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Advancements in the Development of Histamine Glutarimide: A Potential Breakthrough in Autoimmune

Introduction Histamine glutarimide, also known as nomacopan, is an innovative therapeutic compound that shows promise in treating various autoimmune and inflammatory diseases. In recent years, significant progress has been made in the research and development of histamine glutarimide, with ongoing clinical trials and studies across multiple indications. This article explores the latest advancements in the development of histamine glutarimide and its potential impact on the treatment of orphan diseases. I. Background and Clinical Progress 1.1 Overview of Akari Therapeutics Akari Therapeutics Plc is a late-stage biopharmaceutical company that focuses on developing therapeutics for rare autoimmune and inflammatory diseases where complement (C5) and/or leukotriene (LTB4) systems play a critical role. Their lead drug candidate, histamine glutarimide (nomacopan), is a C5 complement inhibitor that also inhibits leukotriene B4 (LTB4) activity. 1.2 Ongoing Clinical Trials and Studies Akari Therapeutics has several ongoing clinical trials and studies to evaluate the efficacy of histamine glutarimide in various indications:

  1. Bullous Pemphigoid (BP): A Phase III study of nomacopan in patients with BP is currently open for enrollment in the U.S. and Europe. BP is a severe autoimmune blistering disease of the elderly, and histamine glutarimide has shown potential as a treatment option.

  2. Pediatric Hematopoietic Stem Cell Transplant-Related Thrombotic Microangiopathy (HSCT-TMA): Another Phase III study of nomacopan is underway to evaluate its effectiveness in severe pediatric HSCT-TMA, a disease with no approved treatment options.

  3. Dry Age-Related Macular Degeneration (AMD): Ongoing pharmacokinetic (PK) studies are being conducted to assess the potential of histamine glutarimide as a treatment for dry AMD. The inhibition of both complement (C5) and VEGF by histamine glutarimide may offer a new treatment option for this condition.

  4. Lung Program: Akari Therapeutics is focusing on developing histamine glutarimide for the treatment of exacerbations in lung diseases such as COVID-19 pneumonia and severe asthma. Both complement (C5) and leukotriene (LTB4) are implicated in these conditions, and histamine glutarimide can potentially be delivered directly to the lungs.

  5. Severe Trauma Studies: Under a Cooperative Research and Development Agreement (CRADA) with the U.S. Army Institute of Surgical Research (USAISR), histamine glutarimide is being investigated for its potential in treating severe trauma, including brain injury due to subarachnoid hemorrhage.

1.3 Active Pipeline Development In addition to the ongoing clinical trials and studies, Akari Therapeutics is actively developing its pipeline, which includes a new anti-histamine called votucalis. Votucalis, a biopharmaceutical with a similar structure to histamine glutarimide, is currently in pre-clinical development in dermatology and neurology. II. Corporate Expansion and Team Akari Therapeutics is expanding its senior operational team in the U.S. and the UK. The company recently appointed Dr. Sanjeev Khindri as the new senior medical director, who brings extensive experience in Phase II and Phase III clinical trials. Dr. Khindri is responsible for overseeing the pivotal Phase III programs in BP and HSCT-TMA. III. Phase III Trials 3.1 Phase III Clinical Trial in Patients with Bullous Pemphigoid (BP) BP, a severe autoimmune blistering disease, is the focus of a Phase III clinical trial for histamine glutarimide. The trial aims to evaluate the efficacy and safety of nomacopan in treating BP. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug designation and Fast Track designation for nomacopan in BP. Recruitment for the trial is expected to begin in the third quarter of 2021 in the U.S. and Europe. 3.1.1 Expansion to Other Dermatological Conditions The success of the Phase III trial in BP may pave the way for the expansion of histamine glutarimide into other dermatological conditions, such as hidradenitis suppurativa (HS). HS is a disease that affects a significant portion of the population in developed economies, and both complement C5 activation and LTB4 are believed to play crucial roles in its pathology. 3.2 Phase III Clinical Trial in Patients with Pediatric HSCT-TMA Pediatric HSCT-TMA is a severe disease with a high mortality rate and no approved treatments. Akari Therapeutics has initiated a Phase III study in pediatric HSCT-TMA, and the trial is now open for enrollment in the U.S. and Europe. The FDA has granted Fast Track and Orphan Drug designations for pediatric HSCT-TMA patients. Success in this trial could lead to opportunities for expanding into adult HSCT-TMA and related diseases where complement and LTB4 are implicated. 3.2.1 Potential Expansion into Related Diseases The positive outcomes of the Phase III trial in pediatric HSCT-TMA may provide opportunities for expanding the use of histamine glutarimide in other related diseases, such as atypical hemolytic uremic syndrome, systemic lupus erythematosus, and anti-phospholipid syndrome. These conditions also involve complement and LTB4 in their pathology. 3.3 Long-Term Data in PNH Patients Long-term treatment data for paroxysmal nocturnal hemoglobinuria (PNH) patients in Phase II and Phase III studies demonstrate the efficacy and tolerability of histamine glutarimide. The data shows that a significant percentage of formerly transfusion-dependent patients became transfusion-independent with the use of nomacopan. These positive results in PNH patients contribute to the de-risking of Akari Therapeutics' clinical programs. IV. Other Clinical Programs Akari Therapeutics is actively exploring other clinical programs in large disease areas with high unmet needs. These programs involve alternative formulations of histamine glutarimide, such as topical, nebulized, or long-acting formulations, providing potential opportunities for partnering options. 4.1 Ophthalmology Program In the surface of the eye program, histamine glutarimide delivered topically has shown a positive safety profile and tolerability in a Phase I/II study in atopic keratoconjunctivitis. There is an unmet need for severe surface of the eye inflammatory diseases, and Akari Therapeutics is currently exploring the potential for a Phase II study in this area. Recent publications suggest a potential therapeutic role for long-acting histamine glutarimide in sight-threatening retinal diseases, including dry age-related macular degeneration (AMD), where both complement and VEGF inhibition may be beneficial. 4.1.1 Extended Half-Life and Reduced Injection Frequency PAS-nomacopan, an engineered form of histamine glutarimide, significantly extends the half-life of the drug. This characteristic provides an opportunity to reduce the frequency of patient injections for back-of-the-eye diseases, such as AMD. PK studies are ongoing to evaluate the residence time and injection interval of PAS-nomacopan. 4.2 Lung Program Histamine glutarimide shows potential in treating poorly treated lung inflammatory conditions, including COVID-19 pneumonia and severe asthma. The combined role of complement and LTB4 in these conditions makes histamine glutarimide a promising candidate. The ability to deliver histamine glutarimide directly to the lungs in nebulized or dry powder form further enhances its potential benefits to patients. 4.3 Trauma Under a CRADA with the USAISR, histamine glutarimide is being investigated in models of blast injury and hemorrhagic shock. Akari Therapeutics is also exploring the potential of histamine glutarimide in traumatic brain injury and subarachnoid hemorrhage, where complement and LTB4 are implicated. Trauma is a global health issue, and early drug intervention may help reduce multi-organ dysfunction following trauma. 4.4 Histamine Inhibitor Votucalis Votucalis, a new histamine inhibitor with a similar structure to histamine glutarimide, is being developed in collaboration with two United Kingdom University Centers. The focus is on expanding Akari Therapeutics' dermatology franchise in atopic dermatitis and pain management. Initial data suggests the potential for topical delivery in these indications, and further data is expected later in 2021. V. First Quarter 2021 Financial Results As of March 31, 2021, Akari Therapeutics had approximately $6.7 million in cash. The company has a securities purchase agreement with Aspire Capital Fund, LLC, providing up to $30 million in funding. Research and development expenses for the first quarter of 2021 were approximately $3.5 million, primarily due to additional manufacturing costs for Phase III studies. General and administrative expenses for the same period were approximately $2.0 million. The net loss for the first quarter of 2021 was approximately $5.8 million. Conclusion The advancements in the development of histamine glutarimide offer new hope in the treatment of autoimmune and inflammatory diseases. Ongoing clinical trials and studies, along with the expansion of Akari Therapeutics' team and pipeline, demonstrate a commitment to addressing unmet medical needs. With successful Phase III trials in BP and pediatric HSCT-TMA, histamine glutarimide has the potential to make a significant impact on patients' lives. The exploration of alternative formulations and the development of other clinical programs further expand the possibilities for histamine glutarimide's therapeutic applications. As research and development continue, histamine glutarimide may pave the way for a new era in treating orphan diseases.

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