Temozolomide

VANCOUVER, Washington, Dec. 17, 2024 (GLOBE NEWSWIRE) -- Dear Shareholders, As I look back on 2024, during which CytoDyn Inc. (“CytoDyn” or the “Company”) achieved multiple crucial milestones, and look forward to 2025 and the exciting developments that lie ahead, I remain truly grateful for your continued support. As described in detail below, we made important progress over the last year and I firmly believe the Company is poised for even more success in the year to come. I am pleased to confirm that the Company has sufficient cash and drug supplies on hand to complete its clinical priorities in 2025. We also continue to make progress on the development of a long-acting formulation of leronlimab that should provide greater patient convenience and help secure additional patent protection for the Company. Since my last update, we have also welcomed several new consultants to the Company, including three key members of our development team. In October, Dr. Melissa Palmer joined as Lead Consultant in Hepatology, leveraging her expertise to help guide the development of leronlimab in the treatment of MASH and liver fibrosis. We also welcomed Dr. Max Lataillade as Senior Vice President and Head of Clinical Development, capitalizing on his significant pharmaceutical experience and connections to help oversee the Company’s global research and development strategy, as well as to support our programs in inflammation and HIV. In November, Dr. Richard Pestell joined as Lead Consultant in Oncology to support our programs in colorectal cancer (CRC), triple-negative breast cancer (TNBC) and glioblastoma (GBM). The addition of this team of seasoned experts and top-tier consultants should enable CytoDyn to capitalize on our positive momentum, push our clinical development pipeline forward and make 2025 a pivotal year for the Company. I believe our current strategy will result in significant value return to the Company and its shareholders and should give us the opportunity to do so on an abbreviated timeline. We are on good terms with the FDA, we have the funds required to pursue our key development objectives and we have the requisite expertise and associations to execute on our vision. Entering 2025, the Company is in control of its own destiny. Shareholders are the lifeblood of the Company, and we remain committed to acting in your best interests. We will continue to take one thoughtful step at a time to hit our milestones and, in turn, drive value for our shareholders. It is my pleasure to provide a detailed update on some exciting new developments with this letter. My dedication to CytoDyn continues to be grounded in my core belief that leronlimab has the potential to be a life-changing therapeutic. I remain fully committed to the mission of bringing value to our shareholders and to completing studies that will unequivocally demonstrate the impact of leronlimab in the clinic. Thank you again for your patience, support and trust. Best wishes to all for this holiday season. As we enter 2025, I am truly excited about the possibilities that lie just ahead. With Gratitude, Jacob Lalezari, MDCEO Oncology – December 2024 Update The Company will be prioritizing oncology in 2025, as we believe this indication holds the potential for the highest value return to the Company in the form of a significant partnership and/or drug approval. As recently announced, CytoDyn has received FDA clearance to initiate a Phase II study of leronlimab in patients with relapsed/refractory micro-satellite stable colorectal cancer (CRC). As noted in our prior release, we recently completed the kickoff meeting with Syneos Health, the CRO for the study, and enrollment efforts are set to begin in January. I am also delighted to announce that Dr. Ben Weinberg from Georgetown University and the MedStar Health Alliance has agreed to be the lead Principal Investigator for the CRC study. As requested by the FDA, the first five patients enrolled in this study will receive 350 mg of leronlimab SQ once/week in combination with TAS-102 and Bevacizumab. After a preliminary safety review, subsequent patients will then be randomized to 350 or 700 mg of weekly leronlimab with the same background regimen. The Data and Safety Monitoring Board (DSMB) will perform a second safety review after the first 20 patients have completed at least 1 cycle of therapy. The DSMB can then recommend restricting further enrollment to a single dose level, should they identify a signal of superior activity in either one of the treatment arms. For additional information, the CRC study protocol is posted on the NCI Clinical Trials website, and can be viewed here: (https://clinicaltrials.gov/study/NCT06699836?cond=colorectal%20cancer&intr=leronlimab&rank=1). CytoDyn also remains focused on the possible role for leronlimab in TNBC. As previously announced, we are launching two preclinical studies in TNBC that will seek to further clarify the mechanism of action of leronlimab in oncology and identify potential treatment synergies to optimize the design of a follow-up clinical study. Lastly, the Company remains focused on the possible use of leronlimab in the treatment of GBM. Preliminary results from a preclinical study performed at the Albert Einstein College of Medicine do not appear to show a difference in outcome with leronlimab compared to the control arm. The Company has committed to repeating the study based on unpublished observations by Dr. Pestell’s lab and will now employ a treatment sequence involving temozolomide and leronlimab. This follow-up study will start immediately and should help clarify the potential therapeutic benefit of leronlimab in the treatment of GBM. CytoDyn is also currently in discussions with a key opinion leader in neuro-oncology about the possibility of initiating a pilot study in patients with GBM based on Dr. Pestell’s unpublished work and the outcome of the follow-up preclinical study. Inflammation – December 2024 Update We continue to believe that treatment of inflammation with leronlimab remains a viable and important development pathway, and we are moving forward in three indications associated with chronic inflammation on a cost-efficient basis. First, CytoDyn previously announced exciting results from an initial preclinical study with SMC Laboratories evaluating leronlimab in the treatment of a mouse model of MASH. The results from this preliminary study demonstrated that high dose leronlimab was significantly better at reversing liver fibrosis compared to an IgG 4 isotype control and demonstrated a trend toward better fibrosis reversal compared to Resmetirom. The final results from that study have now also demonstrated that leronlimab (both high and low dose) was significantly better than Resmetirom at reversal of fat deposition (steatosis) in the liver. These exciting findings have been submitted as a late breaker abstract to the MASH TAG conference and, if accepted, will be presented at the meeting in January. In September, CytoDyn launched two follow up studies to confirm and expand on these preliminary results. The first follow-up study seeks to confirm the observations of the original study with larger cohorts of mice (12 versus the original 8/group) and will compare leronlimab with a GLP-1 agonist (Semaglutide) in addition to confirming the comparisons with Resmetirom. The second follow-up study involves the administration of CCL4, a drug that directly causes liver fibrosis in mice. This study will clarify if the observed reversal of liver fibrosis is restricted to the MASH/fat deposition pathway or might occur independently of the etiology of fibrosis (e.g. alcohol, viral hepatitis, etc.). The results from both follow-up studies will become available in January. As a side note, we have been contacted by colleagues at a major academic institution who indicated that, if the liver fibrosis reversal results are confirmed in the follow-up studies, they would be interested in funding a pilot study of leronlimab in the treatment of patients with pulmonary fibrosis at their own center. Second, in September, CytoDyn applied to the NIH/RECOVER-TLC group for the potential inclusion of leronlimab in their next round of Long Covid treatment studies. We expect to learn the group’s decision in the next several months. In the meantime, we have paused the launch of our previously announced pilot study in patients with myalgic encephalitis/chronic fatigue syndrome (ME/CFS) since the two conditions (Long Covid and ME/CFS) essentially overlap. If the RECOVER-TLC team decides to move forward with leronlimab, we will formally suspend the ME/CFS study. If the RECOVER-TLC team declines to include leronlimab, we will resume the pursuit of a pilot study in patients with ME/CFS, for which we already have a draft protocol synopsis and lead investigator identified. Third, we have finalized the protocol for a pilot study of leronlimab in the treatment of patients with mild to moderate Alzheimer’s disease. That study will take place at Cornell Medical Center in New York and will evaluate an objective neuroradiology primary endpoint that will provide a clear measure of leronlimab’s potential role in treating Alzheimer’s disease. I am pleased to announce the study is now fully funded by an outside foundation, and the protocol will soon be submitted to both the FDA and the Cornell IRB. Other – December 2024 Update As previously announced, CytoDyn is partnering with the American Foundation for AIDS Research (amfAR) to sponsor an HIV cure study called LATCH (Leronlimab in Allogenic stem cell Transplant to Cure HIV). The study will employ leronlimab to protect CCR5+ donor immune cells from HIV infection, while aiming for a cure in the setting of bone marrow transplant to an HIV+ recipient. We are confident in the likelihood of success of the LATCH program, given the announcement over the summer by investigators in Germany of a successful cure using donor cells from an individual who was heterozygous for the CCR5-delta 32 mutation. Indeed, those same investigators have asked CytoDyn if they too can run the LATCH study at their research center in Berlin. The LATCH protocol is scheduled to complete final updates at the end of December, and we look forward to the launch of this program in 2025. CytoDyn has also continued to prioritize the publication of our existing clinical data. The CD10 manuscript describing the trial of patients with mild to moderate COVID-19 was recently published in Clinical Therapeutics. The manuscript for the CD02 Phase 3 study in patients with multi-drug-resistant HIV has also just been accepted for publication by the Journal of Acquired Immune Deficiency Syndromes (JAIDS). The Company is pursuing publication of four additional manuscripts, including the CD12 manuscript (severe and critical COVID-19), twin papers on the TNBC study results, and the MASH manuscript. Those submissions were delayed by various obstacles but are now moving forward. In addition, CytoDyn is preparing a draft manuscript summarizing the integrated safety data from the almost 1,600 patients who have now been treated with leronlimab. The final draft of that manuscript will go out for author review in the coming weeks and will be submitted for peer review shortly thereafter. Note Regarding Forward-Looking Statements This letter contains forward-looking statements relating to, among other things, clinical drug development and research strategy. The reader is cautioned not to rely on these statements, which are based on current expectations of future events. For important information about these statements and our Company, including the risks, uncertainties and other factors that could cause actual results to vary materially from the assumptions, expectations and projections expressed in any forward-looking statements, the reader should review our Annual Report on Form 10-K for the fiscal year ended May 31, 2024, including the section captioned “Forward-Looking Statements,” and in Part I, Item 1A, as well as subsequent reports filed with the Securities and Exchange Commission. CytoDyn Inc. does not undertake to update any forward-looking statements as a result of new information or future events or developments other than as required by law. Media Contacts CytoDynRiyaz LalaniGagnier CommunicationsCytoDyn@gagnierfc.com

热休克蛋白90（Heat Shock Proteins 90，HSP90）是一类ATP依赖的分子伴侣，负责调控细胞中数百种底物蛋白的成熟与翻译后修饰，在细胞蛋白质稳态中发挥重要作用。 细胞分裂周期37（Cell Division Cycle 37，CDC37）是HSP90重要的共伴侣蛋白，参与调控HSP90由开放状态到关闭状态的构象变化循环，主要负责特异性识别与招募蛋白激酶从而促进其正确折叠与成熟。 丝/苏氨酸蛋白磷酸酶5（Protein Phosphatase 5，PP5）作为HSP90的另一种共伴侣蛋白，同时具有磷酸酶功能，能够被HSP90招募并形成HSP90-CDC37-PP5分子伴侣复合物，协助HSP90完成构象变化并调控蛋白激酶的翻译后修饰。致癌蛋白激酶的异常表达和过度磷酸化常见于多种恶性肿瘤。 因此，HSP90-CDC37-PP5分子伴侣体系被认为是治疗疾病的药物靶标。利用分子伴侣系统的构象变化及动态蛋白互作识别机制，靶向HSP90-CDC37-PP5分子伴侣复合物，有望从折叠成熟与翻译后修饰两方面实现致癌蛋白激酶的特异性调控。 近年来，中国药科大学王磊/尤启冬团队围绕靶向分子伴侣系统复杂蛋白相互作用的小分子药物设计开展了大量研究工作，基于伴侣系统与底物识别机制提出了多种分子设计新策略并取得了多项重要研究成果。他们开发了全球首个靶向HSP90-CDC37相互作用的小分子先导物、首个靶向CDC37的小分子化合物、首个通过招募PP5进而加速底物蛋白去磷酸化的小分子调控剂等。 王磊/尤启冬团队取得这些突破成果的背后有怎样的思考？与传统小分子药物相比，靶向分子伴侣的药物有何优势？靶向HSP90-CDC37-PP5分子伴侣体系在癌症及其他疾病领域有怎样的应用前景？近日，医药魔方Pro有幸就这些话题采访到了中国药科大学药学院研究员王磊博士。 王磊，中国药科大学药学院研究员，博士生导师。研究方向聚焦于靶向分子伴侣系统的小分子药物研究，设计并发现多个首创性小分子先导物。围绕HSP90-CDC37-PP5-Kinases分子伴侣系统，从靶标的成药性研究和创新的分子设计策略两个方向开展研究工作，前期成果在J. Am. Chem. Soc., Angew. Chem. Int. Ed., Sci.Adv, J.Med.Chem（×9），Med. Res. Rev. APSB等学术期刊发表论文40余篇。入选中国科协青年人才托举工程、获江苏省优青、江苏省科创U35创新奖。作为主要贡献人参与研发的小分子抗肿瘤药物NTQ1062已进入临床Ⅱ期研究。担任南京药学会药物化学专委会委员、《药学学报》中英双刊青年编委、《中国药科大学学报》、《中国药学杂志》等期刊的青年编委。 医药魔方Pro：您的团队是怎样一步一步地开展HSP90-CDC37-PP5分子伴侣复合物体系研究的？ 王磊：分子伴侣系统在维持蛋白稳态中扮演着重要角色，负责调控众多底物蛋白的成熟折叠与翻译后修饰。其中HSP90-CDC37-PP5-Kinase互作体系调节蛋白激酶成熟，并且在肿瘤发展进程中发挥重要作用。如何实现该复杂体系的精细化调控以获得适宜的治疗窗口是困扰学界已久的药物设计难题。我们团队围绕靶标发现和创新的分子设计策略两个方向，展开了分子伴侣复合物体系研究。 靶标发现层面，经典的HSP90 ATP靶向策略会造成底物蛋白无选择性降解进而导致安全性问题，为了解决这一难题，我们利用CDC37特异性识别激酶类底物的特性，提出靶向HSP90-CDC37蛋白互作体系，获得了全球首个靶向HSP90-CDC37相互作用的小分子先导物DDO-5936（first-in-class）。 化合物DDO-5936通过高效干扰HSP90-CDC37蛋白互作，特异性抑制下游关键癌性蛋白激酶（如CDK4/6和AKT等），但不抑制HSP90非激酶类客户蛋白。机制研究表明，DDO-5936对HSP90无ATPase抑制作用，有效避免了经典的ATPase类抑制剂的热休克毒副作用，实现了对分子伴侣系统激酶类客户蛋白的特异性调控，成为国际上本领域首个小分子调控剂[1]。 靶向HSP90-CDC37相互作用的DDO-5936的开发[1] 此外，先前的研究表明，CDC37在许多癌症组织中的表达水平显著高于正常组织，这提供了潜在的治疗窗口；同时，CDC37蛋白表面缺乏经典药物口袋，小分子设计困难，暂无机制明确的抑制剂报道。 为明确直接靶向抑制CDC37的潜在效应，我们开展了CDC37抑制剂的研究，并发现了首个靶向CDC37的小分子化合物DDO-6079，该化合物以变构作用机理，同时实现了对HSP90-CDC37和CDC37-CDK4/6复杂蛋白互作的协同抑制。此外，研究阐明了DDO-6079逆转Palbociclib耐药的机制，结果表明，DDO-6079通过抑制CDK4/6的成熟和降低CDK6蛋白的热稳定性，进而恢复CDK4/6抑制剂在耐药细胞中的敏感性[2]。 靶向CDC37的DDO-6079的开发[2] 除蛋白折叠成熟外，翻译后修饰也是影响蛋白功能及活性的关键生物学过程。在分子伴侣复合物中，PP5同时具有共伴侣蛋白和磷酸酶属性，负责调节底物蛋白的磷酸化状态，进而影响底物蛋白的活性、稳定性等重要特性。然而，目前对调控PP5的继发生物学效应研究尚不明确，致使靶向PP5药物应用受限。 为此，我们团队同时进行PP5抑制剂和激动剂开发。其中PP5抑制剂28a可诱导细胞周期阻滞和逆转TMZ耐药性[3]；PP5激动剂DDO-3733解决了因PP5自抑制状态产生的激动剂设计难题，还发现其与HSP90抑制剂联合使用在降低热休克蛋白毒性方面的潜在价值[4]。两项研究探索了PP5调控效应及应用，为PP5的研究和应用提供了新的工具和思路，是对HSP90-CDC37-PP5分子伴侣复合物体系功能和调控策略研究的重要补充。 PP5抑制剂28a的开发[3] PP5激动剂DDO-3733的开发[4] 在以上新型靶标发现工作中，我们深入研究分子伴侣复合物体系中各蛋白及蛋白间的功能及作用机制，为基于分子伴侣系统发展新的分子设计策略提供了基础。体系中的HSP90、PP5等蛋白具备重要的功能特性和众多的底物蛋白，在突破“不可成药靶点”的多特异性分子设计策略中，是理想的生物效应器选择。 我们以共伴侣蛋白PP5的磷酸酶功能为基础，通过将PP5和底物蛋白ASK1的小分子配体通过化学连接链相连，发现了PhoRCs磷酸酶募集嵌合体双功能小分子DDO-3711，可特异性将p-ASK1T838去磷酸化。DDO-3711是首个通过招募PP5进而加速底物蛋白去磷酸化的小分子调控剂，解决了胃癌细胞中因ASK1的过度磷酸化而导致的细胞异常增殖问题[5]。该研究充分利用了共伴侣蛋白PP5的磷酸酶功能，巧妙地设计小分子调控剂将其与过度磷酸化的底物蛋白相连，在不影响底物蛋白表达的同时，实现了对其磷酸化过程的精准调控，为小分子调控蛋白的翻译后修饰过程提供了重要研究思路与范例。 PhoRCs磷酸酶募集嵌合体双功能小分子DDO-3711的开发[5] 医药魔方Pro：与单独靶向HSP90或HSP90-CDC37相比，靶向HSP90-CDC37-PP5分子伴侣复合物体系有何优势？ 王磊：相较于单独靶向HSP90，靶向HSP90-CDC37-PP5分子伴侣复合物体系最大的优势在于，可以实现对底物蛋白的差异化识别和特异性调控。 HSP90具有800余种底物蛋白，包括蛋白激酶、转录因子和激素受体等。经典的HSP90抑制策略是，靶向其靶向N端ATP结合位点。然而，单一的ATPase抑制会完全阻断HSP90的功能，无选择性地降解大量底物蛋白，造成不可逆的热休克反应与机理毒性。而HSP90-CDC37-PP5分子伴侣复合物体系通过差异化的蛋白-蛋白相互作用识别激酶底物蛋白，特异性调控蛋白激酶的成熟与磷酸化修饰。 医药魔方Pro：您认为HSP90-CDC37-PP5分子伴侣体系在未来的癌症或其他治疗领域中会有怎样的应用前景？ 王磊：分子伴侣系统在维持生物体内环境稳定中具体关键作用，研究发现，在癌症、炎症、感染性疾病以及神经退行性病变等多种病理过程中，均存在分子伴侣系统的功能异常或失调现象。因此，靶向分子伴侣系统开展小分子药物设计极具前景。 在癌症治疗领域，靶向HSP90-CDC37-PP5分子伴侣体系的药物一方面可基于现有机制明确的先导化合物，持续进行活性和成药性优化，提升单药治疗效力；另一方面，依托其对激酶上游调控机制优势，可探索其在突破当前治疗致癌激酶药物耐药上的应用。 而对于非癌症治疗领域，已有较多临床前阶段的研究，尤其是在真菌感染和神经退行性疾病，已有机制明确和初具效应的先导分子报道，但还存在着选择性和毒性等亟待解决的问题。如何获得适宜的治疗窗口将是靶向分子伴侣的药物在非癌症适应症研究中的关键所在。 医药魔方Pro：与传统小分子药物相比，靶向分子伴侣的药物有何优势？ 王磊：靶向分子伴侣的药物具备疾病/组织特异性的靶向特性和蛋白多层次调控的机制优势。疾病/组织特异性源于分子伴侣蛋白的表达与分布特点，研究表明，HSP90和CDC37在肿瘤细胞中特异性高表达，这有助靶向药物在肿瘤组织选择性蓄积，提高疾病和组织特异性。 此外，分子伴侣系统对蛋白的调控覆盖折叠、成熟、释放和翻译后修饰等众多生物学过程，这种独特的机制不仅使靶向分子伴侣的药物在药效上具备潜在优势，同时还可有效遏制或逆转传统小分子药物因调控模式单一而诱发的耐药。 医药魔方Pro：目前针对分子伴侣的药物开发整体进展如何？您的团队在此领域的药物开发方面有何进展？ 王磊：靶向分子伴侣的药物大致可分为四类：HSP90 ATPase抑制剂、HSP90亚型选择性抑制剂、HSP90-共伴侣蛋白蛋白互作抑制剂和基于分子伴侣的多特异性分子。 HSP90 ATPase抑制剂的开发起源于1997年格尔德霉素（Geldanamycin）的发现，截止目前，已有30余种抑制剂进入临床研究阶段。然而，此类抑制剂会反馈性诱导HSP70、HSP40、HSF1等热休克蛋白及其转录因子的高表达，造成不可逆的热休克反应和机理毒性，缺乏有效的治疗窗口，所以尚未有安全性和疗效俱佳的小分子药物获FDA批准。 HSP90亚型选择性抑制是减少HSP90 泛抑制剂不良反应的替代策略。HSP90各亚型的小分子抑制剂均有报道，但是单一亚型的抑制作用效果不能满足临床需求，且当下对于亚型生物学功能的探索不足以支撑成药性研究，以及临床适应症研究。 随着对分子伴侣系统整体研究的深入，科学家发现干扰伴侣蛋白间的蛋白互作过程是实现其功能精细化调控的有效手段。从2008年开始，靶向HSP90-共伴侣蛋白互作的小分子药物在CDC37、HOP、AHA1和p23等共伴侣蛋白方面取得了突破进展。我们团队深耕HSP90-CDC37-PP5复杂蛋白互作体系调控研究，报导了全球首个HSP90-CDC37互作小分子抑制剂DDO-5936，以及首个CDC37小分子抑制剂DDO-6079；同时，我们深入探索了PP5的调控效应，分别报导了PP5抑制剂28a和PP5激动剂DDO-3733。这些成果为调控HSP90-CDC37-PP5分子伴侣复合物的药物研究和应用提供了新的工具和思路。 最后，在基于分子伴侣的多特异性分子研究上，目前推进最快的来自珃诺生物，其分子伴侣介导的BRD4蛋白降解剂RNK05047已进入临床Ⅰ/Ⅱ期研究。该药物利用分子伴侣系统识别错误折叠的蛋白并加速其经UPS降解的生物学特性，通过双功能分子设计诱导拉近伴侣复合物和靶蛋白，实现分子伴侣介导的降解。我们团队在分子伴侣介导的靶向去磷酸化调节研究中也取得了突破，利用了共伴侣蛋白PP5的磷酸酶功能，巧妙地设计小分子调控剂DDO-3711将其与过度磷酸化的底物蛋白相连，在不影响底物蛋白表达的同时，实现了对其磷酸化过程的精准调控，为小分子调控蛋白的翻译后修饰过程提供了重要研究思路与范例。  -上下滑动查看参考资料 -  [1]Lei Wang et al. Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer. Science Advance（2019） [2]Lixiao Zhang et al. Allosteric CDC37 inhibitor disrupts chaperone complex to block CDK4/6 maturation. Angew. Chem（2024） [3]Zekun Li et al.Design and Synthesis of 7 Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic Acid Derivatives as PP5 Inhibitors To Reverse Temozolomide Resistance in Glioblastoma Multiforme. J. Med. Chem（2024） [4]Qiuyue Zhang et al. Allosteric Activation of Protein Phosphatase 5 with Small Molecules. J. Med. Chem（2024） [5]Qiuyue Zhang et al. Protein phosphatase 5-recruiting chimeras for accelerating apoptosis signal-regulated kinase 1 dephosphorylation with antiproliferative activity. J Am Chem Soc（2022） Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。 免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。