Mechlorethamine Hydrochloride

Two Presentations Highlight HyBryte™ Therapy’s Improved Response Rates with Extended Treatment and Increased Light Doses PRINCETON, N.J. , Oct. 7, 2024 /PRNewswire/ -- Soligenix, Inc. (Nasdaq: SNGX) (Soligenix or the Company), a late-stage biopharmaceutical company focused on developing and commercializing products to treat rare diseases where there is an unmet medical need, announced today that two of its lead investigators are presenting findings from recent additional, supportive trials with HyBryte™ (synthetic hypericin) in the treatment of cutaneous T-cell lymphoma (CTCL). The presentations will occur at the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Tumour Group Annual Meeting in Lausanne , Switzerland on October 9-11 , 2024. Dr. Ellen Kim , Director, Penn Cutaneous Lymphoma Program, Vice Chair of Clinical Operations, Dermatology Department, and Professor of Dermatology at the Hospital of the University of Pennsylvania , will present a poster with expanded preliminary results from the investigator-initiated study (RW-HPN-MF-01) she is leading at the University of Pennsylvania . Dr. Brian Poligone , Director of the Rochester Skin Lymphoma Medical Group, will give an oral presentation on recent results from two expanded treatment studies (HPN-CTCL-02 and HPN-CTCL-04) conducted at the Rochester Skin Lymphoma Medical Group. Oral Presentation: Session Title: ORAL PRESENTATIONS – CLINICAL STUDIES 1 . The official conference program can be found here . Oral Presentation Title: Phase 2a Study of Topical 0.25% Hypericin in Mycosis Fungoides: Results and Review of the FLASH Study presented by Brian Poligone , MD, PhD, Director of the Rochester Skin Lymphoma Medical Group on October 9, 2024 at 5:54 pm . Poster Presentation: Topical hypericin ointment photodynamic therapy for early stage mycosis fungoides/CTCL – a Phase 2 real world investigator-initiated study presented on October 9th, 2024 by Ellen Kim , MD, Director, Penn Cutaneous Lymphoma Program, Vice Chair of Clinical Operations, Dermatology Department, and Professor of Dermatology at the Hospital of the University of Pennsylvania . These presentations further elaborate on the Company’s findings in these supportive studies which have demonstrated the utility of longer treatment times (Study RW-HPN-MF-01; investigator-initiated study), the lack of significant systemic exposure to hypericin after topical application (Study HPN-CTCL-02) and its relative efficacy and tolerability compared to Valchlor ® (Study HPN-CTCL-04). About the EORTC CLTG Meeting An annual meeting of the cutaneous lymphoma tumour group (CLTG), a division of the European Organisation for Research and Treatment of Cancer (EORTC), focuses this year on facilitating the convergence of experts, delegates, and sponsors from Europe and around the globe, all convened to deliberate upon the latest advancements in skin lymphoma as well as the common ground between malignant and benign skin inflammation’s research, diagnostics and treatment. The meeting website is available here . About HyBryte™ HyBryte™ (research name SGX301) is a novel, first-in-class, photodynamic therapy utilizing safe, visible light for activation. The active ingredient in HyBryte™ is synthetic hypericin, a potent photosensitizer that is topically applied to skin lesions that is taken up by the malignant T-cells, and then activated by safe, visible light approximately 24 hours later. The use of visible light in the red-yellow spectrum has the advantage of penetrating more deeply into the skin (much more so than ultraviolet light) and therefore potentially treating deeper skin disease and thicker plaques and lesions. This treatment approach avoids the risk of secondary malignancies (including melanoma) inherent with the frequently employed DNA-damaging drugs and other phototherapy that are dependent on ultraviolet exposure. Combined with photoactivation, hypericin has demonstrated significant anti-proliferative effects on activated normal human lymphoid cells and inhibited growth of malignant T-cells isolated from CTCL patients. In a published Phase 2 clinical study in CTCL, patients experienced a statistically significant (p=0.04) improvement with topical hypericin treatment whereas the placebo was ineffective. HyBryte™ has received orphan drug and fast track designations from the U.S. Food and Drug Administration (FDA), as well as orphan designation from the European Medicines Agency (EMA). The published Phase 3 FLASH trial enrolled a total of 169 patients (166 evaluable) with Stage IA, IB or IIA CTCL. The trial consisted of three treatment cycles. Treatments were administered twice weekly for the first 6 weeks and treatment response was determined at the end of the 8th week of each cycle. In the first double-blind treatment cycle (Cycle 1), 116 patients received HyBryte™ treatment (0.25% synthetic hypericin) and 50 received placebo treatment of their index lesions. A total of 16% of the patients receiving HyBryte™ achieved at least a 50% reduction in their lesions (graded using a standard measurement of dermatologic lesions, the CAILS score) compared to only 4% of patients in the placebo group at 8 weeks (p=0.04) during the first treatment cycle (primary endpoint). HyBryte™ treatment in this cycle was safe and well tolerated. In the second open-label treatment cycle (Cycle 2), all patients received HyBryte™ treatment of their index lesions. Evaluation of 155 patients in this cycle (110 receiving 12 weeks of HyBryte™ treatment and 45 receiving 6 weeks of placebo treatment followed by 6 weeks of HyBryte™ treatment), demonstrated that the response rate among the 12-week treatment group was 40% (p<0.0001 vs the placebo treatment rate in Cycle 1). Comparison of the 12-week and 6-week treatment responses also revealed a statistically significant improvement (p<0.0001) between the two timepoints, indicating that continued treatment results in better outcomes. HyBryte™ continued to be safe and well tolerated. Additional analyses also indicated that HyBryte™ is equally effective in treating both plaque (response 42%, p<0.0001 relative to placebo treatment in Cycle 1) and patch (response 37%, p=0.0009 relative to placebo treatment in Cycle 1) lesions of CTCL, a particularly relevant finding given the historical difficulty in treating plaque lesions in particular. The third (optional) treatment cycle (Cycle 3) was focused on safety and all patients could elect to receive HyBryte™ treatment of all their lesions. Of note, 66% of patients elected to continue with this optional compassionate use / safety cycle of the study. Of the subset of patients that received HyBryte™ throughout all 3 cycles of treatment, 49% of them demonstrated a positive treatment response (p<0.0001 vs patients receiving placebo in Cycle 1). Moreover, in a subset of patients evaluated in this cycle, it was demonstrated that HyBryte™ is not systemically available, consistent with the general safety of this topical product observed to date. At the end of Cycle 3, HyBryte™ continued to be well tolerated despite extended and increased use of the product to treat multiple lesions. Overall safety of HyBryte™ is a critical attribute of this treatment and was monitored throughout the three treatment cycles (Cycles 1, 2 and 3) and the 6-month follow-up period. HyBryte’s™ mechanism of action is not associated with DNA damage, making it a safer alternative than currently available therapies, all of which are associated with significant, and sometimes fatal, side effects. Predominantly these include the risk of melanoma and other malignancies, as well as the risk of significant skin damage and premature skin aging. Currently available treatments are only approved in the context of previous treatment failure with other modalities and there is no approved front-line therapy available. Within this landscape, treatment of CTCL is strongly motivated by the safety risk of each product. HyBryte™ potentially represents the safest available efficacious treatment for CTCL. With very limited systemic absorption, a compound that is not mutagenic and a light source that is not carcinogenic, there is no evidence to date of any potential safety issues. Following the first Phase 3 study of HyBryte™ for the treatment of CTCL, the FDA and the EMA indicated that they would require a second successful Phase 3 trial to support marketing approval. With agreement from the EMA on the key design components, the second, confirmatory study, called FLASH2, is expected to be initiated before the end of 2024. This study is a randomized, double-blind, placebo-controlled, multicenter study that will enroll approximately 80 subjects with early-stage CTCL. The FLASH2 study replicates the double-blind, placebo-controlled design used in the first successful Phase 3 FLASH study that consisted of three 6-week treatment cycles (18 weeks total), with the primary efficacy assessment occurring at the end of the initial 6-week double-blind, placebo-controlled treatment cycle (Cycle 1). However, this second study extends the double-blind, placebo-controlled assessment to 18 weeks of continuous treatment (no “between-Cycle” treatment breaks) with the primary endpoint assessment occurring at the end of the 18-week timepoint. In the first Phase 3 study, a treatment response of 49% (p<0.0001 vs patients receiving placebo in Cycle 1) was observed in patients completing 18 weeks (3 cycles) of therapy. In this second study, all important clinical study design components remain the same as in the first FLASH study, including the primary endpoint and key inclusion-exclusion criteria. The extended treatment for a continuous 18 weeks in a single cycle is expected to statistically demonstrate HyBryte’s™ increased effect over a more prolonged, “real world” treatment course. Given the extensive engagement with the CTCL community, the esteemed Medical Advisory Board and the previous trial experience with this disease, accelerated enrollment in support of this study is anticipated, including the potential to enroll previously identified and treated HyBryte™ patients from the FLASH study. Discussions with the FDA on an appropriate study design remain ongoing. While collaborative, the agency has expressed a preference for a longer duration comparative study over a placebo-controlled trial. Given the shorter time to potential commercial revenue and the similar trial design to the first FLASH study afforded by the EMA accepted protocol, this study is being initiated. At the same time, discussions with the FDA will continue on potential modifications to the development path to adequately address their feedback. In addition, the FDA awarded an Orphan Products Development grant to support the evaluation of HyBryte™ for expanded treatment in patients with early-stage CTCL, including in the home use setting. The grant, totaling $2.6 million over 4 years, was awarded to the University of Pennsylvania that was a leading enroller in the Phase 3 FLASH study. Additional supportive studies have demonstrated the utility of longer treatment times (Study RW-HPN-MF-01), the lack of significant systemic exposure to hypericin after topical application (Study HPN-CTCL-02) and its relative efficacy and tolerability compared to Valchlor ® (Study HPN-CTCL-04). About Cutaneous T-Cell Lymphoma (CTCL) CTCL is a class of non-Hodgkin’s lymphoma (NHL), a type of cancer of the white blood cells that are an integral part of the immune system. Unlike most NHLs which generally involve B-cell lymphocytes (involved in producing antibodies), CTCL is caused by an expansion of malignant T-cell lymphocytes (involved in cell-mediated immunity) normally programmed to migrate to the skin. These malignant cells migrate to the skin where they form various lesions, typically beginning as patches and may progress to raised plaques and tumors. Mortality is related to the stage of CTCL, with median survival generally ranging from about 12 years in the early stages to only 2.5 years when the disease has advanced. There is currently no cure for CTCL. Typically, CTCL lesions are treated and regress but usually return either in the same part of the body or in new areas. CTCL constitutes a rare group of NHLs, occurring in about 4% of the more than 1.7 million individuals living with the disease in the United States and Europe (European Union and United Kingdom ). It is estimated, based upon review of historic published studies and reports and an interpolation of data on the incidence of CTCL that it affects approximately 31,000 individuals in the U.S. (based on SEER data, with approximately 3,200 new cases seen annually) and approximately 38,000 individuals in Europe (based on ECIS prevalence estimates, with approximately 3,800 new cases annually). About Soligenix Soligenix is a late-stage biopharmaceutical company focused on developing and commercializing products to treat rare diseases where there is an unmet medical need. Our Specialized BioTherapeutics business segment is developing and moving toward potential commercialization of HyBryte™ (SGX301 or synthetic hypericin sodium) as a novel photodynamic therapy utilizing safe visible light for the treatment of cutaneous T-cell lymphoma (CTCL). With successful completion of the second Phase 3 study, regulatory approvals will be sought to support potential commercialization worldwide. Development programs in this business segment also include expansion of synthetic hypericin (SGX302) into psoriasis, our first-in-class innate defense regulator (IDR) technology, dusquetide (SGX942) for the treatment of inflammatory diseases, including oral mucositis in head and neck cancer, and (SGX945) in Behçet’s Disease. Our Public Health Solutions business segment includes development programs for RiVax ® , our ricin toxin vaccine candidate, as well as our vaccine programs targeting filoviruses (such as Marburg and Ebola) and CiVax™, our vaccine candidate for the prevention of COVID-19 (caused by SARS-CoV-2). The development of our vaccine programs incorporates the use of our proprietary heat stabilization platform technology, known as ThermoVax ® . To date, this business segment has been supported with government grant and contract funding from the National Institute of Allergy and Infectious Diseases (NIAID), the Defense Threat Reduction Agency (DTRA) and the Biomedical Advanced Research and Development Authority (BARDA). For further information regarding Soligenix, Inc., please visit the Company’s website at and follow us on LinkedIn and Twitter at @Soligenix_Inc . This press release may contain forward-looking statements that reflect Soligenix’s current expectations about its future results, performance, prospects and opportunities, including but not limited to, potential market sizes, patient populations, clinical trial enrollment, the expected timing for closing the offering described herein and the intended use of proceeds therefrom. Statements that are not historical facts, such as “anticipates,” “estimates,” “believes,” “hopes,” “intends,” “plans,” “expects,” “goal,” “may,” “suggest,” “will,” “potential,” or similar expressions, are forward-looking statements. These statements are subject to a number of risks, uncertainties and other factors that could cause actual events or results in future periods to differ materially from what is expressed in, or implied by, these statements, and include the expected amount and use of proceeds from the offering and the expected closing date of the offering. Soligenix cannot assure you that it will be able to successfully develop, achieve regulatory approval for or commercialize products based on its technologies, particularly in light of the significant uncertainty inherent in developing therapeutics and vaccines against bioterror threats, conducting preclinical and clinical trials of therapeutics and vaccines, obtaining regulatory approvals and manufacturing therapeutics and vaccines, that product development and commercialization efforts will not be reduced or discontinued due to difficulties or delays in clinical trials or due to lack of progress or positive results from research and development efforts, that it will be able to successfully obtain any further funding to support product development and commercialization efforts, including grants and awards, maintain its existing grants which are subject to performance requirements, enter into any biodefense procurement contracts with the U.S. Government or other countries, that it will be able to compete with larger and better financed competitors in the biotechnology industry, that changes in health care practice, third party reimbursement limitations and Federal and/or state health care reform initiatives will not negatively affect its business, or that the U.S. Congress may not pass any legislation that would provide additional funding for the Project BioShield program. In addition, there can be no assurance as to the timing or success of any of its clinical/preclinical trials. Despite the statistically significant result achieved in the first HyBryte™ (SGX301) Phase 3 clinical trial for the treatment of cutaneous T-cell lymphoma, there can be no assurance that the second HyBryte™ (SGX301) Phase 3 clinical trial will be successful or that a marketing authorization from the FDA or EMA will be granted. Additionally, although the EMA has agreed to the key design components of the second HyBryte™ (SGX301) Phase 3 clinical trial, no assurance can be given that the Company will be able to modify the development path to adequately address the FDA’s concerns or that the FDA will not require a longer duration comparative study. Notwithstanding the result in the first HyBryte™ (SGX301) Phase 3 clinical trial for the treatment of cutaneous T-cell lymphoma and the Phase 2a clinical trial of SGX302 for the treatment of psoriasis, there can be no assurance as to the timing or success of the clinical trials of SGX302 for the treatment of psoriasis. Further, there can be no assurance that RiVax ® will qualify for a biodefense Priority Review Voucher (PRV) or that the prior sales of PRVs will be indicative of any potential sales price for a PRV for RiVax ® . Also, no assurance can be provided that the Company will receive or continue to receive non-dilutive government funding from grants and contracts that have been or may be awarded or for which the Company will apply in the future. These and other risk factors are described from time to time in filings with the Securities and Exchange Commission (the “SEC”), including, but not limited to, Soligenix’s reports on Forms 10-Q and 10-K. Unless required by law, Soligenix assumes no obligation to update or revise any forward-looking statements as a result of new information or future events. View original content to download multimedia: SOURCE SOLIGENIX, INC.

一、前言 凝胶剂（Gel）是指原料药与能形成凝胶的辅料制成的具凝胶特性的稠厚液体或半固体制剂。凝胶剂可分为全身用凝胶剂（Transdermal gel）和局部用凝胶剂（Topical gel）两类。按给药途径不同，可以进一步将局部用凝胶剂分为皮肤用凝胶剂、眼用凝胶剂、阴道用凝胶剂、直肠用凝胶剂等。 表12000年至2024年FDA批准的局部皮肤用凝胶剂产品（NDA） 笔者研通过调取FDA网站上发布的新药申请批准情况，收集了从2000年至2024年这25年时间里FDA批准上市（已撤市的产品不纳入统计）的具有专有名称的局部皮肤用凝胶剂产品。各产品的具体信息见表1和表2。从表中可以看出，从2000年至2024年，FDA共批准上市了26款局部皮肤用凝胶剂NDA上市申请，平均每年批准1款。 表22000年至2024年FDA批准的局部皮肤用凝胶剂产品处方组成 二、产品分析 2.1 凝胶基质选择 局部皮肤用凝胶剂的常用辅料有凝胶基质、pH调节剂、保湿剂、防腐剂、稳定剂、助溶剂、增溶剂及透皮吸收促进剂等。其中，凝胶基质的选择在凝胶制剂的处方开发中尤为重要。 在FDA批准的这26款局部皮肤用凝胶剂中，除Zelsuvmi用到了两种凝胶基质（羟丙基纤维素+羧甲基纤维素钠）外，其余25款均只用了一种凝胶基质。而在这25款产品中，共有16款使用了卡波姆（Carbomer）作为凝胶基质，占到总数的64%。其次是丙烯酰胺/丙烯酰基二甲基牛磺酸钠共聚物（3款，12%）、羟丙基纤维素（2款，8%）、羟乙基纤维素（2款，8%），黄原胶（1款，4%）、葵花油（1款，4%）。 2.1.1 卡波姆 卡波姆是凝胶剂中一种常用凝胶基质，常用比例为0.5%-2.0%。卡波姆是丙烯酸的高分子聚合物，结构中含有52%至68%的羧基基团，当使用中和剂（如氢氧化钠、三乙醇胺、氢氧化钾等）中和后其卷曲的分子会因电荷斥力而张开，从而显著增加其黏稠度，形成凝胶。 卡波姆有多种型号，包括卡波姆940、941、974、980、981等。在16款以卡波姆为凝胶基质的产品中，有6款使用了卡波姆980（占比37.5%），其次是卡波姆940（5款，31.25%）。卡波姆941、卡波姆981和卡波姆974等型号均各有一款产品（如上图所示）。 根据交联剂的不同可将卡波姆分为卡波姆均聚物、卡波姆共聚物和卡波姆互聚物。卡波姆940、941、974、980、981都属于卡波姆均聚物，即通过烯丙基蔗糖或季戊四醇烯丙基醚交联得到的丙烯酸聚合物。卡波姆940、941在合成过程中使用了苯作为聚合溶液，而如今药品辅料应用中对苯的使用限制越来越严格，因此这两种型号现在很少使用。卡波姆980、981在合成中使用环己烷和乙酸乙酯制成的共溶剂体系，适合作为外用凝胶制剂的凝胶基质；卡波姆980和981是卡波姆940和941的对应产品，若已在上市老品种中使用了卡波姆940和卡波姆941，则可以分别替换成卡波姆980和卡波姆981。卡波姆974使用乙酸乙酯作为聚合溶液，完全不含苯，是更为安全的一种卡波姆型号，可用于口服以及粘膜接触的制剂处方中。 2.1.2丙烯酰胺/丙烯酰基二甲基牛磺酸钠共聚物 法国Seppic公司开发的Sepineo P600主要由丙烯酰胺/丙烯酸二甲基牛磺酸钠共聚物（acrylamide/sodium acryloyldimethyl taurate copolymer）组成，这种共聚物被分散在异十六烷（isohexadecane）中，并以聚山梨酯80（polysorbate 80）作为稳定剂。在FDA批准的这26款局部皮肤用凝胶剂中，共有3款（见表2）使用到了到了这种凝胶基质。该凝胶基质具有自凝胶化、增稠和乳化油相的能力，适合用于凝胶和油包水乳胶剂（emulgel）的处方中，常用比例为1%-5%。Sepineo P600以液体形式存在，遇水时由于静电排斥作用，带负电的聚合物会瞬间膨胀，形成一个三维网络结构。在较低浓度下，Sepineo P 600就能提供较高的粘度，在广泛的pH范围内（3-12）都能保持稳定，这使其能够适应不同配方的需求，且与多种溶剂（如乙醇、甘油等）相容性良好。 2.1.3其它 羟丙基纤维素、羟乙基纤维素、羧甲基纤维素钠均为纤维素衍生物，也常用于外用凝胶剂的制备中，具有良好的生物相容性和安全性，由于型号以及生产厂家众多，因此使用方法及用量还应具体参考的产品说明书。 黄原胶（Xanthan gum）能够在溶液中形成不同形式的螺旋结构，并通过分子间的相互作用（如氢键、疏水作用等）形成复杂的网络结构，这种网络结构是黄原胶作为凝胶基质的基础。黄原胶是一种阴离子聚合物，这意味着它在水中电离后带有负电荷。由于电荷相互作用，黄原胶通常与阳离子表面活性剂、聚合物或防腐剂不兼容，因为它们之间的电荷吸引会导致沉淀现象的发生。黄原胶溶液能在含有高达60%的有机溶剂（如乙醇或异丙醇等）时保持稳定，这意味着黄原胶可以在这些溶剂的混合体系中作为凝胶基质使用。 葵花油（sunflower oil）严格意义上来说并不算是一种凝胶基质，目前它仅在Filsuvez这款产品中作为凝胶基质使用。Filsuvez的活性成分桦木三萜是从桦树皮中得到的提取物，由天然存在的三萜类物质组成，该处方中含有10%的桦木三萜和90%的葵花油。这种桦木三萜提取物可以使油类物质凝胶化，从而可以形成半固体、粘弹性的油凝胶（oleogel），并具有触变性。 2.2 适应症分析 FDA批准的这26款局部皮肤用凝胶剂NDA上市申请中，适应症以寻常痤疮居多，占到总数的一半（即50%）。其次是玫瑰痤疮（11.6%）、足藓（7.7%）、皮肤T细胞淋巴瘤患者的皮肤病变（7.7%）以及其它（23%）。关节炎痛、光化性角化病、热烧伤患者皮肤焦痂的去除、结节性硬化症相关的面部血管纤维瘤、大疱性表皮松解症、传染性软疣等适应症均各有1款产品。 2.3 药物类型分析 在这些局部皮肤用凝胶剂中，药物类型以小分子药物居多，包括贝沙罗汀、克林霉素磷酸酯、壬二酸、甲硝唑、氨苯砜（2款）、特比萘芬、阿达帕林、维A酸、双氯芬酸钠，盐酸萘替芬、盐酸氮芥、酒石酸溴莫尼定、盐酸5-氨基酮戊酸、西罗莫司。此外还包括三款具有特殊结构或组成的药物（anacaulase-bcdb、桦木三萜、贝达西美钠），其中anacaulase-bcdb是一种从菠萝植物的茎中提取的蛋白水解酶混合物，富含多种具有生物活性的蛋白质和糖类，通过无菌过滤和冷冻干燥技术制成；桦木三萜是从桦树的树皮中提取的植物药（botanical drug）, 是一种由五环三萜类化合物组成的混合物；贝达西美钠结构复杂，是一种包含多个硅氧烷和硅酸根的共聚物，这些部分通过特定的比例和方式连接在一起，可以释放一氧化氮从而发挥治疗作用。 这些产品中还包含4种固定剂量组合复方药物，即过氧苯甲酰+克林霉素磷酸酯（3款）、克林霉素磷酸酯+维A酸（2款）、阿达帕林+过氧苯甲酰（2款）、阿达帕林+过氧苯甲酰+克林霉素磷酸酯（1款），均用于治疗寻常痤疮。这些组合通过药物间的协同作用可以更好地发挥治作用。 来源：药事纵横 投稿/内容沟通：华籍美人（Ww_150525） 近期精华文章