On September 30, 2020 Tiziana Life Sciences plc ("Tiziana", AIM: TILS, NASDAQ: TLSA), a biotechnology company that focuses on the discovery and development of novel molecules to treat human diseases in oncology, inflammation and infectious diseases reported its interim results for the six months ended 30 June 2020 (Press release, Tiziana Life Sciences, SEP 30, 2020, View Source [SID1234568598]).
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Highlights during the period:
RESEARCH & DEVELOPMENT
Foralumab is a fully human engineered anti-CD3 monoclonal antibody (mAB). It was in-licensed in December 2014 from Novimmune.
As the only fully human engineered human anti-CD3 mAB in clinical development, Foralumab has significant potential advantages such as a shorter treatment duration and reduced immunogenicity. With completion of the intravenous dosing for our Phase 2a trial in Crohn’s Disease, Foralumab’s ability to modulate T-cell response enables potential extension into a wide range of other autoimmune and inflammatory diseases, such as multiple sclerosis, inflammatory bowel disease (IBD), psoriasis and rheumatoid arthritis.
Foralumab is being developed as both an immunosuppressive and immunomodulatory agent, with therapeutic benefits of rendering T-cells unable to orchestrate an immune response and induction of immune tolerance via maintenance of regulatory T-cells. There is further potential for Foralumab to be combined with the Company’s TZLS-501, a fully human anti-IL-6R mAB in development to target autoimmune and inflammatory diseases.
On 16 April, 2018, the Group entered into an exclusive license agreement with The Brigham and Women’s Hospital, Inc. relating to a novel formulation of Foralumab dosed in a medical device for nasal administration. An investigational new drug application (IND) for the first-in-human evaluation of the nasal administration of Foralumab in healthy volunteers for progressive multiple sclerosis indication was filed in the second quarter of 2018. Phase 1 clinical data demonstrated that nasally administered Foralumab, 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 pre-dose, 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 µg stimulated production of anti-inflammatory cytokine IL-10 and suppressed production of pro-inflammatory cytokine IFN-γ. Taken together, the treatment showed significant positive effects on the biomarkers for activation of mucosal immunity, which are capable of inducing site-targeted immunomodulation to elicit anti-inflammatory effects. Based on the results we intend to conduct a Phase 2 trial in secondary progressive MS patients. Protocol for Phase 2 nasal clinical trial is finalized. The briefing package and protocol was submitted to FDA on July 22, 2020 requesting type C meeting and FDA response expected by mid October, 2020. The trial is anticipated to begin in Q4 2020.
An enteric-coated capsule formulation has been developed for oral administration of Foralumab. cGMP manufacturing of clinical trial materials for a Phase 1 study has been completed. The Phase 1 clinical trial for Foralumab in healthy volunteers was a single-center, single-arm, ascending dose study in which low doses (1.25, 2.5 and 5.0 mg/dose) of Foralumab and placebo were orally administered. The primary endpoint of the Phase 1 study was safety and tolerability of oral Foralumab in humans. The Phase 1 trial was initiated on December 2, 2019and results were reported on January 20, 2020 The proprietary oral formulation, comprising the lyophilized and stabilized free-flowing powder of formulated Foralumab encapsulated in an enteric-coated capsule, was well-tolerated at all doses tested and there were no drug-related safety issues even at the highest dose of 5 mg in this trial. Based on the positive outcome of the Phase 1 trial, a Phase 2 trial in Crohn’s Disease patients is expected to begin in Q2/Q3 2021.
Anti IL-6R mAb
TZLS-501, formerly NI-1201
TZLS-501 is a fully human engineered mAb targeting the interleukin-6 receptor (IL-6R). Tiziana Life Sciences licensed the intellectual property from Novimmune in January 2017. This fully human mAb has a unique mechanism of action that binds to both the membrane-bound and soluble forms of the IL-6R resulting in lowering of circulating levels of IL-6 in the blood. Excessive production of IL-6 is regarded as a key driver of chronic inflammation, associated with autoimmune diseases such as multiple myeloma, oncology indications and rheumatoid arthritis, and the Group believes that TZLS-501 may have potential therapeutic value for these indications.
In preclinical studies, TZLS-501 demonstrated the potential to overcome limitations of other IL-6 blocking pathway drugs. Compared to tocilizumab and sarilumab, while binding to the membrane-bound IL-6R complex TZLS-501 has shown a higher affinity for the soluble IL-6 receptor as seen from the antibody binding studies conducted in cell culture. TZLS-501 also demonstrated the potential to block or reduce IL-6 signalling in mouse models of inflammation. The soluble form of IL-6 has been implicated to have a larger role in disease progression compared to the membrane-bound form. (Kallen, K.J. (2002). "The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases". Biochimica et Biophysica Acta. 1592 (3): 323–343.).
On April 9, 2020 Tiziana announced the clinical development of anti-IL6R mAb as a treatment for "cytokine storm" induced lung damage in COVID-19 patients. Early clinical studies conducted by doctors in China suggest that anti-IL6R mAb may be used in clinical practice for treatment of COVID-19. Consequently, China’s National Health Commission has recommended the use of Roche’s blockbuster drug, Actemra for treatment of patients infected with COVID-19, with serious lung damage and elevated IL6 levels. Actemra was first approved by the FDA in 2010 for rheumatoid arthritis. Besides Actemra, Sanofi and Regeneron are currently exploring Kevzara, an FDA-approved anti-IL-6 receptor therapy for rheumatoid arthritis, for treatment of severe COVID-19. The Company believes that of TZLS-501 may have greater clinical effect than Actemra or Kevzara based on higher binding affinity for IL6 receptor complex compared to Actemra and Kevzara. Also TZLS-501 reduces circulating levels of IL6 via the trans-signaling pathways.
The treatment utilizes a novel mode of administrationusing hand-held nebulizer to deliver aerosolized anti-IL6R mAb solution to inflamed tissue of deep lung. On April 9,2020, Tiziana announced filing of patent application in support of treatment of COVID-19 utilizing Anti-IL6R via inhaled delivery (Kunwar Shailubhai, inventor). Initial work on CMO selection, technology transfer and transfer of lead cell line candidate from Novimmune to CMO initiated in April 2020. A rigorous CMO selection process was initiated in April and STC Biologics, a boutique CMO located in Newton MA was selected as the finalist based on their ability to deliver drug substance (DS) in approximately 10 months timeline and most competitive pricing. Tiziana shipped a lead non-clonal cell line from Novimmune to STC Biologics in June 2020. STC Biologics is expanding the cell line, establishing monoclonality, screening for cell line stability and antibody titer and expanding the monoclonal cell line to larger scale for development and cGMP manufacturing. Concurrently they are purifying a batch of monoclonal antibody from the 70L Novimmune pilot batch, manufactured using the lead, non-clonal cell line. STC’s generic downstream process is being used for the purification of test article for Inhalation Safety Toxicology studies using Cynomolgous monkeys at ITR Laboratories Canada
Work at Sciarra Laboratories in Hicksville, NY was initiated in May 2020, Sciarra is currently evaluating two hand-held nebulizer devices for use in the study and characterizing physical/performance characteristics. Once a device has been selected, a few candidate formulations of anti-IL6R mAb, from formulation development studies at STC Biologics, will be manufactured at small scale and evaluated using the devices. Sciarra will execute cGMP manufacturing of drug product solution, packaging and ICH stability studies in Q1 2021.
In July 2020, Tiziana engaged FHI clinical as CRO to conduct Phase1/2 clinical trials of TZLS-501 in for the COVID-19 indication. FHI Clinical is a CRO specializing in infectious disease and COVID-19 clinical trials, located in Durham North Carolina. Initial scope of work is regulatory, preparing for a FDA Type C meeting in Q4 2020. FHI will help design a multisite, Phase1/2 adaptive trial with sites located mostly ex-US in COVID-19 hot spots to speed enrollment to start in Q1 2021
In August 2020, Brand Institute was engaged for selection, qualification and Application for INN and USAN non-proprietary names for anti-IL6R mAb (TZLS-501)
ITR Laboratories Canada specializes in inhalation toxicology studies in primates and will start inhalation safety toxicology studies in Cynomolgous monkeys in October 2020 using the purified, characterized anti-IL6R mAb test. Results from the study will be used to establish dosing for the Phase 1 study in healthy volunteers.
The Company is actively evaluating alternative, non-parenteral routes of monoclonal antibody (mAb) administration, namely oral, nasal and inhalation routes, to facilitate topical or local therapeutic action.
Milciclib, Tiziana’s lead small molecule drug, was exclusively licenced in January 2015 from Nerviano Medical Sciences. Milciclib is an orally bioavailable, broad spectrum inhibitor of Cyclin Dependent Kinases (CDKs): 1, 2, 4, 5 and 7 and Src family kinases. Cyclin dependent kinases are a family of highly conserved enzymes that are involved in regulating the cell cycle. Src family kinases regulate cell growth and potential transformation of normal cells to cancer cells. A unique feature of Milciclib is its ability to reduce microRNAs, miR- 221 and miR-222, which silence gene expression. miR-221 and miR-222 promote the formation of blood vessels (angiogenesis) that are important for the spread of cancer cells (metastasis). Levels of these microRNAs are consistently increased in hepatocellular carcinoma ("HCC") patients and may contribute towards resistance to treatment with Sorafenib. As a result, the Group are investigating Milciclib both as a monotherapy and as a combination treatment with Sorafenib.
To date, Milciclib has been studied in a total of eight completed and ongoing Phase 1 and 2 clinical trials in 316 patients. In these trials, Milciclib was observed to be well-tolerated and showed initial signals of anti-tumour action.
The Group initiated a Phase 2a trial (CDKO-125a-010) of Milciclib safety and tolerability as a single therapy in Sorafenib-resistant patients with HCC in the first half of 2017. Typically, this population of patients have an advanced form of the disease with poor prognosis and an average overall survival expectancy of 3-5 months In May 2018, the Independent Data Monitor committee (IDMC) completed an interim analysis of tolerability data from the first eleven treated patients and recommended expansion of the initial cohort to an additional 20 patients to complete the trial enrolment, which was completed in December 2018. .
The Phase 2a trial was completed in June 2019 with clinical safety and efficacy result reported in July 2019. 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. A Phase 1 dose-escalation study of Milciclib in combination with gemcitabine in patients with refractory solid tumors exhibited clinical activity in patients including those refractory to gemcitabine. We plan to explore a combination approach in patients with HCC.
On May 14, 2020 the Company announced the online publication of two abstracts on clinical studies with Milciclib, a small molecule pan-inhibitor of cyclin dependent kinases (CDKs) in the proceedings of the virtual annual meeting of American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 (ASCO20). The first abstract reported Phase 2a clinical data with orally administered Milciclib in sorafenib-resistant hepatocellular carcinoma (HCC) patients, for which it met the primary endpoint, that oral treatment with Milciclib was well tolerated with manageable toxicities and no recorded drug-related deaths. The second abstract reported preliminary clinical data from an ongoing investigator-originated trial with a combination of orally administered Milciclib and Regorafenib in liver transplant patients with recurrent HCC. Thus far, the study has shown mean AFP levels (a common tumor biomarker) reduced by approximately 20% within one month of treatment.
StemPrintER is a multi-gene signature assay intended for use in patients diagnosed with estrogen-receptor positive ER+/HER2 negative breast cancers. The Group believes this in-vitro prognostic test will be used in conjunction with clinical evaluation to identify those patients at increased risk for early and/or late metastasis.
On May 29,2020, the Company announced results from from a poster selected for discussion session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Virtual Conference, demonstrating the superiority of StemPrintER stem cell based genomic prognostic tool versus the market leader, Oncotype DX, in predicting recurrence in ER+/HER2- postmenopausal breast cancer patients. A second poster describing results on prediction of distant recurrence using a next generation StemPrintER model, named SPARE, presented in a separate ASCO (Free ASCO Whitepaper) session, showed even more refined accuracy than standard clinicopathological markers in predicting risk of distant recurrence. The company also announced its plans to demerge StemPrintER and SPARE technology and create a separate company to advance commercialization of the technology.
On April 24.2020 the Company announced that 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 for potential use as a treatment for Coronavirus infection.
On June 19, 2020, the Company announced that the United States Patent and Trademark Office ("USPTO") has granted a patent covering its proprietary platform technology for the oral administration of Foralumab, its proprietary fully human monoclonal antibody, and all other anti-CD3 monoclonal antibodies (mAb).
Three US Patent Applications filed in the reporting period:
IL-6 Antibodies for the treatment of Coronavirus (COVID-19; No. 62/987,837 filed March 10, 2020)
IL-6/IL-6R Antibodies to treat Coronavirus (No. 63/006,612 filed April 7, 2020)
Composition of IL-6/IL-6R antibodies and Dactinomycin and methods of use thereof (No. 63/014,800 filed April 24, 2020)
Highlights post period:
Three US Patents were issued in September 2020:
Patent No. 10,759,858 B2: Use and methods of treatment of Crohn’s disease with Foralumab (Tiziana Press Release August 18, 2020)
Patent No. 10,758,541 B2: Use of Milciclib in Combination with Tyrosine Kinase Inhibitors for Treatment of Hepatocellular Carcinoma and other Cancers (Tiziana Press Release August 21, 2020)
Patent No. 10,759,862 B2: Methods and Use of Anti-IL-6/IL-6 receptor mAbs as Prophylactic and Therapeutic Interventions for Covid-19 and other pulmonary diseases (Tiziana Press Release August 24, 2020)
Two US Patent Applications were filed:
CD-3 Antibodies for the treatment of Coronavirus (No. 63/058,978 filed July 30, 2020)
Composition and methods for augmenting chimeric antigen receptor (CAR) T cell therapies (No. 63/058,783 filed July 30, 2020)
On September 16, 2020 the Company announced its plans for demerging its StemPrintER asset into a separate and independently listed public company, Accustem Sciences Limited. Accustem Sciences will begin the process of seeking CE Mark approval in November of 2020 with anticipated commercialization in Europe in the second quarter of 2021. Subsequently, the Company also intends to seek FDA approval.
For the six months to 30 June 2020 the consolidated Group made a loss of £3.91m (restated six months to 30 June 2019: £3.57m).
The Group ended the period with £7.2m cash as at 30 June 2020 (31 December 2019: £153k).
The Company continues to carefully manage its working capital position and continues the process, as referred to below, to seek to raise further funds through the issue of ADSs through a United States Offering as well as through private placements.
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