By John Vandermosten, CFA
NASDAQ:TLSA
READ THE FULL TLSA RESEARCH REPORT
First Half 2021 Results
Tiziana Life Sciences (NASDAQ:TLSA) updated on first half 2021 financial and operational results in a press release and SEC-filed Form 6-K. In the update, Tiziana reviewed recent clinical milestones for its candidates, new appointments, and financial results including plans to restructure as a Bermuda-incorporated company. We highlight major events year-to-date.
Highlights for the first half ended June 30th and to-date include:
➣ Completion of Brazil Phase I foralumab in COVID-19 - January 2021
➣ Appointment of Neil Graham MBBS, MD, MPH as CMO - January 2021
➣ Uplisting to LSE market, AIM delisting - January 2021
➣ Safety results from Phase I foralumab in COVID-19 - February 2021
➣ Thomas Adams, Ph.D. appointed Head of Drug Development - February 2021
➣ Phase II foralumab in COVID-19 planned - March 2021
➣ SPMS patient access granted - March 2021
➣ Strategic initiative with Takanawa Japan K.K. - May 2021
➣ Immunomodulation evidence in Phase I - May 2021
➣ UK-CTAP grant application - June 2021
➣ Kevin Schutz, Pharm.D. appointed VP of Regulatory Affairs - June 2021
➣ Phase II trial with foralumab in severe COVID-19 patients - June 2021
➣ Result of Annual General Meeting - June 2021
➣ Article publication on foralumab in COVID-19 patients - August 2021
➣ Files scheme for corporate reorganization - August 2021
➣ License Agreement to evaluate foralumab with CAR T & conference call - September 2021
Financial Results
Tiziana generated no revenue in first half 2021 and incurred operating expense of (£12.6) million which after adjusting for some minor non-operational items yielded comprehensive loss attributable to equity holders of (£12.6) million or (£0.074)1 per share.
For the first half ending June 30, 2021 and versus the same period ending June 30, 2020:
➣ Research & development expense grew 473% to £4.4 million from £0.76 million, driven by expenses related to advancing TZLS-401 and TZLS-501;
➣ Operating expense grew 159% to £8.2 million from £3.2 million;
➣ Total comprehensive loss attributable to equity holders was (£12.6) million vs. (£3.9) million.
As of June 30, 2021, cash and equivalents totaled £38.6 million. This amount compares to a £48.2 million balance in cash and equivalents held at the end of 2020. Tiziana carries no debt on its balance sheet. Cash used in operations was (£9.4) million versus (£5.1) million for the six months ended 2021 and 2020, respectively.
Anti-CD3 and CAR T: Joining with Precision
On September 2, 2021, Tiziana announced that it had entered into an exclusive licensing agreement with Precision BioSciences (NASDAQ:DTIL) to evaluate Tiziana's foralumab in conjunction with Precision's allogeneic CAR T portfolio. In this arrangement, foralumab, an anti-CD3 fully human monoclonal antibody, is being investigated as a lymphodepletion agent, an agent that purposely destroys the patient's immune system, including T cells, to make way for CAR T cells. Lymphodepletion is performed before receiving adoptive cell therapy (ACT). The aim is to determine whether or not foralumab can improve the outcome of ACT. Lymphodepletion typically comprises short-course chemotherapy to destroy T, B and NK cells. This can have the effect of debulking the tumor, altering the tumor phenotype, modifying the tumor microenvironment, and modulating the cytokine profile.2 Common lymphodepletion agents include fludarabine and cyclophosphamide, typically used in combination. These agents have severe side effects and in the case of fludarabine, are associated with neurotoxicity. Foralumab has the potential to either replace or reduce the chemotherapy regimen, thereby improving the side effect profile for patients.
Foralumab may induce tolerance of allogeneic CAR T, or CAR T cells not from the patient's own body, but from a donor, which may attack the patient (host) in what is known as graft-versus-host-disease (GVHD). Allogeneic CAR T has advantages over autologous approaches in that generation of autologous CAR T cells can be challenging, especially in patients of advanced disease due to the length of time needed to generate the cells.3
The Cluster of Differentiation 3 (CD3) is a receptor on effector T cells. Precision's processing of T cells uses ARCUS gene editing to knock out the TRAC gene and depletes CD3, producing allogeneic CAR T cells that are greater than 99.9% CD3-negative. Lymphodepletion has been shown to augment T cell adoptive immunotherapy through enhanced intratumoral proliferation. Management has noted the potential of its anti-IL-6 receptor monoclonal antibody (TZLS-501) to be included in CAR T therapy to address cytokine storm syndrome, although this was not discussed as part of the deal with Precision.
Under the terms of the agreement, Precision gained exclusive license to use foralumab as a lymphodepletion agent to complement its CAR T portfolio in the treatment of cancers. Precision will be responsible for development, commercialization, and costs associated with its use of foralumab in exchange for upfront payment, certain milestone payments and royalties to Tiziana. Amounts for upfronts, milestones and royalties were not disclosed; however, some of the milestones are payable upon start of a Phase II and Phase III study and upfront payments will be received shortly after execution of the deal.
Tiziana Update Call with Analysts and Investors
On September 8, 2021 following the market close, Tiziana hosted a web conference addressing its recent exclusive license agreement with Precision BioSciences for foralumab lymphodepletion support of allogeneic chimeric antigen receptor T cell (CAR T) therapy in cancer. Precision specializes in allogeneic CAR T therapy which provides advantages over autologous CAR T. More broadly, Precision is a genome editing company offering its ARCUS genome editing program. Its primary clinical programs are in blood cancers including Non-Hodgkin lymphoma (NHL) and B cell acute lymphoblastic leukemia (B-ALL).
One of the key benefits of Precision's CAR T offering is that it can be administered off the shelf. Precision's CAR T cells are specially engineered not to express Cluster of Differentiation 3 (CD3), a receptor that is normally found on effector T cells. Foralumab is an anti-CD3 fully human monoclonal antibody (mAb) and is expected to bind to T cell CD3 receptors, thereby preventing them from clearing the allogeneic CAR T cells. The use of foralumab can replace other conditioning agents such as cyclophosphamide, which is associated with neurotoxicity. Thus, adding foralumab to the therapy is expected to spare Precision's T cells while suppressing the patient's T cells, improving the side effect profile and the efficacy of Precision's T cells.
Tiziana CEO, Dr. Kunwar Shailubhai, began the call with a review of foralumab. Foralumab is the only fully human anti-CD3 mAb. Much clinical development has been performed on anti-CD3 mAb, in particular the earlier generation OKT-3, a fully mouse anti-CD3 antibody developed by Johnson & Johnson and approved by the FDA. However, because it is a mouse antibody, it elicited a strong, negative immune reaction and formation of anti-drug antibodies and stimulated cytokine release syndrome. OKT-3 was withdrawn from the market as a result; however, it presented favorable clinical efficacy. Thus, it was worth investigating the development of a fully human anti-CD3 antibody, especially for renal transplant or graft-versus-host-disease (GVHD). Visilizumab and teplizumab are follow-on humanized anti-CD3 antibodies previously developed by PDL Biopharma. Efficacy for these iterations was satisfactory, but long-term treatment was limited by formation of anti-drug antibodies. To sidestep the immune response to the mouse elements, Tiziana's foralumab was designed as a fully human anti-CD3 mAb, and has not produced anti-drug antibodies in clinical work thus far and has not triggered the immune reactions observed in previous anti-CD3 candidates.
Precision's CAR T cells do not express CD3 and foralumab will not bind to them, providing an appropriate candidate for lymphodepletion. Proper lymphodepletion can extend the durability of the CAR T cell therapy and lower the risk of cancer recurrence. Cyclophosphamide and fludarabine chemotherapies are often used for lymphodepletion conditioning; however, their use has been limited by neurotoxicity. Foralumab could replace other lymphodepleting agents, or even function by itself as a solution. Together, the allogeneic non-CD3-expressing CAR T with foralumab could provide better efficacy in currently unmanaged cancers.
Clinical Trials and Analyst Questions
Dr. Shailubhai updated on Tiziana's clinical progress. In the last year and a half, four trials were completed including Phase I trials for oral and nasal foralumab which laid the foundation for Phase II, as well as oral foralumab in Crohn's and nasal foralumab in multiple sclerosis. Tiziana also completed a preliminary trial in Brazil for COVID-19 and is currently targeting a Phase II for hospitalized COVID-19 patients.
During the Q&A session, topics began with teplizumab's (sponsored by Provention Bio) recent BLA Complete Response Letter (CRL). Teplizumab is a humanized anti-CD3 antibody being developed for prevention of Type 1 diabetes that recently received a CRL from the FDA for its candidate teplizumab. Shailubhai cited deficiencies with CMC and issues related to pharmacokinetic comparability.4 Tiziana management has not seen anti-drug antibody response thus far in clinical evaluation nor has immunotoxicity been observed. Autoimmune disorders could be another area where a fully-humanized anti-CD3 antibody could become useful.
Other topics discussed during the call reviewed the mechanism of lymphodepletion. When allogeneic (foreign) therapeutic CAR T cells are injected into the body, the patient's immune cells may attack the CAR T cells that are intended to treat the patient. Thus, cancer progression is an issue especially if CAR T therapy is terminated prematurely by the patient's own immune system. Lymphodepletion drugs are used to attenuate the patient's immune system, thereby enhancing clinical outcomes. However, neurotoxicity is an issue for lymphodepletion agents. Foralumab binds to CD3, depleting the cells expressing it (patient's non-CAR T cells), allowing the CAR T cells that were engineered and administered to work. Precision's CAR T cells lack CD3 and can be used for long periods of time avoiding systemic immunosuppression and toxicity.
Analyst questions then shifted direction towards Tiziana's clinical progress and expectations for upcoming milestones. Tiziana completed a Phase I study with nasal foralumab in COVID-19 with positive results. Foralumab was given once daily for ten consecutive days. Post-study analysis provided evidence that T regs were upregulated which is a favorable finding in light of a study conducted by Johns Hopkins where researchers found that T regs are depleted in COVID-19. By restoring T reg balance, foralumab may be able to provide clinical benefit for these patients.
Next steps for foralumab in Crohn's Disease include a Phase II multicenter trial in the US and Europe. Management anticipates the Crohn's study starting by end of this year or early next year. The nasal foralumab for secondary progressive multiple sclerosis (SPMS) program is underway and under the individual access program, one patient has completed three months of treatment. Management believes the data generated so far is favorable and nasal administration during the three months of therapy has shown no signs of toxicity. When complete, the data will be reviewed and will guide further efforts in conjunction with FDA guidance. Tiziana is also now considering a similar program in Europe.
Building on preliminary work in Brazil, Tiziana plans to target a total of 80 patients in multiple sites for its next trial of nasal foralumab in hospitalized COVID-19 patients. Tiziana must wait for the Agência Nacional de Vigilância Sanitária (ANVISA) or in English the Brazilian Health Regulatory Agency to grant approval to initiate the trial. Following approval, the trial should be able to begin a few weeks later.
Dr. Shailubhai concluded the call highlighting the recent additions to clinical leadership, Dr. Neil Graham, Dr. Kevin Schutz, as Tiziana continues its venture deeper into the clinic.
Corporate Reorganization
On August 20, Tiziana announced the official commencement of its strategic plan to change its corporate structure by establishing Tiziana Life Sciences as the Bermuda-incorporated, NASDAQ-traded parent of the Tiziana Group, subject to legal and shareholder approval. Existing shareholders, including American Depositary Share (ADS) holders, will have their shares exchanged, two-for-one, for the new parent company and the current company will then become a wholly-owned subsidiary. The new shares are expected to be listed while old shares are delisted from the London Stock Exchange and ADSs are delisted from the NASDAQ. The reorganization is intended to structure Tiziana in a manner more fitting to its US-centric operations, including enhanced trading and coverage characteristics, and reduce cost to shareholders. All outstanding options and warrants pursuant to the 2014 and 2016 Share Option Plans are intended to continue on the same basis but deliver the new shares. Likewise, holders of loan notes are intended to be converted as well.
Intranasal Foralumab in Hospitalized, Severe COVID-19
On June 23, 2021, Tiziana announced that it had entered into a collaboration with FHI Clinical to conduct a Phase II trial for intranasal foralumab in hospitalized, severe COVID-19. The Phase II study will be conducted in Brazil, and is intended as a proof-of-concept effort, as well as to evaluate safety, tolerability and efficacy of the candidate in severe COVID-19 and pulmonary inflammation. In the trial, foralumab will be delivered intranasally through a metered atomizing device. The trial will be randomized, placebo-controlled and double-blind. It will expand on the findings of intranasal foralumab in mild to moderate, non-hospitalized COVID-19 patients announced in February and will examine attenuation of pulmonary pathology characteristic of severe COVID-19 patients. Up to seven sites in Brazil will participate in the study, targeting enrollment of 80 patients with CT-confirmed pulmonary involvement. The study will also evaluate foralumab's effect on resolution of symptoms via chest CT, inflammatory biomarkers, T cell subpopulations, safety and mucosal inflammatory response following 14 days of intranasal administration.
FHI Clinical is a subsidiary of FHI 360, specializing in clinical development of drugs for infectious diseases. FHI Clinical is involved with COVID-19 trials in all phases for vaccines and therapeutics, as well as observational studies to characterize SARS-CoV-2 infection. FHI Clinical has a network of clinical sites across 16 countries and 43 states in the US.
On August 17th, Tiziana informed investors via press release that a peer-reviewed article had been published featuring data from the foralumab trial in mild to moderate COVID-19 patients in Brazil, which was conducted in February. The article was published in Frontiers in Immunology titled "Nasal Administration of Anti-CD3 Monoclonal Antibody (foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study." The study was a collaboration with teams from Harvard Medical School and INTRIALS, a CRO based in São Paulo. The aim of the study was to assess safety of intranasal foralumab and its potential efficacy in treating immune hyperactivity and lung inflammation associated with mild/moderate COVID-19 patients. 39 patients were randomized into three cohorts: control, 100 µg foralumab + dexamethasone, and foralumab monotherapy.
Foralumab was well tolerated and all patients completed the study. No serious adverse events (SAEs) were observed. 11 patients experienced an adverse event including headache (n=4), burning in the nostril (n=1), retrosternal pain (n=2), pustular lesions and itching in cervical area (n=1), dysuria (n=1), tachycardia associated with anxiety (n=1), and insomnia (n=1). On the efficacy front, foralumab treatment resulted in significant reduction in lung inflammation, as observed with CT scans, which revealed improvement in clearance of lung infiltrates versus baseline. The CT data were correlated by reduction in levels of inflammatory markers such as IL-6 levels (69%; p=0.03) and CRP6 (85%; p=0.03) at day 10. Management anticipates initiation of Phase II proof-of-concept study in Brazil to further evaluate
Summary
Tiziana Life updated on first half 2021 financial and operational results. We've highlighted major milestones year to date including a partnership with Precision BioSciences to evaluate foralumab as a lymphodepletion agent with allogeneic CAR T, Tiziana's intent to reorganize as a Bermuda-incorporated company and progress on the intranasal foralumab COVID-19 program. Additional highlights year-to-date included the appointment of multiple key positions in the firm, as well as preliminary work with Takanawa to survey for Japanese partners, as well as grant application submission to UK-CTAP proposing intranasal foralumab as a potential take-home therapy for COVID-19.
As Tiziana updates investors with its financial performance, our focus turns to the two Phase II trials in Crohn's Disease and Multiple Sclerosis. These programs drive the majority of the value in our assessment and address unmet needs in important indications.
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1. As calculated by the company. Our calculation using the reported 150.2 million basic and diluted average number of shares outstanding yielded a loss per share of (£0.084).
2. Lymphodepletion optimization for CAR T-cell therapy (multiplemyelomahub.com)
3. McCreedy BJ, Senyukov VV, Nguyen KT. Off the shelf T cell therapies for hematologic malignancies. Best Pract Res Clin Haematol. 2018 Jun;31(2):166-175. doi: 10.1016/j.beha.2018.03.001. Epub 2018 Mar 28. PMID: 29909917.
4. Provention Bio Receives Complete Response Letter (CRL) to Biologics License Application (BLA) for Teplizumab for the Delay of Clinical Type 1 Diabetes (T1D) in At-risk Individuals - Jul 6, 2021
5. https://doi.org/10.3389/fimmu.2021.709861
6. C-reactive protein
约翰·范德莫斯滕(John Vandermosten),CFA
纳斯达克:TLSA
阅读完整的TLSA研究报告
2021年上半年业绩
Tiziana生命科学公司(纳斯达克市场代码:TLSA)在一份新闻稿和SEC提交的Form 6-K中更新了2021年上半年的财务和运营业绩。在更新中,Tiziana回顾了其候选人最近的临床里程碑、新的任命和财务结果,包括重组为一家百慕大注册公司的计划。我们重点介绍今年到目前为止的重大事件。
截至6月30日的上半年要闻到目前为止,包括:
➣在新冠肺炎完成巴西校友一期工程-2021年1月
➣任命尼尔·格雷厄姆·MBBS,医学博士,公共卫生硕士为首席营销官-2021年1月
➣提升至伦敦证交所市场,AIM退市-2021年1月
新冠肺炎校友第一阶段的➣安全结果-2021年2月
➣Thomas Adams,博士被任命为药物开发负责人--2021年2月
新冠肺炎校友➣第二阶段计划-2021年3月
批准➣自发性骨质疏松症患者进入-2021年3月
➣与高川日本K.K.的战略倡议-2021年5月
➣免疫调节证据在第一阶段-2021年5月
➣UK-CTAP赠款申请-2021年6月
➣凯文·舒茨,药学博士被任命为监管事务副总裁-2021年6月
福拉单抗用于重症新冠肺炎患者的➣II期试验-2021年6月
➣年度股东大会结果-2021年6月
➣关于新冠肺炎患者使用Foralab的文章发表-2021年8月
➣企业重组文件计划-2021年8月
➣许可协议通过CAR T和电话会议评估Alumab-2021年9月
财务业绩
蒂齐亚纳在2021年上半年没有产生收入,发生了1260万英镑的运营费用,扣除一些次要的非运营项目后,股权持有人的综合亏损为1260万英镑或0.074英镑。1每股。
截至2021年6月30日的上半年与截至2020年6月30日的同期比较:
➣的研发费用从76万GB增长到440万GB,增长了473%,这主要是由于与推进TZLS401和TZLS501相关的费用;
➣运营费用从320万GB增长到820万GB,增幅为159%;
➣股东应占的全面亏损总额为(1,260万英镑),而不是(390万英镑)。
截至2021年6月30日,现金及现金等价物共计3860万GB。这一数额与2020年底持有的4820万GB现金和等价物余额形成对比。Tiziana的资产负债表上没有债务。截至2021年和2020年的6个月,运营中使用的现金分别为(GB 940万)和(GB 510万)。
抗CD3抗体与CAR T:与Precision结合
2021年9月2日,Tiziana宣布与Precision BioSciences(纳斯达克股票代码:DTIL)达成独家许可协议,与Precision的同种异体汽车T组合一起评估Tiziana的Alumab。在这一安排中,一种完全抗CD3的人类单克隆抗体foralab正在被作为淋巴清除剂进行研究,这种试剂故意破坏患者的免疫系统,包括T细胞,为CAR T细胞让路。在这种安排中,foralab被作为淋巴清除剂进行研究,这种试剂故意破坏患者的免疫系统,包括T细胞,为CAR T细胞让路。在接受过继细胞治疗(ACT)之前要进行淋巴滤除。目的是确定Foralab是否可以改善ACT的结果。淋巴枯竭通常包括短程化疗以破坏T、B和NK细胞。这可以起到清除肿瘤、改变肿瘤表型、改变肿瘤微环境和调节细胞因子分布的作用。2常见的淋巴清除剂包括氟达拉滨和环磷酰胺,通常联合使用。这些药物有严重的副作用,在氟达拉滨的情况下,与神经毒性有关。Foralab有可能取代或减少化疗方案,从而改善患者的副作用情况。
Foralab可能会诱导同种异体CAR T或CAR T细胞的耐受,这些细胞不是来自患者自己的身体,而是来自捐赠者,这可能会攻击患者(宿主),这就是众所周知的移植物抗宿主病(GVHD)。与自体方法相比,异体CAR T的优势在于,自体CAR T细胞的生成可能具有挑战性,特别是在晚期疾病患者中,因为生成细胞所需的时间很长。3
分化簇3(CD3)是效应性T细胞上的受体。Precision对T细胞的处理使用Arcus基因编辑来敲除TRAC基因并耗尽CD3,产生大于99.9%CD3阴性的同种异体CAR T细胞。淋巴耗竭已被证明通过增强肿瘤内增殖来增强T细胞过继免疫治疗。管理层已经注意到,其抗IL-6受体单克隆抗体(TZLS-501)有可能被纳入CAR T疗法,以应对细胞因子风暴综合征,尽管这并未作为与Precision交易的一部分进行讨论。
根据协议条款,Precision获得了使用foralumab作为淋巴清除剂的独家许可,以补充其治疗癌症的CAR T产品组合。Precision将负责其开发、商业化以及使用ForAlumab的相关成本,以换取向Tiziana支付的预付款、某些里程碑付款和特许权使用费。预付款、里程碑和特许权使用费的金额没有披露;不过,一些里程碑在第二阶段和第三阶段研究开始时支付,并将在交易执行后不久收到预付款。
Tiziana Update与分析师和投资者的电话会议
2021年9月8日,市场收盘后,Tiziana主持了一次网络会议,就其最近与Precision BioSciences就用于治疗癌症的同种异体嵌合抗原受体T细胞(CAR T)疗法的单抗淋巴耗竭支持达成的独家许可协议发表讲话。Precision专门从事同种异体CAR T疗法,这提供了比自体CAR T更广泛的优势。更广泛地说,Precision是一家提供Arcus基因组编辑程序的基因组编辑公司。它的主要临床项目是血癌,包括非霍奇金淋巴瘤(NHL)和B细胞急性淋巴细胞白血病(B-ALL)。
Precision提供的Car T的主要好处之一是,它可以现成管理。Precision的CAR T细胞经过特殊设计,不表达分化簇3(CD3),这是一种通常在效应器T细胞上发现的受体。Foralab是一种抗CD3的全人单克隆抗体(MAb),有望与T细胞CD3受体结合,从而阻止它们清除同种异体CAR T细胞。使用foralab可以替代其他调节剂,如环磷酰胺,这与神经毒性有关。因此,在治疗中加入foralab有望节省Precision的T细胞,同时抑制患者的T细胞,改善副作用和Precision的T细胞的疗效。
Tiziana首席执行官昆瓦尔·沙鲁拜博士首先对foralab进行了回顾。Foralab是唯一一种完全人源性抗CD3单抗。针对抗CD3mAb,特别是早期的OKT-3,已经进行了大量的临床研究,OKT-3是由强生研制并获得美国食品和药物管理局批准的全鼠型抗CD3mAb。但是,由于它是一种小鼠抗体,它会引起强烈的阴性免疫反应,形成抗药物抗体,并刺激细胞因子释放综合征。OKT-3因此退出市场,但表现出良好的临床疗效。因此,开发一种完全人源性的抗CD3抗体,特别是用于肾移植或移植物抗宿主病(GVHD),是值得研究的。Visilizumab和teplizumab是PDL Biophma以前开发的后续人源化抗CD3抗体。这些迭代的疗效令人满意,但长期治疗受到抗药抗体形成的限制。为了避开对小鼠成分的免疫反应,Tiziana的foralab被设计成一种完全人源性的抗CD3单抗,到目前为止还没有在临床工作中产生抗药抗体,也没有引发以前的抗CD3候选抗体中观察到的免疫反应。
Precision的CAR T细胞不表达CD3,单抗也不会与其结合,为淋巴枯竭提供了合适的候选细胞。适当的淋巴净化可以延长CAR T细胞治疗的耐受性,降低癌症复发的风险。环磷酰胺和氟达拉滨化疗常用于淋巴枯竭调节,然而,它们的使用受到神经毒性的限制。Foralab可以替代其他淋巴清除剂,甚至可以单独作为一种解决方案。总之,非CD3表达的同种异体CAR T与foralab联合使用可以在目前未经治疗的癌症中提供更好的疗效。
临床试验和分析师问题
Shailubhai医生更新了Tiziana的临床进展。在过去的一年半里,完成了四项试验,包括为第二阶段奠定基础的口服和鼻用福尔马单抗的第一阶段试验,以及用于克罗恩病的口服福尔马单抗和用于多发性硬化症的鼻福尔马单抗。Tiziana还完成了新冠肺炎在巴西的初步试验,目前目标是住院的新冠肺炎患者的第二阶段试验。
在问答环节,话题从替普利珠单抗(由Provention Bio赞助)最近的BLA完全回复信(CRL)开始。Teplizumab是一种人源化的抗CD3抗体,正在开发用于预防1型糖尿病,最近获得了FDA对其候选teplizumab的CRL。沙鲁拜列举了CMC的不足之处以及与药代动力学可比性相关的问题。4到目前为止,Tiziana治疗在临床评估中没有看到抗药抗体反应,也没有观察到免疫毒性。自身免疫性疾病可能是另一个完全人源化的抗CD3抗体可能有用的领域。
电话会议期间讨论的其他话题回顾了淋巴枯竭的机制。当异基因(外来)治疗性CAR T细胞被注射到体内时,患者的免疫细胞可能会攻击原本用于治疗患者的CAR T细胞。因此,癌症进展是一个问题,特别是如果CAR T治疗被患者自身的免疫系统提前终止的话。淋巴耗竭药物用于减弱患者的免疫系统,从而提高临床疗效。然而,对于淋巴清除剂来说,神经毒性是一个问题。Foralab与CD3结合,耗尽表达CD3的细胞(患者的非CAR T细胞),允许设计和使用的CAR T细胞工作。Precision的CAR T细胞缺乏CD3,可以长期使用,避免全身免疫抑制和毒性。
分析师的问题随后转向了Tiziana的临床进展和对即将到来的里程碑的期望。Tiziana在新冠肺炎完成了鼻用Foralab的I期研究,结果呈阳性。Foralab每日一次,连续服用10天。研究后的分析提供了T基因上调的证据,考虑到约翰·霍普金斯大学进行的一项研究,研究人员发现新冠肺炎中的T基因缺失,这是一个有利的发现。通过恢复T-reg平衡,foralab可能会为这些患者提供临床益处。
下一步用于治疗克罗恩病的单抗包括在美国和欧洲进行的第二阶段多中心试验。管理层预计克罗恩的研究将于今年年底或明年初开始。针对继发性进行性多发性硬化症(SPMS)的鼻孔治疗计划正在进行中,在个人准入计划下,一名患者已经完成了三个月的治疗。管理层认为,到目前为止产生的数据是有利的,在三个月的治疗期间,鼻腔给药没有显示出毒性的迹象。完成后,数据将被审查,并将结合FDA的指导意见指导进一步的工作。Tiziana现在也在考虑在欧洲推出类似的计划。
在巴西前期工作的基础上,Tiziana计划在多个地点针对总共80名患者进行下一次在住院新冠肺炎患者中进行鼻用Foralab的试验。Tiziana必须等待巴西国家卫生监督管理局(ANVISA)或巴西卫生管理署批准启动试验。在获得批准后,审判应该可以在几周后开始。
Shailubhai博士在电话会议结束时强调,随着Tiziana继续深入临床,尼尔·格雷厄姆(Neil Graham)博士和凯文·舒茨(Kevin Schutz)博士最近加入了临床领导层。
企业重组
8月20日,Tiziana宣布正式开始其改变公司结构的战略计划,将Tiziana生命科学公司设立为Tiziana集团在百慕大注册、在纳斯达克上市的母公司,这还有待法律和股东的批准。包括ADS(American Depositary Share)持有者在内的现有股东将以二比一的方式换取新母公司的股份,目前的公司随后将成为全资子公司。新股预计将上市,而旧股将从伦敦证券交易所(London Stock Exchange)退市,美国存托凭证(ADS)将从纳斯达克(NASDAQ)退市。重组的目的是以一种更适合其以美国为中心的业务的方式构建Tiziana,包括增强交易和覆盖特点,并降低股东的成本。根据2014年和2016年购股权计划,所有已发行的期权和认股权证都打算在相同的基础上继续,但会交付新股。同样,借款票据的持有者也打算进行转换。
重症新冠肺炎住院患者鼻腔内应用Foralab
2021年6月23日,Tiziana宣布它已经与FHI临床达成合作,在住院的重症新冠肺炎中进行鼻内Foralab的第二阶段试验。第二阶段研究将在巴西进行,旨在作为一项概念验证努力,以及评估候选药物治疗严重新冠肺炎和肺部炎症的安全性、耐受性和有效性。在试验中,foralab将通过计量雾化装置鼻腔给药。这项试验将是随机、安慰剂对照和双盲的。它将在2月份宣布的轻中度非住院新冠肺炎患者中鼻内应用Foralab的研究结果基础上进行扩展,并将检查重度新冠肺炎患者的肺部病理特征的减弱情况。巴西将有多达7个地点参与这项研究,目标是招募80名CT证实的肺部病变患者。这项研究还将通过胸部CT、炎症生物标志物、T细胞亚群、安全性和鼻腔给药14天后的粘膜炎症反应来评估foralab在缓解症状方面的效果。
FHI临床是FHI 360的子公司,专门从事传染病药物的临床开发。三菱重工临床公司参与了新冠肺炎所有阶段的疫苗和治疗试验,以及表征SARS-CoV-2感染特征的观察性研究。FHI临床拥有遍布美国16个国家和43个州的临床站点网络。
8月17日,Tiziana通过新闻稿通知投资者,已经发表了一篇同行评议的文章,文章内容是2月份在巴西对轻中度新冠肺炎患者进行的foralab试验的数据。这篇文章发表在免疫学前沿一项名为“鼻腔给药抗CD3单克隆抗体(Foralab)减少轻中度新冠肺炎患者fl中的肺和fl中的血液中的炎症生物标志物:一项先导性研究”的研究。这项研究是与哈佛医学院和总部设在圣保罗的CRO InTrials的团队合作进行的。本研究的目的是评价鼻腔内应用Foralab的安全性及其对轻中度新冠肺炎患者免疫功能亢进和肺部炎症的潜在疗效。39例患者被随机分成3组:对照组、100µg阿莫单抗+地塞米松组和阿莫单抗单药治疗组。
Foralab耐受性良好,所有患者都完成了研究。未观察到严重不良反应(SAE)。不良反应11例,头痛4例,鼻孔灼热1例,胸骨后疼痛2例,颈部脓疱、瘙痒1例,排尿困难1例,心动过速伴焦虑1例,失眠1例。在疗效方面,正如CT扫描所观察到的那样,Foralab治疗导致肺部炎症显著减少,这表明肺浸润的清除比基线有所改善。CT数据与炎症标记物,如IL-6水平(69%;p=0.03)和CRP水平降低相关6(85%;p=0.03)在第10天。管理层预计在巴西启动第二阶段概念验证研究,以进一步评估
摘要
Tiziana Life更新了2021年上半年的财务和运营业绩。我们重点介绍了今年到目前为止的主要里程碑事件,包括与精密生物科学公司合作评估Foralab作为同种异体CAR T淋巴去除剂的作用、Tiziana打算重组为百慕大注册公司以及鼻腔Foralab新冠肺炎计划的进展。今年到目前为止的其他亮点包括在公司任命了多个关键职位,以及与高川一起为日本合作伙伴进行调查的初步工作,以及向英国-CTAP提交的拨款申请,提议将foralab作为新冠肺炎的潜在带回家疗法。
随着Tiziana向投资者介绍其最新的财务表现,我们的焦点转向克罗恩病和多发性硬化症的两个第二阶段试验。这些计划推动了我们评估中的大部分价值,并解决了重要适应症中未得到满足的需求。
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1.按公司计算。我们使用报告的150,200,000股基本和稀释后的流通股平均数计算得出的每股亏损为(GB 0.084)。
2.CAR T细胞治疗的淋巴耗竭优化(Multiemyelomahub.com)
3.McCreedy BJ,Senyukov VV,Nguyen KT.针对血液系统恶性肿瘤的现成T细胞疗法。最佳实践者克莱恩·海马托尔(Clin Haematol)。2018年6月;31(2):166-175。Doi:10.1016/j.behavi.2018.03.001。EPub 2018年3月28日。29909917。
4.Proventive Bio收到针对Teplizumab用于延迟高危个人临床1型糖尿病(T1D)的生物制品许可证申请(BLA)的完整回复信(CRL)-2021年7月6日
5.https://doi.org/10.3389/fimmu.2021.709861
6.C反应蛋白