-side to compare PK, tolerability, and toxicity. Results from these animal studies indicated that the PK of NP-Act D was slow, and sustained for over 32 hours, whereas the PK in blood within an equivalent dose of free Act D activity was rapid. Importantly, another study comparing side-by-side free Act D with an equivalent dose of NP-Act D, showed 0% mortality in rats dosed with NP-Act D for up to 13 days. By contrast, mortality in rats dosed with free Act D began on 6th day, reaching >90% mortality on 13th day of the study. These results demonstrate that PK of IV administered NP-Act D is slow and sustained for extended period and it is relatively well-tolerated with minimal toxicities. However, safety and tolerability of NP-Act D needs to be evaluated in healthy volunteers prior to clinical studies.
It is important to note that the Company has not, at the current time, conducted any clinical or pre-clinical research into the use of NP-ACT D as a treatment for COVID-19 but is basing its assessment for potential on research involving NP-ACT D with other strains of coronavirus.
Citations
1. Hollstein U (1974). “Actinomycin. Chemistry and mechanism of action”. Chemical Reviews. 74 (6): 625-652.
2. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO
3. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005; 352:254-66.
4. Kennedy, D.A., and Johnson-Lussenburg (1978). Inhibition of Coronavirus 229E Replication by Actinomycin D JOURNAL OF VIROLOGY, Jan. 1978, p. 401-404.
About NP-Act D
Broad-spectrum antibiotics that have been deemed ‘safe-in-man’ through testing in early phase clinical trials have been touted as good drug repurposing candidates for treatment of emerging infectious diseases. Actinomycin D, an inhibitor of RNA-dependent RNA polymerase, is a potent antibiotic with therapeutic utilities in infectious diseases and cancer. As intravenous administration of Actinomycin D is known to produce severe toxicities, its therapeutic utility has been limited. The nanoparticle-based Actinomycin D (NP-ACT D) is formulated to control and slow release of Act D such that the Cmax in blood can be adjusted to a desired level. In animal studies, NP-Act D was found to produce minimal toxicities and it was found to safe and well-tolerated.
About Tiziana Life Sciences
Tiziana Life Sciences plc is a UK 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”), ulcerative colitis, multiple sclerosis, type-1 diabetes (“T1D”), Crohn’s disease, psoriasis and rheumatoid arthritis, where modulation of a T-cell response is desirable.
Receive news and updates from Tiziana Life Sciences plc by signing up to get email alerts straight to you on https://ir.tizianalifesciences.com
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.
The person who arranged for the release of this information was Dr Kunwar Shailubhai, the Company’s Chief Executive and Chief Medical Officer.
Contacts :
Tiziana Life Sciences plc
United Kingdom:
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)
Antonio Bossi / Fiona Conroy +44 (0)20 7601 6125
United States:
Investors
Scott Gordon
CORE IR
(516) 222-2560
scottg@coreir.com
Media
Jules Abraham
CORE IR
(917) 885-7378
julesa@coreir.com
Tiziana Life Sciences #TILS – Initiates Phase 1 Clinical Trial with Orally Administered Foralumab, a Fully Human anti-CD3 monoclonal antibody, in Healthy Volunteers
London/New York, 4 December 2019 – Tiziana Life Sciences plc (Nasdaq: TLSA / AIM: TILS), a clinical-stage biotechnology company focused on developing innovative therapeutics for inflammatory diseases and cancers, is pleased to announce initiation of a Phase I clinical trial in healthy volunteers with a proprietary oral formulation of Foralumab encapsulated in enteric-coated capsules. The primary objective of this single ascending dose (SAD) phase 1 study, being led by Dr. Tanuja Chitnis at the Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA, is to determine safety and tolerability of orally administered Foralumab. The clinical protocol also includes evaluation of pharmacokinetics to determine if there is any systemic absorption of Foralumab following oral administration.
“Oral administration of Foralumab in enteric-coated capsules is a novel approach to upregulate T regulatory cells (Tregs) that have the capability to cross-through blood brain barrier and provide clinical benefits. Successful demonstration of safety in this study will facilitate immediate evaluation of orally administered Foralumab in a phase 2 clinical study in patients with progressive multiple sclerosis, a neurodegenerative disease for which there are limited treatment options”, said Dr. Howard Weiner
“We are excited to initiate this trial because this is the first-ever clinical study with orally administered Foralumab in enteric-coated capsules. The oral route of administration is expected to minimize toxicities associated with intravenous administration of anti-CD3 mAbs and it may also improve the clinical outcome through activation of gut mucosal immunity. Our proprietary oral formulation technology has the potential to be useful for treatment of neurodegenerative and gastrointestinal diseases,” commented Kunwar Shailubhai, CEO and CSO of Tiziana.
About Dr. Howard Weiner
Dr. Howard L. Weiner is the Robert L. Kroc Professor of Neurology at the Harvard Medical School, Director and Founder of the Partners Multiple Sclerosis (MS) Center and Co-Director of the Ann Romney Center for Neurologic Diseases at Brigham & Women’s Hospital in Boston. He has pioneered immunotherapy in MS and has investigated immune mechanisms in nervous system diseases including MS, Alzheimer’s disease, amyotrophic lateral sclerosis, stroke and brain tumors. He has also pioneered the investigation of the mucosal immune system for the treatment of autoimmune and other diseases and the use of anti-CD3 to induce Tregs for the treatment of these diseases.
About Dr. Tanuja Chitnis
Dr. Tanuja Chitnis is a Professor of Neurology at the Harvard Medical School, and Director of the Translational Neuroimmunology Research Center at Brigham & Women’s Hospital in Boston. She has led studies including the testing of nasal Foralumab in healthy volunteers and a study of fingolimod in pediatric MS that led to FDA approval.
About Harvard Medical Centre
Brigham and Women’s Hospital (BWH) is located adjacent to Harvard Medical School, of which it is the second largest teaching affiliate. It is the largest hospital of the Longwood Medical and Academic Area in Boston, Massachusetts, USA. With Massachusetts General Hospital, it is one of the two founding members of Partners HealthCare, the largest healthcare provider in Massachusetts. BWH conducts the second largest hospital-based research program in the world, with an annual research budget of more than $630 million. Pioneering milestones include the world’s first successful heart valve operation and the world’s first solid organ transplant.
About Neurodegenerative diseases
Neurodegenerative diseases include Alzheimer’s, multiple sclerosis, Huntington’s disease, Parkinson’s disease, ALS and others. Among these, Alzheimer’s is the most prevalent disease. In 2013 the global market for AD was 4.9 billion and expected to rise to 13 billion by the end of 2023. Current treatments for neurodegenerative diseases are mainly symptomatic, but new disease-modifying drugs to slow or stop the progression of the disease are now emerging. Three AChE inhibitors are currently in use for AD, i.e. donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl) and cladribine (Mavenclad) for MS. It is recognized that inflammation plays a critical role in neurodegenerative diseases of the CNS. Immune-directed therapies for neurodegenerative diseases target immune system cells such as the T cells that cause inflammatory and autoimmune disease in MS and microglia in ALS and show promise. It has been shown in animal models of progressive MS that anti-CD3 antibody targeting T cells ameliorates disease. These effects were shown to be IL-10 dependent, mediated by regulatory T cells leading to suppression of the disease. There is great promise in ongoing studies of inflammation-targeted neuroprotective strategies, which may ultimately be used across neurodegenerative diseases.
About Tiziana Life Sciences
Tiziana is a UK 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 mAbs in clinical development in the world. This compound has potential application in a wide range of autoimmune and inflammatory diseases, such as crohn’s disease (CD), 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.
For more information go to http://www.tizianalifesciences.com
The person who arranged for the release of this announcement on behalf of the Company was Kunwar Shailubhai, CEO of Tiziana.
Contacts:
|
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) Antonio Bossi / Fiona Conroy |
Tiziana Life Sciences #TILS Announces FDA Approval to Initiate Phase I Clinical Trial with Orally Administered Foralumab in Healthy Volunteers
THE INFORMATION CONTAINED IN THIS ANNOUNCEMENT IS DEEMED BY THE COMPANY TO CONSTITUTE INSIDE INFORMATION AS STIPULATED UNDER THE EU MARKET ABUSE REGULATION (596/2014). UPON PUBLICATION OF THE ANNOUNCEMENT VIA A REGULATORY INFORMATION SERVICE, THIS INFORMATION IS CONSIDERED TO BE IN THE PUBLIC DOMAIN.
Tiziana Life Sciences Announces FDA Approval to Initiate Phase I Clinical Trial with Orally Administered Foralumab in Healthy Volunteers.
A breakthrough approach for treatment of autoimmune and inflammatory diseases
London, 16 September, 2019– Tiziana Life Sciences plc (NASDAQ:TLSA and AIM: TILS), a clinical stage biotechnology company focused on developing targeted drugs for cancer and inflammatory diseases, is pleased to announce (further to the announcement made on 1 May 2019) that the U.S. Food and Drug Administration (FDA) has allowed the initiation of a Phase I clinical trial in healthy volunteers using a novel oral enteric-coated capsule formulation of Foralumab, a fully human monoclonal antibody (mAb), in collaboration with the Brigham and Women’s Hospital (BWH), Harvard Medical School, Boston, MA. We believe this is the first clinical trial in which Foralumab will be administered orally to healthy subjects. Our objective is to develop orally administered Foralumab for treatment of autoimmune and inflammatory diseases.
The scientific rationale for this approach was originally discovered by Dr. Howard Weiner, professor at the Brigham and Women’s Hospital, Harvard Medical School. Dr. Weiner discovered that oral or nasal administration of anti-CD3 mAb induces mucosal tolerance to upregulate T regulatory cells (Tregs) capable of providing site-targeted immunomodulation to suppress inflammation. Therefore, this scientific concept could be effective for the treatment of a variety of autoimmune and inflammatory diseases1-5.
“The therapeutic approach of oral administration with Foralumab greatly enhances our ability to treat neurodegenerative and inflammatory diseases. We have also explored the nasal administration of Foralumab for the treatment of progressive MS. We believe nasal and oral administration with Foralumab opens innovative avenues to treat inflammatory and autoimmune diseases by inducing different classes of Tregs. Thus, mucosal activation stimulating Tregs is a physiological mechanism which we think might be safer than other treatment approaches,”commented Dr. Weiner.
Cited References
- Wu HY, Maron R, Tukpah AM, Weiner HL. Mucosal anti-CD3 monoclonal antibody attenuates collagen-induced arthritis that is associated with induction of LAP+ regulatory T cells and is enhanced by administration of an emulsome-based Th2-skewing adjuvant. J Immunol. 2010; 185(6):3401-3407.
- Ochi, H.,et al.,Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25-LAP+ T cells. Nature Medicine 2006: 12: (6); 627-635
- Lior Mayo, Andre Pires Da Cunha, Asaf Madi, Vanessa Beynon, Zhiping Yang,Jorge I. Alvarez, Alexandre Prat, Raymond A. Sobel, Lester Kobzik, Hans Lassmann, Francisco J. Quintana and Howard L. Weiner. IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. Brain 2016: 139; 1939–1957
- Chantal Kuhn, Rafael M. Rezende, Andre Pires da Cunha, Fabrice Valette, Francisco J. Quintana, Lucienne Chatenoud, Howard L. Weiner. Mucosal administration of CD3-specific monoclonal antibody inhibits diabetes in NOD mice and in a preclinical mouse transgenic for the CD3 epsilon chain. Journal of Autoimmunity (2016) 76: 1-8
- Ogura M, et al., Prevention of human xenograft rejection with oral anti-CD3 mAb. Clinical Immunology 183: 2017; 240-246
About Howard Weiner
Howard L. Weiner is the Robert L. Kroc Professor of Neurology at the Harvard Medical School, Director and Founder of the Partners Multiple Sclerosis (MS) Center and Co-Director of the Ann Romney Center for Neurologic Diseases at Brigham & Women’s Hospital in Boston. He has pioneered immunotherapy in MS and has investigated immune mechanisms in nervous system diseases including MS, Alzheimer’s disease, amyotrophic lateral sclerosis, stroke and brain tumours. He has also pioneered the investigation of the mucosal immune system for the treatment of autoimmune and other diseases and the use of anti-CD3 to induce regulatory T cells for the treatment of these diseases.
About Harvard Medical Centre
Brigham and Women’s Hospital (BWH, “The Brigham”) is located adjacent to Harvard Medical School, of which it is the second largest teaching affiliate. It is the largest hospital of the Longwood Medical and Academic Area in Boston, Massachusetts, USA. With Massachusetts General Hospital, it is one of the two founding members of Partners HealthCare, the largest healthcare provider in Massachusetts. Brigham and Women’s Hospital conducts the second largest hospital-based research program in the world, with an annual research budget of more than $630 million. Pioneering milestones include the world’s first successful heart valve operation and the world’s first solid organ transplant.
About Autoimmune Diseases and Foralumab
Autoimmune diseases constitute a major medical problem and include diseases such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and inflammatory bowel disease. Other diseases, that have inflammatory components include diseases such as NASH, atherosclerosis and stroke. The induction of regulatory cells at mucosal surfaces by the oral or nasal administration of antigens has been shown to treat a large variety of autoimmune and inflammatory diseases in animal models with minimal toxicity. Foralumab was developed by Novimmune and has been acquired by Tiziana Life Sciences PLC. Foralumab (formerly NI-0401) is thus far the only entirely human anti-CD3 mAb, shows reduced release of cytokines after IV administration in patients with Crohn’s disease with decreases in the classic side effects of cytokine release syndrome (CRS) and improves the overall safety profile of foralumab.
In a humanized mouse model (NOD/SCID IL2γc-/-) developed in Dr Kevan Herold’s laboratory, it was show that while targeting the T cell receptor, orally administered foralumab modulates immune responses of the T cells, enhances regulatory T cells and thus provides therapeutic benefit in treating inflammatory and autoimmune diseases without the occurrence of potential adverse events usually associated with parenteral mAb therapy (Ogura M. et al., 2017). Based on animal studies, the nasal and oral administration of foralumab offers the potential for the immunotherapy of autoimmune and inflammatory diseases in a safe manner by the induction of regulatory T cells.
About Tiziana Life Sciences
Tiziana Life Sciences plc is a UK 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 compound has potential application in a wide range of autoimmune and inflammatory diseases, such as non-alcoholic 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.
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
For more information go to http://www.tizianalifesciences.com
This announcement contains inside information for the purposes of Article 7 of EU Regulation 596/2014.
Contacts:
| 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 (Nominated brokers)
Antonio Bossi / Andy Crossley
|
+44 (0)20 7408 4050 |
Receive news and updates from Tiziana Life Sciences plc by signing up to get email alerts straight to you on https://ir.tizianalifesciences.com
Tiziana Life Sciences #TILS Reports Phase 1 Clinical Data Demonstrating Nasal Treatment with Foralumab was Well-tolerated and Produced Positive Trend in Biomarkers
THE INFORMATION CONTAINED IN THIS ANNOUNCEMENT IS DEEMED BY THE COMPANY TO CONSTITUTE INSIDE INFORMATION AS STIPULATED UNDER THE EU MARKET ABUSE REGULATION (596/2014). UPON PUBLICATION OF THE ANNOUNCEMENT VIA A REGULATORY INFORMATION SERVICE, THIS INFORMATION IS CONSIDERED TO BE IN THE PUBLIC DOMAIN.
Tiziana Life Sciences plc
Tiziana Reports Phase 1 Clinical Data Demonstrating Nasal Treatment with Foralumab was Well-tolerated and Produced Positive Trend in Biomarkers of Immunomodulation and Anti-inflammation in Healthy Volunteers
New York, 10 September 2019 – Tiziana Life Sciences plc (Nasdaq: TLSA) (“Tiziana” or the “Company”), a biotechnology company focused on innovative therapeutics for inflammatory diseases and cancers, is pleased to report Phase 1 clinical data demonstrating that nasally administered Foralumab, a fully human anti-CD3 monoclonal antibody (mAb), was well-tolerated at all doses. Importantly, the treatment showed significant positive effects on the biomarkers for activation of mucosal immunity, which is capable of inducing site-targeted immunomodulation to elicit anti-inflammatory effects. These clinical data are consistent with the findings from numerous pre-clinical studies.1-3
This Phase 1 trial, conducted at the Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, was a single-site, double-blind, placebo-controlled, dose-ranging study with nasally administered Foralumab at 10, 50 and 250 µg per day, consecutively for 5 days in healthy volunteers for the treatment of progressive multiple sclerosis (pMS). 18 subjects received Foralumab treatment and 9 patient received placebo. All nasal doses were well tolerated. Biomarker analysis showed significant positive immune effects, that were most prominent in the 50 mg cohort with minimal immunomodulatory effects at the 10 µg and 250 µg doses.
Major Highlights
- Treatment was well-tolerated and no drug-related safety issues were reported at any of the doses.
- No drug-related changes were observed in vital signs among subjects at predose, during treatment and at discharge. The mean blood pressure (BP) during the 5 days of treatment were; Cohort A (10 µg/d):124/73, Cohort B (50 µg/d): 119/67 and Cohort C (250 µg/d):113/65 compared to placebo:118/67). Heart rates, respiratory rates and oral temperatures were unchanged among the 3 cohorts compared to the placebo.
- Nasally administered Foralumab at the 50 µg dose suppressed cytotoxic CD8+ as well as perforin secreting CD8+ cells, which have been implicated in neurodegeneration in multiple sclerosis (MS).
- Treatment at 50 mg stimulated production of anti-inflammatory cytokine IL-10 and suppressed production of pro-inflammatory cytokine IFN-γ.
- Taken together, these results suggest stimulation of Tregs that are needed to provide clinical benefits
“Nasal administration of Foralumab is a revolutionary approach to treat patients with neurodegenerative diseases such as progressive MS (pro-MS) and amyotrophic lateral sclerosis (ALS). Extensive data from animal studies with intranasal delivery of anti-CD3 demonstrate that this route of administration induces anti-inflammatory and immunomodulatory effects. This study demonstrates for the first-time that nasally administered Foralumab, at the identified optimal dose of 50 mg, induces immunomodulatory effects capable of providing clinical benefit to treated subjects.This is a major accomplishment providing the scientific rationale to move forward with further clinical development of nasally administered Foralumab in patients with neurodegenerative diseases,”commented Dr. Howard L. Weiner, a member of scientific advisory board of Tiziana Life Sciences. He added that “both oral and nasal administration routes are physiologic approaches to stimulate the mucosal immune system to induce disease modifying immunomodulation. Our immediate focus is on developing Foralumab for treatment of pro-MS.”
“The demonstration of the positive immunomodulatory effects provides the scientific rationale to move forward with further studies in the pro-MS population”,stated Dr. Tanuja Chitnis, the study PI at the Brigham and Women’s Hospital.
“We are very pleased with what we believe is the first-ever demonstration that nasally administered Foralumab is not only well-tolerated, but it also exhibited significantly positive immunomodulatory effects that are indicative of stimulation of Tregs. We are excited as these results provide the scientific rationale for the nasal and oral treatment with Foralumab, our core proprietary platform technologies which could potentially revolutionize treatment with antibodies”stated Kunwar Shailubhai, CEO & CSO of Tiziana.
The person who arranged for the release of this announcement on behalf of the Company was Dr Kunwar Shailubhai, CEO & CSO of Tiziana.
About Foralumab
Foralumab (formerly NI-0401), the only entirely human anti-CD3 mAb, shows reduced release of cytokines after IV administration in patients with Crohn’s disease with decreases in the classic side effects of cytokine release syndrome (CRS) and improves the overall safety profile of Foralumab. In a humanized mouse model (NOD/SCID IL2γc-/-), it was shown that while targeting the T cell receptor, orally administered Foralumab modulates immune responses of the T cells, enhances Tregs and thus provides therapeutic benefit in treating inflammatory and autoimmune diseases without the occurrence of potential adverse events usually associated with parenteral mAb therapy (Ogura M. et al., 2017). Based on animal studies, the nasal and oral administration of Foralumab offers the potential for the immunotherapy of autoimmune and inflammatory diseases in a safe manner by the induction of Tregs.
Preclinical studies on nasal and oral administration with Anti-CD3 mAbs
Preclinical and clinical studies have shown that mucosal induction of Tregs by oral or nasal administration of anti-CD3 mAbs is an innovative approach to treat autoimmune and anti-inflammatory diseases (Kuhn and Weiner 2016)4. Nasally administered anti-CD3 mAbs were shown to ameliorate disease in an animal model of multiple sclerosis by inducing IL-10+LAP+(latency-associated peptide) T cells3, demonstrating nasal anti-CD3 mAbs as a new approach to treat progressive forms of multiple sclerosis and other types of chronic CNS inflammation. Additionally, nasally administered anti-CD3 mAbs suppressed lupus in lupus-prone mice (BWF1) by inducing IL-10 and TGF-β dependent mechanisms associated with a suppression of IL-17 and IL-21 pro-inflammatory cytokines5.
About Tiziana Life Sciences
Tiziana Life Sciences plc is a UK 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), ulcerative colitis, multiple sclerosis, type-1 diabetes (T1D), crohn’s disease, psoriasis and rheumatoid arthritis, where modulation of a T-cell response is desirable.
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.
Cited References
- Weiner HL et al. Oral tolerance. Immunol Rev. 2011; 241(1):241-259
- Ochi H, Abraham M, Ishikawa H et al. New immunosuppressive approaches: Oral administration of CD3-specific antibody to treat autoimmunity. J Neurol Sci 2008; 274(1- 2):9-12
- Mayo, L et al. IL-10-dependent TrI cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. Brain. 2016: 139; 1939-1957
- Kuhn C. and Weiner HL. Therapeutic anti-DC3 monoclonal antibodies: from bench to bedside. Immunotherapy 2016; 8(8):889-906
- Wu, H.Y, Quintana, F.J and Weiner, H.L. Nasal Anti-CD3 Antibody Ameleorates Lupus by Inducing an IL-10-Secreting CD4+CD25-LAP+ Regulatory T cell and Is Associated with Down-Regulation of IL-17+CD4+ICOS+CXCR5+ Follicular Helper T Cells. J Immunol 2008; 181:6038-6050
For further enquiries:
Tiziana Life Sciences plc +44 (0)20 7495 2379 Gabriele Cerrone, Chairman and founder
Cairn Financial Advisers LLP (Nominated adviser) +44 (0)20 7213 0883
Liam Murray / Jo Turner
| Shore Capital (Broker)
Andy Crossley / Antonio Bossi
|
+44 (0)20 7601 6125 |
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