An In-Depth Analysis of Xagrotin: An Investigational Herbal Medicine for COVID-19

1. Executive Summary

Xagrotin is an investigational herbal medicine, developed by the originator organization Biomad AS, currently under clinical evaluation primarily for the treatment of COVID-19.[1] Composed of a combination of six distinct plants, Xagrotin has been studied for its potential therapeutic effects against SARS-CoV-2, the virus responsible for COVID-19.[2] Preclinical research, encompassing in-silico modeling, in-vitro cell studies, and in-vivo animal testing, has suggested a potential mechanism of action involving the binding of its constituent ligands to the spike receptor-binding domain and main protease of the coronavirus, thereby potentially interfering with viral entry and replication.[2] These preliminary studies also indicated no significant toxicity in normal human cell lines (HFF-2) and in animal models, paving the way for human trials.[2]

The clinical development program for Xagrotin has included a completed Phase 1/2 trial (NCT05017493) and an ongoing/pending Phase 3 trial (NCT05222425), both focused on COVID-19.[1] The Phase 1/2 trial, which investigated Xagrotin in patients with early-stage COVID-19, was notably stopped early due to observed significant therapeutic benefits.[5] Published results from this trial indicated substantial reductions in mortality rates, disease duration, and the rate and duration of hospitalization in patients receiving Xagrotin compared to a control group.[2] The subsequent Phase 3 trial aims to further evaluate Xagrotin extract (2 grams administered three times daily) in a larger population of non-severe SARS-CoV-2 outpatients, with a planned enrollment of 3000 participants across treatment, placebo (green tea), and standard of care arms.[4]

The development of Xagrotin appears to have been significantly influenced by the COVID-19 pandemic, with clinical investigations commencing relatively early in the global health crisis and showing a strong regional focus, particularly in Iraq.[1] The herbal nature of Xagrotin presents both potential appeal, possibly due to perceptions of natural origin, and challenges typical for botanical medicines, including the need for rigorous standardization, comprehensive chemical characterization, and robust clinical data to meet international regulatory standards. While its primary investigational target is COVID-19, Xagrotin is also categorized under the broader therapeutic areas of infectious and respiratory diseases, suggesting a wider potential scope of application.[1] Currently, Xagrotin remains an investigational agent, with its regulatory status contingent upon the outcomes of the ongoing Phase 3 clinical trial.

2. Introduction to Xagrotin

2.1. Overview of Xagrotin as an Investigational Herbal Medicine

Xagrotin is a therapeutic agent currently under clinical investigation, classified as an "Herbal medicine".[1] This designation is crucial as it distinguishes Xagrotin from synthetically derived pharmaceutical compounds and implies a composition based on plant-derived materials. The primary focus of research and development efforts for Xagrotin, as indicated by available data, is its potential efficacy and safety in the treatment of COVID-19, the disease caused by the SARS-CoV-2 virus.[2]

The development pathway of Xagrotin reflects an approach that integrates traditional botanical sources with modern clinical evaluation methodologies. As an herbal medicine, its characterization involves not only assessing clinical outcomes but also understanding its complex phytochemical composition and ensuring consistency in its formulation. The progression of Xagrotin through preclinical studies to Phase 3 clinical trials underscores a systematic effort to evaluate its therapeutic utility within the established framework for drug development, albeit with considerations unique to plant-based medicines.

2.2. Origin and Development Context

The impetus for Xagrotin's development appears to be strongly linked to the global COVID-19 pandemic. The initiation of its first significant clinical trial, NCT05017493, in July 2020, aligns with the period of intense global effort to find effective treatments for the novel coronavirus.[5] This timeline suggests a responsive development program aimed at addressing an urgent and unmet medical need. The pandemic context often accelerated research timelines and encouraged the exploration of diverse therapeutic modalities, including herbal remedies, particularly in regions with established traditional medicine practices. The report that Xagrotin was "synthesized and made available continuedly to the indigenous people" during the onset of the pandemic further highlights a rapid, possibly localized, response that may have preceded or run parallel to formal clinical trial structures.[5] Such early availability, while potentially addressing immediate needs, necessitates careful documentation and integration with formal research findings to fully understand the drug's developmental origins and early use patterns.

While COVID-19 is the most prominent investigational target for Xagrotin, pharmaceutical intelligence databases also categorize it under the broader therapeutic areas of "Infectious Diseases" and "Respiratory Diseases".[1] This wider classification, supported by conclusions from research suggesting Xagrotin's potential utility in "viral and pulmonary infections" beyond COVID-19, indicates a strategic vision for the drug that may extend past the immediate pandemic.[2] Success in treating COVID-19, a severe acute respiratory infection, could provide a strong rationale for exploring its efficacy in other related conditions. The proposed multi-target antiviral mechanism, if validated, might also hold promise against other viral pathogens, particularly those affecting the respiratory system, potentially offering a longer-term therapeutic role for Xagrotin.

3. Developer and Manufacturer Profile

3.1. Originator Organization: Biomad AS

Biomad AS is consistently identified in pharmaceutical intelligence sources as the "Originator Organization" for Xagrotin.[1] This entity is also listed as the "Active Organization" concerning Xagrotin's ongoing development and is the primary sponsor for its clinical trials, namely the completed Phase 1/2 study NCT05017493 and the current Phase 3 study NCT05222425.[4]

Despite its central role in Xagrotin's development, detailed public information about Biomad AS, specifically the entity involved with Xagrotin, is not readily apparent from general web searches within the provided documentation. Searches for "Biomad AS" yield results for organizations such as BioMADE (a US bioindustrial manufacturing institute), BioMed Realty (a real estate provider for life sciences), and entities involved in biogas or biomethane, which do not appear to be directly connected to the pharmaceutical development of Xagrotin.[6] This lack of a clear, public-facing corporate profile for the specific Biomad AS developing Xagrotin could suggest it is a smaller, private, or relatively new enterprise, or one that maintains a limited public profile. This opacity makes it challenging to independently assess the company's broader research portfolio, financial stability, manufacturing capabilities, or prior experience in navigating international drug regulatory landscapes, factors that are important for understanding its capacity to advance Xagrotin through to potential market authorization and global distribution.

3.2. Other Associated Entities and Collaborators

The clinical investigation of Xagrotin has involved formal collaborations with regional health authorities. Specifically, the "Directorate of health of Sulaimani, Iraq -KRG" is documented as a collaborator for the NCT05017493 clinical trial.[5] This partnership indicates engagement with local governmental health institutions in Iraq, where the clinical trials have been predominantly conducted.[1]

Separately, another Iraqi entity, Shireen Nature Company for General Trading, Ltd., is associated with a patent (US2022022263, inventor Mustafa Barzani) for "WILLOW EXTRACT AND ITS USE IN TREATING CORONAVIRUS INFECTION, INFLAMMATION, AND ASSOCIATED MEDICAL CONDITIONS".[9] This patent describes a therapeutic composition containing willow extract, particularly willow leaf extract, for treating coronavirus infections and inflammation.[10] While both Xagrotin and this patented willow extract are herbal products originating from entities with Iraqi connections and targeting COVID-19, the available information does not establish a direct link between Shireen Nature Company's willow extract patent and the composition of Xagrotin. Xagrotin is explicitly described by Biomad AS and in the Hosseini et al. publication as a "combined drug, from 6 plants" [2], and there is no indication in the provided materials that willow is one of these six plants or that Shireen Nature Company is involved in Xagrotin's development or manufacture. Shireen General Trading Co. is primarily described as a business focused on uniforms and safety wear, though its patent activity clearly shows an interest in herbal therapeutic inventions.[10]

These observations could suggest independent, parallel research initiatives within the same geographical region leveraging local botanical resources or traditional knowledge. Pharmaceutical databases mention "100 Patents (Medical) associated with Xagrotin," but this information is too general to confirm whether the willow patent is among them or to identify specific patents held by Biomad AS directly covering the 6-plant formulation of Xagrotin.[1] Thus, any connection between Xagrotin and the Shireen Nature Company's willow extract patent remains speculative based on the current documentation.

4. Composition, Formulation, and Proposed Mechanism of Action

4.1. Drug Type and Known Composition

Xagrotin is consistently identified as an "Herbal medicine".[1] Its composition is derived from a combination of six distinct plants, which are reported to possess therapeutic properties against viruses and infectious lung diseases.[2] However, the specific identities of these six constituent plants are not disclosed in the publicly available research summaries. This lack of disclosure regarding the precise botanical sources is a common characteristic in the early stages of herbal medicine development, often to protect proprietary information. Nevertheless, for comprehensive scientific validation and eventual regulatory scrutiny, full disclosure and detailed characterization of each botanical component would be essential.

4.2. Key Phytochemicals and Active Constituents

The Xagrotin extract is described as being "rich in fat-/water-soluble vitamins and many antiviral phytochemical compounds".[2] Investigations into its chemical makeup have involved analytical techniques such as High-Performance Liquid Chromatography (HPLC), Inductively Coupled Plasma (ICP) spectrometry, and Gas Chromatography-Mass Spectrometry (GC-MS).[2] These methods are standard for identifying and quantifying the chemical constituents of complex mixtures like herbal extracts. While these analyses were performed, the specific results—such as the identities and concentrations of the individual phytochemicals or vitamins detected in Xagrotin—are not detailed in the provided abstracts. Access to the full research publications would be necessary to understand the phytochemical fingerprint of Xagrotin.

4.3. Formulation and Dosage Form (Clinical Trials)

In the Phase 3 clinical trial (NCT05222425), Xagrotin is administered as an "Xagrotin extract".[4] The dosage specified for this trial is "2 grams three times a day".[4] The exact physical form of this extract (e.g., powder, granules, encapsulated powder, liquid solution/suspension) and details regarding any excipients used in the formulation are not explicitly provided in the available trial summaries. Understanding the formulation is important for drug delivery, stability, and bioavailability.

4.4. Proposed Antiviral Mechanism of Action

The proposed mechanism by which Xagrotin may exert its antiviral effects against SARS-CoV-2 has been investigated through in-silico (computational) modeling studies. These studies suggest that "Four ligands of this extract bind to spike receptor-binding domain and main protease of Coronavirus".[2] The spike protein is crucial for viral entry into host cells, as its receptor-binding domain (RBD) interacts with the ACE2 receptor on human cells. The main protease (Mpro, also known as 3CLpro) is a viral enzyme essential for cleaving polyproteins translated from the viral RNA, a critical step in the viral replication cycle.

By potentially targeting both the spike RBD and Mpro, Xagrotin could interfere with two vital stages of the SARS-CoV-2 lifecycle:

1. Inhibition of Viral Entry: Binding to the spike RBD might prevent or reduce the efficiency of the virus attaching to and entering host cells.
2. Inhibition of Viral Replication: Binding to the main protease could disrupt the processing of viral polyproteins, thereby hindering the formation of functional viral components necessary for replication.

This multi-target hypothesis is characteristic of many herbal medicines, which often contain numerous phytochemicals capable of interacting with multiple biological targets. Such a mechanism, if validated, could offer advantages, including a potentially higher barrier to the development of viral resistance compared to antiviral drugs that act on a single target. However, it also presents complexities in elucidating the specific contribution of each of the "four ligands" or other active compounds to the overall therapeutic effect and in defining a singular active pharmaceutical ingredient (API) in the conventional sense.

Table 1: Overview of Xagrotin Composition and Proposed Mechanism

Feature	Description	Source References
Drug Type	Herbal medicine	1
Source	Combination of 6 plants with therapeutic properties against viruses and infectious lung diseases	2
Known Active Constituents/ Phytochemicals	Rich in fat-/water-soluble vitamins and many antiviral phytochemical compounds; Ingredients evaluated by HPLC, ICP, GC-MS. (Specifics not detailed in available materials)	2
Formulation (Phase 3 Trial)	Xagrotin extract	4
Dosage (Phase 3 Trial)	2 grams, three times a day	4
Proposed Mechanism of Action (SARS-CoV-2)	Four ligands from the extract bind to spike receptor-binding domain (RBD) and main protease (Mpro) of Coronavirus	2

5. Therapeutic Indications and Investigational Use

5.1. Primary Investigational Target: COVID-19

The predominant focus of Xagrotin's clinical development and research has been its application in the treatment of COVID-19.[1] Clinical trials have specifically targeted patient populations with "early-stage Covid-19" in the Phase 1/2 study (NCT05017493) and "Non-severe SARS-CoV-2 Outpatients" in the ongoing Phase 3 study (NCT05222425).[1] This strategic focus on early intervention in non-severe cases suggests an aim to mitigate disease progression, reduce the likelihood of severe outcomes, and potentially lessen the burden on healthcare systems by treating patients in an outpatient setting. Such a niche was particularly relevant early in the pandemic when treatment options for mild-to-moderate COVID-19 were limited.

An apparent discrepancy exists in some pharmaceutical intelligence data, which lists COVID-19 as an "inactive indication" for Xagrotin, while simultaneously reporting its highest development phase as "Pending Phase 3" for COVID-19 and detailing the active Phase 3 trial.[1] This contradiction could be attributable to various factors, such as lags in database updates, specific definitions of "active indication" employed by the data provider (e.g., requiring post-approval status), or internal strategic shifts by the developer not yet fully reflected in all public records. Given the active status of the Phase 3 trial (NCT05222425) designed to evaluate Xagrotin for COVID-19, this indication should be considered the primary and active focus of its current investigational use.[4]

5.2. Broader Therapeutic Areas

Beyond the immediate and primary target of COVID-19, Xagrotin is associated with the broader therapeutic areas of "Infectious Diseases" and "Respiratory Diseases" in pharmaceutical databases.[1] This classification is further supported by conclusions from the Hosseini et al. publication, which posits that Xagrotin "could be a potentially useful drug in the treatment of viral and pulmonary infections, especially Covid-19".[2] This suggests a potential for Xagrotin that extends beyond SARS-CoV-2. If its proposed antiviral mechanisms and observed clinical benefits in COVID-19 are substantiated, there could be a rationale for investigating its efficacy against other viral pathogens, particularly those affecting the respiratory tract, or in other pulmonary conditions characterized by inflammation or infection.

6. Preclinical Research Findings

The preclinical evaluation of Xagrotin followed a conventional pathway in early drug discovery, progressing from computational predictions to laboratory-based cell studies and finally to animal models, primarily to assess safety and establish a basis for its proposed mechanism of action.

6.1. In-silico Modeling Studies

Computational (in-silico) modeling played an initial role in hypothesizing Xagrotin's antiviral activity. These studies predicted that four distinct molecular entities (ligands) present within the Xagrotin extract could interact with and bind to two critical targets on the SARS-CoV-2 virus: the spike receptor-binding domain (RBD) and the main protease (Mpro).[2] The spike RBD is essential for viral attachment and entry into host cells, while Mpro is a key enzyme in viral replication. These in-silico findings provided a theoretical basis for Xagrotin's potential to interfere with the viral lifecycle and likely guided subsequent experimental validation.

6.2. In-vitro Efficacy and Toxicity Studies

Following the computational predictions, Xagrotin was subjected to laboratory-based (in-vitro) testing. A significant finding from these studies was related to its safety profile: the Xagrotin extract reportedly "shows no significant toxicity on HFF-2 normal cells".[2] HFF-2 (Human Foreskin Fibroblast) cells are a standard normal (non-cancerous) human cell line used for initial cytotoxicity screening of potential therapeutic compounds. Observing no significant toxicity in these cells is an important early indicator of a potentially favorable therapeutic window, suggesting that the extract might be able to exert its effects without causing undue harm to healthy host cells at effective concentrations.

While the overall positive trajectory of research and the progression to clinical trials imply some level of in-vitro antiviral efficacy, specific quantitative metrics, such as the half-maximal inhibitory concentration (IC50​) against SARS-CoV-2 or the percentage reduction in viral load at given concentrations of Xagrotin, are not detailed in the available abstracts. Such data would be crucial for a more precise understanding of its intrinsic antiviral potency.

6.3. In-vivo Safety and Efficacy Data

Animal (in-vivo) studies were also conducted as part of the preclinical assessment. These studies reportedly "confirmed" the lack of significant toxicity that was initially observed in the in-vitro cell culture assays.[2] This step is critical for evaluating the systemic effects of a drug candidate in a whole organism. However, the available abstracts do not provide specific details regarding these in-vivo studies. Information such as the animal species used (e.g., mice, hamsters), the dosages of Xagrotin administered, the duration of the studies, the specific toxicological parameters assessed (e.g., organ function tests, histopathology), or any observed adverse effects at different dose levels is not present. Similarly, while in-vivo efficacy against SARS-CoV-2 in relevant animal models would be a key preclinical milestone, details of such experiments are not provided in these summaries.

The positive preclinical safety signals, particularly the lack of significant toxicity on HFF-2 cells and the reported confirmation in vivo, were likely pivotal in the decision to advance Xagrotin into human clinical trials. However, the absence of detailed quantitative data from these preclinical studies in the provided materials limits a full independent assessment of the robustness of the preclinical package. The complete findings, presumably in the full Hosseini et al. publication or other regulatory submissions, would be necessary for a thorough evaluation of these foundational studies.

7. Clinical Development Program for COVID-19

7.1. Overview of Clinical Trials

Xagrotin's clinical development for the treatment of COVID-19 has been marked by a structured progression through clinical trial phases. At least two key trials are documented: NCT05017493, a Phase 1/2 study that has been completed, and NCT05222425, a larger Phase 3 study that is reported as ongoing or with a pending status.[1] Both trials have been sponsored by Biomad AS.[4] A notable characteristic of this clinical program is its geographical focus, with significant trial activities and collaborations occurring in Iraq. The Directorate of health of Sulaimani, Iraq -KRG, was a named collaborator for the initial NCT05017493 trial, highlighting local health authority involvement.[5]

The following table provides a comparative summary of these two pivotal clinical trials:

Table 2: Summary of Xagrotin Clinical Trials (NCT05017493 & NCT05222425)

Feature	NCT05017493	NCT05222425
Trial ID	NCT05017493	NCT05222425
Phase	Phase 1/2 1	Phase 3 1
Status	Completed 1	Unknown status/Pending Phase 3 1
Title (Source)	Treatment of Early-Stage Covid-19 With a Herbal Compound, Xagrotin 1	Treatment of Non-severe SARS-CoV-2 Outpatients With Herbal Compound Xagrotin, Phase 3 1
Sponsor	Biomad AS 1	Biomad AS 1
Collaborator(s)	Directorate of health of Sulaimani, Iraq -KRG 5	Not explicitly stated, but trial location is Iraq 1
Indication	Early-Stage COVID-19 1	Non-severe SARS-CoV-2 Outpatients 1
Key Population	361 in Xagrotin arm, 178 in control arm; Adults with COVID-19 2	Adults (18-99 yrs), newly diagnosed (≤10 days), PCR or clinically confirmed COVID-19. Est. 3000 participants (1000/arm) 4
Intervention Arms	Xagrotin (+/- Standard of Care) vs. Standard of Care (SOC) alone 12	1. Xagrotin extract 2g TID + SOC; 2. Placebo (green tea 2g TID) + SOC; 3. SOC alone (Control) 4
Primary Purpose	Treatment 5	Treatment 4
Start Date	July 1, 2020 (Actual) 1	June 1, 2022 1
Completion Date	February 8, 2021 (Actual Study Completion) 1	May 5, 2025 (Estimated) 1
Key Efficacy Outcomes Reported	Significant reductions in mortality, hospitalization (rate & duration), disease duration 2	Primary/Secondary outcomes not yet reported.
Key Safety Information Reported	Aimed to evaluate safety.5 Preclinical: no significant toxicity.2 Specific human trial AEs not detailed in provided materials.	Adverse events will be registered.4

7.2. Phase 1/2 Clinical Trial (NCT05017493)

7.2.1. Study Design, Population, and Status

The clinical trial NCT05017493 was an interventional, multi-center, randomized study designed to evaluate the efficacy and safety of Xagrotin in patients diagnosed with "early-stage Covid-19".[1] The trial commenced with an actual start date of July 1, 2020, and reached its actual study completion on February 8, 2021.[5] It was sponsored by Biomad AS, with collaboration from the Directorate of health of Sulaimani, Iraq -KRG.[5]

A total of 539 patients were enrolled and divided into two groups: 361 patients were assigned to the study group receiving Xagrotin (potentially with or without standard of care, depending on investigator discretion or evolving SOC), and 178 patients were randomly assigned to the control group, receiving the standard of care (SOC) for COVID-19 available at the time.[2] The study population consisted of adults with confirmed COVID-19.[1]

A critical aspect of this trial was its early termination. The decision to stop the trial prematurely was based on interim analysis results which showed a statistically significant benefit in the Xagrotin arm (P<0.001), meeting predefined criteria for stopping for benefit (Haybittle-Peto boundary).[5] Ethical considerations, particularly the high mortality rate associated with COVID-19 at the time and the observation of a "major therapeutic advancement," also contributed to this decision, prompting a desire to publish the results promptly.[5]

7.2.2. Intervention Details

In the NCT05017493 trial, patients in the treatment arm received Xagrotin. This was administered in combination with, or as an adjunct to, the standard of care (SOC) for COVID-19.[12] The control group received SOC alone.[12] While the Phase 3 trial (NCT05222425) specifies a clear dosage of "Xagrotin extract 2 grams three times a day" [4], the precise dosage regimen (amount, frequency, duration of treatment) for Xagrotin used in this earlier Phase 1/2 trial is not explicitly detailed in the provided summaries. The statistical analysis plan mentions that Xagrotin is a "herbal combination drug".[5]

7.2.3. Key Efficacy Outcomes (from Hosseini et al. publication)

The primary publication detailing the findings from NCT05017493, authored by Hosseini et al., reported significant therapeutic effects favoring Xagrotin.[2] The key efficacy outcomes included:

• Mortality Rate: A substantial reduction in the 30-day mortality rate was observed in the Xagrotin group (0.55%) compared to the control group (5.6%). This difference was statistically significant (p<0.001) and represented an over 9-fold decrease in mortality risk for patients treated with Xagrotin.
• Duration of Disease: Xagrotin treatment was associated with a 2-fold shortening of the overall duration of COVID-19 illness.
• Hospitalization:
• The rate of hospitalization was reduced by 10-fold in the Xagrotin group.
• For patients who were hospitalized, the duration of their hospital stay was reduced by 9-fold if they received Xagrotin.
• Symptom Severity and Recovery: The study also reported general decreases in the severity of COVID-19 symptoms and an accelerated recovery among patients in the Xagrotin arm.

The statistical analysis plan for the trial indicated an intention to use regression analysis to evaluate the effect of Xagrotin on the risk of mortality and hospitalization.[5] The reported outcomes from Hosseini et al. align with these analytical goals. The patient characteristics table from this publication shows that the mean age was similar between groups (around 44 years), but the duration of symptoms before enrollment was longer in the Xagrotin group (7.2 days vs. 3.5 days, p<0.001), a factor the authors noted for adjustment in subsequent analyses.[2]

Table 3: Key Efficacy Results from NCT05017493 (Data from Hosseini et al. [2])

Outcome Measure	Xagrotin Group (n=361)	Control Group (n=178)	P-value	Reported Benefit Statement (from text)
Mortality Rate (Day 30)	0.55%	5.6%	<0.001	Over 9-fold less mortality rate
Duration of Disease	Not specified in text	Not specified in text	N/A	Shortened by 2-fold
Rate of Hospitalization	Not specified in text	Not specified in text	N/A	Rate reduced by 10-fold
Duration of Hospitalization	Not specified in text	Not specified in text	N/A	Duration reduced by 9-fold

Note: Specific mean/median values for duration/rate reductions and associated Odds Ratios (ORs) with 95% Confidence Intervals (CIs) would typically be found in the full publication's tables, which are only partially referenced in the provided materials.

7.2.4. Safety and Tolerability Profile

The statistical analysis plan for NCT05017493 explicitly stated that one of its aims was to evaluate the safety of Xagrotin in patients with COVID-19.[5] The associated publication by Hosseini et al. references the preclinical findings, reiterating that the Xagrotin extract demonstrated "no significant toxicity on HFF-2 normal cells" and that this was "confirmed by In-Vivo study".[2] However, specific details regarding the human safety and tolerability profile observed during the NCT05017493 trial itself—such as the incidence and nature of adverse events (AEs), serious adverse events (SAEs), or reasons for discontinuation due to AEs—are not provided in the available abstracts or summaries. A comprehensive assessment of Xagrotin's safety in humans would require access to this detailed trial data. The early termination for benefit suggests that no overriding safety concerns emerged that would have halted the trial for safety reasons.

7.3. Phase 3 Clinical Trial (NCT05222425)

7.3.1. Study Design, Population, and Status

Following the promising results from the Phase 1/2 study, a larger Phase 3 clinical trial, NCT05222425, was designed to further evaluate Xagrotin. This trial is described as an interventional, multi-center, randomized study.[1] Its status is reported as "Unknown statusPhase 3" or "PendingPhase 3," indicating it is either ongoing, about to commence, or its current operational status is not yet updated in all databases.[1] The trial has a planned start date of June 1, 2022, and an estimated primary completion date of May 5, 2025.[1] The study is sponsored by Biomad AS [1] and is being conducted in Iraq.[1]

The target population for NCT05222425 is "Non-severe SARS-CoV-2 Outpatients".[1] Eligibility criteria include adults aged 18 to 99 years who are newly diagnosed with COVID-19 (no longer than 10 days prior to enrollment) with PCR or clinically confirmed infection.[4] The trial aims to recruit an estimated 3,000 participants, who will be divided into three groups of 1,000 patients each.[4]

7.3.2. Intervention Details

The Phase 3 trial employs a three-arm design [4]:

1. Treatment Group: Patients in this arm will receive Xagrotin extract at a dosage of 2 grams, administered three times a day (TID), in combination with the standard of care (SOC) for SARS-CoV-2.
2. Placebo Group: Patients in this arm will receive a placebo, identified as green tea (2 grams TID), in combination with SOC. The use of green tea as a placebo is a notable detail.
3. Control Group (No Intervention Group): Patients in this arm will receive SOC for SARS-CoV-2 alone.

This design allows for a comparison of Xagrotin against both a placebo and the current standard of care, which is a robust approach for evaluating efficacy in a Phase 3 setting.

7.3.3. Primary and Secondary Outcomes

The specific primary and secondary outcome measures for NCT05222425 are not detailed in the provided snippets. However, the primary purpose of the trial is "Treatment".[4] It is anticipated that the outcomes would be similar to those assessed in the Phase 1/2 trial, likely focusing on metrics such as time to symptom resolution, rates of hospitalization, disease progression to severe COVID-19, mortality, and viral clearance, among others. The investigators also plan to analyze the impact of various characteristics (e.g., gender, age, duration of disease, smoking habits, concomitant diseases) on the outcomes.[4]

7.3.4. Safety Monitoring

Safety assessment is an integral part of the Phase 3 trial, with the protocol stating that "Adverse events will be registered".[4] Comprehensive monitoring and reporting of AEs and SAEs will be crucial for establishing the safety profile of Xagrotin in this larger and more diverse patient population.

The progression from a Phase 1/2 trial that was stopped early due to compelling efficacy signals to a large, placebo-controlled Phase 3 trial reflects a standard drug development pathway. The design of NCT05222425, with its considerable sample size and inclusion of both placebo and standard-of-care comparators, aims to provide definitive evidence regarding Xagrotin's efficacy and safety in non-severe COVID-19 outpatients. The choice of green tea as a placebo is an interesting methodological aspect that may warrant further consideration in the interpretation of results, particularly concerning blinding and patient expectations.

8. Regulatory Status and Market Access

8.1. Current Regulatory Status

Based on the available information, Xagrotin is an investigational herbal medicine. Its highest reported development phase is "PendingPhase 3" for the treatment of COVID-19, corresponding to the clinical trial NCT05222425.[1] This status indicates that Xagrotin has not yet received marketing authorization from any major regulatory agency (such as the FDA, EMA, or others explicitly mentioned in the context of Xagrotin). The completion and successful outcome of the Phase 3 trial will be critical prerequisites for seeking such approvals.

No information regarding applications for, or granting of, emergency use authorization (EUA), compassionate use programs (outside of the early local availability mentioned [5]), or other expedited regulatory pathways is provided in the snippets for major international jurisdictions. The development has a strong regional focus in Iraq, and initial regulatory interactions may be concentrated there.[1]

8.2. Potential Pathways to Market

The pathway to market for Xagrotin will depend on several factors, including the comprehensive results from the Phase 3 trial (NCT05222425), the regulatory requirements of the target countries, and the ability of the sponsor, Biomad AS, to compile a complete regulatory dossier. For herbal medicines, this dossier typically requires not only robust clinical efficacy and safety data but also extensive information on the botanical sourcing, manufacturing processes, quality control, standardization of the extract, and detailed phytochemical characterization to ensure consistency and purity.[2]

Given its development for an infectious disease with pandemic potential (COVID-19), there might have been opportunities for expedited review processes, but this would be contingent on the data quality and the policies of specific regulatory bodies. The lack of a clear public profile for Biomad AS makes it difficult to ascertain its experience with navigating complex international regulatory submissions.[6]

The "inactive indication" status for COVID-19 listed by Synapse, despite the ongoing Phase 3 trial, adds a layer of uncertainty that would need clarification to fully understand the intended regulatory and market access strategy.[1] If Xagrotin proves successful in its Phase 3 trial, Biomad AS would likely pursue marketing authorization initially in Iraq, given the trial locations and collaborations, and potentially expand to other regions based on regulatory feasibility and commercial strategy.

9. Discussion and Future Perspectives

The emergence of Xagrotin as an investigational herbal medicine for COVID-19 highlights several important aspects of contemporary drug development, particularly in response to global health crises. Its rapid progression through early-phase clinical trials, culminating in an early halt of the Phase 1/2 study (NCT05017493) due to significant therapeutic benefit, is noteworthy.[2] This outcome, reporting over a 9-fold reduction in mortality and substantial decreases in disease duration and hospitalization, provided a strong impetus for advancing to a large-scale Phase 3 trial (NCT05222425).[2]

The herbal nature of Xagrotin, derived from a combination of six plants, presents both opportunities and challenges.[2] Herbal remedies often benefit from a perception of being "natural," which can enhance patient acceptance. The proposed multi-target mechanism of action, with ligands from the extract potentially binding to both the SARS-CoV-2 spike protein and its main protease, aligns with the often pleiotropic effects of botanical medicines and could offer an advantage in terms of efficacy and mitigating viral resistance.[2] However, the path to regulatory approval and widespread clinical adoption for herbal products is frequently more complex than for single-chemical-entity drugs. Key challenges include the rigorous identification and quantification of all active phytochemical constituents, ensuring batch-to-batch consistency in composition and potency, and elucidating the contribution of individual components to the overall therapeutic effect. While analyses like HPLC, ICP, and GC-MS have been performed on Xagrotin, the lack of detailed public disclosure of its specific six plant ingredients and their comprehensive phytochemical profiles remains a significant gap for independent scientific scrutiny.[2]

The development of Xagrotin has been strongly centered in Iraq, with local health authorities collaborating on clinical trials.[1] This regional focus, combined with the report of Xagrotin being made available to "indigenous people" early in the pandemic, suggests that local knowledge or resources may have played a role in its initial conception or early application.[5] While addressing an urgent local need, this pathway also underscores the importance of bridging such initiatives with globally accepted standards for drug development and regulatory approval to ensure broader applicability and trust. The limited public visibility of the originator organization, Biomad AS, also adds a layer of complexity when assessing its capacity for global-scale manufacturing, distribution, and regulatory engagement.[1]

Future perspectives for Xagrotin are heavily contingent on the outcomes of the ongoing Phase 3 trial, NCT05222425. Positive results from this large, placebo-controlled study would be a critical step towards seeking marketing authorization, initially perhaps in the Middle East and then potentially more broadly. Beyond COVID-19, the classification of Xagrotin under "Infectious Diseases" and "Respiratory Diseases," and the suggestion of its utility in "viral and pulmonary infections," opens avenues for future research into its efficacy against other pathogens or in other respiratory conditions.[1] However, any such expansion would require dedicated preclinical and clinical investigations.

The journey of Xagrotin underscores the potential of exploring diverse therapeutic modalities, including traditional and herbal medicines, in the fight against emerging infectious diseases. It also highlights the universal requirements for scientific rigor, transparency in composition and data, and adherence to established regulatory pathways to translate promising early findings into widely accepted and accessible treatments.

10. Conclusions

Xagrotin is an investigational herbal medicine, developed by Biomad AS, that has shown notable promise in early-phase clinical trials for the treatment of COVID-19. Composed of a proprietary blend of six plants, its proposed mechanism involves interference with SARS-CoV-2 viral entry and replication by targeting the spike protein and main protease.

Key findings from the completed Phase 1/2 clinical trial (NCT05017493) in Iraq indicated statistically significant reductions in mortality, disease duration, and hospitalization rates among patients with early-stage COVID-19 treated with Xagrotin compared to standard care.[2] These compelling results led to the early termination of the trial for benefit and the initiation of a larger, multicenter, randomized, placebo-controlled Phase 3 trial (NCT05222425).[4] This ongoing Phase 3 study, targeting non-severe COVID-19 outpatients with a Xagrotin extract dosage of 2 grams three times daily, is crucial for further validating these efficacy signals and comprehensively establishing the safety profile in a broader population.[4]

Despite the positive preliminary clinical data, several aspects require further clarification for a complete assessment of Xagrotin. The specific identities of the six constituent plants and a detailed phytochemical characterization of the extract are not yet publicly available, which is essential for understanding its pharmacology, ensuring standardization, and assessing potential interactions or toxicities. Furthermore, while preclinical studies reported no significant toxicity [2], detailed data from these studies and comprehensive safety data from human trials are necessary. The limited public information regarding the originator, Biomad AS, also presents challenges in evaluating its broader capabilities in drug development and market access.

The development trajectory of Xagrotin, rooted in a response to the COVID-19 pandemic and with a strong regional focus, illustrates the potential for rapid investigation of herbal remedies. However, for Xagrotin to achieve wider regulatory acceptance and clinical use, the successful completion of the Phase 3 trial with robust, transparently reported data on both efficacy and safety is paramount. If these milestones are met, Xagrotin could emerge as a valuable therapeutic option for COVID-19, particularly in early or non-severe disease, and potentially for other related infectious or respiratory conditions, contingent upon further research. Its journey will also serve as an important case study for the integration of herbal medicines into mainstream evidence-based therapeutic paradigms.

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