Comprehensive Report on 9MW-3011: A Novel TMPRSS6-Targeting Monoclonal Antibody for Iron Homeostasis Disorders

I. Introduction

9MW-3011 (also known by its US R&D code MWTX-003 and as DISC-3405 by Disc Medicine) is an investigational monoclonal antibody engineered to target Transmembrane Serine Protease 6 (TMPRSS6).[1] Developed by Mabwell (Shanghai) Bioscience at its San Diego Innovation and R&D Center, 9MW-3011 represents a novel therapeutic approach aimed at regulating iron homeostasis in the human body.[1] The primary mechanism involves the upregulation of hepcidin, a key hormone controlling iron absorption and mobilization.[1] Mabwell has entered into a significant licensing agreement with Disc Medicine, Inc. for the development and commercialization of 9MW-3011 in major territories outside of Greater China and Southeast Asia.[1]

This report provides a comprehensive analysis of 9MW-3011, detailing its mechanism of action, preclinical evidence, the current status of its clinical development program across various indications, its regulatory designations, the commercial and intellectual property landscape, and its therapeutic potential in addressing unmet medical needs in disorders characterized by iron dysregulation.

Table 1: Key Characteristics of 9MW-3011

Characteristic	Details	Citations
Name	9MW-3011	N/A
Alternative Names	MWTX-003 (US R&D code), DISC-3405 (Disc Medicine code)	1
Originator	Mabwell (Shanghai) Bioscience	3
Developers	Mabwell (Shanghai) Bioscience; Disc Medicine	3
Drug Type / Class	Monoclonal antibody; Antineoplastics; Immunotherapies; TMPRSS6 protein inhibitors; New Molecular Entity	3
Mechanism of Action	Inhibits TMPRSS6, leading to upregulation of hepcidin, reduced iron absorption and release, and lower serum iron levels, thereby regulating iron homeostasis.	1
Key Regulatory Designations	Orphan Drug Designation (FDA for Polycythemia Vera), Fast Track Designation (FDA for Polycythemia Vera)	1

II. Mechanism of Action

9MW-3011 exerts its therapeutic effect by targeting Transmembrane Serine Protease 6 (TMPRSS6), also known as matriptase-2. TMPRSS6 is a type II transmembrane serine protease predominantly expressed on the surface of liver cells.[4] It plays a critical negative regulatory role in iron homeostasis by cleaving hemojuvelin (HJV), a co-receptor in the bone morphogenetic protein (BMP)-SMAD signaling pathway.[8] This cleavage attenuates the signaling cascade that normally leads to the expression of hepcidin, the master hormonal regulator of systemic iron balance.[8] Consequently, under normal physiological conditions or in states of iron deficiency, TMPRSS6 activity suppresses hepcidin production.[8]

9MW-3011 is a monoclonal antibody designed to specifically bind to TMPRSS6.[1] By inhibiting TMPRSS6 activity, 9MW-3011 effectively removes this negative regulation on the BMP-SMAD pathway. This allows for increased signaling and consequently leads to an upregulation of hepcidin expression by hepatocytes.[1] Elevated hepcidin levels then act to reduce serum iron by binding to the iron exporter protein ferroportin on enterocytes (inhibiting dietary iron absorption) and macrophages (inhibiting the release of recycled iron from stores), leading to ferroportin internalization and degradation.[8] The net effect is a decrease in iron absorption from the gut, reduced iron release from bodily stores, and a lowering of serum iron levels, thereby restoring or improving iron homeostasis in vivo.[1]

The proposed indications for 9MW-3011, including β-thalassemia and polycythemia vera, are conditions where dysregulation of iron metabolism and hepcidin expression are central to the pathophysiology.[1] It is highlighted that there are currently no mature and effective macromolecular drugs targeting these indications through this mechanism, positioning 9MW-3011 as a potential first-in-class therapeutic agent for regulating iron homeostasis.[1]

III. Preclinical Development

The progression of 9MW-3011 into clinical trials was supported by a body of preclinical evidence demonstrating its intended biological activity and therapeutic potential. In vivo studies with r4K12B, a murine analog of DISC-3405 (9MW-3011), showed that pharmacological inhibition of TMPRSS6 significantly increased hepcidin production and suppressed serum iron levels.[9]

These preclinical investigations extended to disease-specific animal models. Efficacy was demonstrated in mouse models of β-thalassemia and polycythemia vera.[9] The citations "Chen, 2023" and "Chen, 2021" refer to publications in Blood (Chen B, Wang J, Huang L, et al. Blood. 2023;142(Suppl 1):3837 and Chen B, Wang J, Zheng B, et al. Blood. 2021;138(Suppl 1):941, respectively), which presumably detail these findings.[9] While the specific data from these studies are not fully elaborated in the available abstracts, the conclusions drawn indicate a positive impact on disease parameters in these models. For instance, in β-thalassemia models, where hepcidin is inappropriately low leading to iron overload and ineffective erythropoiesis, upregulating hepcidin via TMPRSS6 inhibition is expected to ameliorate these conditions.[8] Similarly, in polycythemia vera, where excessive erythropoiesis occurs, limiting iron availability through hepcidin increase could control red blood cell production.

Furthermore, preclinical trials have also been conducted for sickle cell anemia in the USA using a parenteral formulation, suggesting exploration of 9MW-3011's utility in other hematologic disorders characterized by iron dysregulation.[3] The consistent observation of increased hepcidin and reduced serum iron in these preclinical settings provided a strong rationale for advancing 9MW-3011 into human clinical trials to assess its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in humans.

IV. Clinical Development Program

The clinical development of 9MW-3011 is being pursued through a dual strategy, with Mabwell leading efforts in Greater China and Southeast Asia, and Disc Medicine responsible for the United States, Europe, and other territories.[1] This approach allows for parallel data generation and potentially expedited global development.

A. Overview of Clinical Strategy

The clinical strategy aims to first establish the safety, tolerability, PK, and PD (proof-of-mechanism) of 9MW-3011 in healthy volunteers, followed by evaluation in patient populations with target indications such as polycythemia vera (PV) and β-thalassemia. Both intravenous (IV) and subcutaneous (SC) routes of administration have been explored.[11]

B. Clinical Trials

1. Healthy Volunteer Studies

Two key Phase 1 studies in healthy volunteers have been conducted:

• CTR20230046 (Mabwell, China): This Phase 1, single-center, randomized, double-blind, placebo-controlled, ascending dose study was launched in March 2023 to evaluate the safety, tolerability, PK, PD, and immunogenicity of 9MW-3011 in healthy adult participants in China.[5] Larvol Sigma indicates this study, referred to as a "Single Ascending Dose Study of 9MW3011 in Chinese Healthy Subject," was completed by December 27, 2024, enrolling 48 participants.[13] An abstract (EHA2024EHA_4101) likely related to data from one of the healthy volunteer programs reported that single ascending doses resulted in sustained elevation of serum hepcidin and reduction of iron levels, with dose-dependent increases in hepcidin and sustained reductions in serum iron and transferrin saturation (TSAT), alongside a favorable safety profile.[13]
• NCT06050915 (DISC-3405, Disc Medicine, US): This Phase 1 study in healthy volunteers was initiated in October 2023.[14] It is a randomized, double-blind, placebo-controlled, single-ascending dose (SAD) and multiple-ascending dose (MAD) study designed to evaluate the safety, tolerability, PK, and PD of DISC-3405.[11] The study aimed to enroll 64 healthy male and female volunteers aged 18-65 years.[14] Interim data from the SAD portion of this study were presented at the European Hematology Association (EHA) 2024 Congress (data cut-off April 19, 2024).[11] Larvol Sigma indicates this study (DISC-3405-101) was completed by December 18, 2024.[13] The EHA 2024 poster detailed findings from 40 participants in the SAD cohorts who received DISC-3405 (75 mg IV; 37.5 mg, 75 mg, 150 mg, or 300 mg SC) or placebo.[11]
• Safety and Tolerability: DISC-3405 was well-tolerated. No serious adverse events (AEs), AEs greater than Grade 2, or AEs leading to study withdrawal were reported. Possibly related AEs were generally Grade 1. Two Grade 2 AEs were observed: one participant experienced a self-limited headache (37.5 mg SC group), and one participant had isolated, self-limited elevations of AST and ALT (150 mg SC group).[11]
• Pharmacokinetics (PK): Subcutaneous administration resulted in dose-dependent PK profiles. The terminal half-life (T1/2​) at the 300 mg SC dose was reported to be more than 11 days.[11]
• Pharmacodynamics (PD): DISC-3405 produced dose-related increases in serum hepcidin and corresponding reductions in serum iron across all dose levels. Mean serum iron reduction of more than 50% from baseline was achieved for both the 150 mg and 300 mg SC doses. Notably, this greater than 50% reduction in serum iron was sustained for at least 4 weeks following the 300 mg SC dose. Meaningful reductions in selective hematological parameters, including reticulocyte hemoglobin content (CHr), hemoglobin, and hematocrit, were also observed with the 300 mg SC dose.[11]
• Conclusion from EHA poster: The data suggest DISC-3405 is a promising treatment with a convenient dosing regimen for conditions that would benefit from iron restriction, supporting its continued clinical development.[11]

The successful completion and positive readouts from these two healthy volunteer studies provide a robust foundation for 9MW-3011. They not only establish initial human safety and tolerability but also demonstrate clear proof-of-mechanism through observed changes in hepcidin and serum iron. This significantly de-risks the program as it moves into patient populations and informs dose selection for subsequent trials, including the Phase 2 study planned by Disc Medicine. The exploration of subcutaneous administration is particularly noteworthy. The long half-life observed (T1/2​ >11 days at 300mg SC) supports the potential for a convenient, less frequent dosing regimen, such as once-monthly, which would be a considerable advantage for patients with chronic conditions like PV and β-thalassemia, enhancing compliance and quality of life.[11]

Table 2: Summary of Key Findings from Phase 1 Healthy Volunteer Study NCT06050915 (DISC-3405, EHA 2024 SAD Data)

Parameter	37.5 mg SC	75 mg IV	75 mg SC	150 mg SC	300 mg SC	Placebo	Citations
Participants (n)	6	6	6	6	6	10	11
Terminal Half-life (T1/2​)	N/A	N/A	N/A	N/A	>11 days	N/A	11
Hepcidin Increase	Dose-related increase observed across all DISC-3405 dose levels.	N/A	11
Serum Iron Reduction	Dose-related reduction observed.	Dose-related reduction observed.	Dose-related reduction observed.	>50% mean reduction from baseline.	>50% mean reduction from baseline, sustained for at least 4 weeks.	N/A	11
Hematological Changes (CHr, Hb, Hct)	N/A	N/A	N/A	N/A	Meaningful reductions observed.	N/A	11
Key Adverse Events (Possibly Related)	Headache (Grade 2, n=1)	None reported	None reported	AST/ALT elevation (Grade 2, n=1, self-limited)	Other Grade 1 AEs reported (e.g. sore throat, nausea, cough, rhinorrhea, lightheadedness, n=1 each in various dose groups)	None reported	11
Overall Tolerability	Well-tolerated. No SAEs, >Grade 2 AEs (other than listed), or AEs leading to withdrawal.	N/A	11

N/A: Not explicitly provided for this specific dose in the summarized source or not applicable.

2. Patient Cohort Trials

Following the healthy volunteer studies, trials in patient populations have been initiated, primarily by Mabwell in China:

• Polycythemia Vera (PV):
• NCT06752746 (Mabwell, China): This Phase 1 study, titled "A Study of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of 9MW3011 in Patients With Polycythemia Vera," aims to assess 9MW3011 in 108 Chinese PV patients (male/female, $\geq$18 years) who are resistant to or intolerant of hydroxyurea or Interferon alpha.[16] The trial is active and recruiting, having started on March 21, 2024, with an estimated completion date of June 30, 2026. It is being conducted at multiple sites in China.[16]
• CTR20242945 (Mabwell, China): An open-label Phase Ib clinical study is also listed as recruiting, designed to evaluate the safety, tolerability, PK, PD, and immunogenicity of 9MW3011 injection after multiple administrations in patients with newly diagnosed and previously treated PV.[7] This may be related to or an extension of NCT06752746.
• β-Thalassemia (Non-Transfusion-Dependent, NTDT):
• NCT06772766 (Mabwell, China): This Phase Ib study is titled "A Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of 9MW3011 in Patients With Non-transfusion-dependent β-Thalassemia".[3] The study plans to enroll 40 male/female subjects (18-65 years) with a documented genetic diagnosis of NTDT β-thalassemia or hemoglobin E/β-thalassemia, baseline hemoglobin between 70-100 g/L, and evidence of iron overload. Participants will be randomized 4:1 to receive 9MW3011 or placebo via IV infusion in multiple ascending dose cohorts.[17] The trial is active and recruiting, with a start date of December 30, 2024, and an estimated completion date of October 31, 2026. Study locations include Hainan General Hospital and The First Affiliated Hospital of Guangxi Medical University in China.[17]

The initiation of these patient trials in China by Mabwell, chronologically ahead of Disc Medicine's planned Phase 2 study in PV, suggests that initial patient safety and efficacy signals for 9MW-3011 might first emerge from these studies. Should the data be shared in a timely manner as per their licensing agreement, these early indicators of therapeutic effect or safety in PV and β-thalassemia patients could significantly inform Disc Medicine's trial designs, dose selection, or even pivotal strategic decisions for development in Western territories.

C. Planned Phase 2 and Future Studies

Disc Medicine has clearly signaled its intent to advance DISC-3405 into further clinical development. A key upcoming step is the initiation of a Phase 2 clinical trial for Polycythemia Vera (PV), which is planned for the first half of 2025.[3] This study will be crucial for evaluating the efficacy and safety of DISC-3405 in this patient population in territories covered by Disc Medicine.

Beyond PV, Disc Medicine is also continuing to develop the scientific rationale for therapeutic iron restriction with DISC-3405 in other indications, including sickle cell disease.[15] Preclinical data in sickle cell anemia models have already been generated.[3]

Mabwell's ongoing Phase 1 studies in PV (NCT06752746) and NTDT β-thalassemia (NCT06772766) in China will naturally inform their next steps for these indications within their licensed territories.

D. Consolidated Summary of Efficacy and Safety Findings to Date

Based primarily on the healthy volunteer data (notably the EHA 2024 SAD data from NCT06050915):

• Efficacy (Pharmacodynamic Proof-of-Mechanism): 9MW-3011/DISC-3405 has demonstrated clear, dose-dependent increases in serum hepcidin levels. This was accompanied by sustained reductions in serum iron and TSAT.[11] A mean serum iron reduction of over 50% was achieved and sustained for at least four weeks with the 300 mg SC dose. Furthermore, meaningful reductions in CHr, hemoglobin, and hematocrit were observed at higher doses in healthy volunteers, indicating a physiological response to iron restriction.[11]
• Safety: The drug has been generally well-tolerated in healthy volunteers. No serious adverse events or AEs greater than Grade 2 (apart from one instance of self-limited headache and one of transient AST/ALT elevation) were reported in the EHA 2024 SAD dataset.[11] This favorable safety profile supports continued clinical development.[13]

Data from patient cohort studies are not yet available but will be critical in confirming these effects and assessing clinical benefit in the target disease settings.

Table 3: Overview of 9MW-3011 Clinical Trials

Study ID (NCT/CTR)	Drug Code Used	Phase	Indication/Population	Sponsor(s)	Key Objectives	Current Status (as of early 2025)	Participants (Actual/Planned)	Start / Est. Completion Dates	Regions	Citations
CTR20230046	9MW3011	1	Healthy Volunteers	Mabwell	Safety, tolerability, PK, PD, immunogenicity	Completed	48/48	Mar 2023 / Dec 27, 2024	China	5
NCT06050915	DISC-3405	1	Healthy Volunteers (SAD/MAD)	Disc Medicine	Safety, tolerability, PK, PD	Completed	64/64	Oct 2023 / Dec 18, 2024	US	11
NCT06752746	9MW3011	1	Polycythemia Vera (resistant/intolerant to HU/IFN)	Mabwell	Safety, tolerability, PK, PD, immunogenicity	Active - Recruiting	-/108	Mar 21, 2024 / Jun 30, 2026	China	16
CTR20242945	9MW3011	Ib	Polycythemia Vera (newly diagnosed & previously treated)	Mabwell	Safety, tolerability, PK, PD, immunogenicity (multiple administration)	Recruiting	N/A	N/A	China	7
NCT06772766	9MW3011	Ib	Non-Transfusion-Dependent β-Thalassemia (NTDT)	Mabwell	Safety, tolerability, PK, PD, immunogenicity (multiple ascending dose)	Active - Recruiting	-/40	Dec 30, 2024 / Oct 31, 2026	China	3
Planned	DISC-3405	2	Polycythemia Vera	Disc Medicine	Efficacy, safety	Planned (H1 2025 initiation)	N/A	H1 2025 / N/A	US/EU (likely)	3

V. Regulatory Status and Designations

9MW-3011 has achieved several important regulatory milestones that underscore its potential and facilitate its development pathway.

A. Investigational New Drug (IND) Approvals

• Food and Drug Administration (FDA, US): The FDA formally approved the IND application for 9MW3011 Injection for clinical trials in patients with polycythemia vera in November 2022.[4] This approval was crucial for Disc Medicine to commence its clinical program in the United States.
• National Medical Products Administration (NMPA, China): The NMPA accepted the clinical trial application for 9MW3011 Injection in October 2022.[4] This paved the way for Mabwell to initiate clinical studies in China for proposed indications including β-thalassemia and polycythemia vera.[6]

The near-concurrent IND approvals from two major global regulatory agencies, based on what was presumably a similar comprehensive preclinical data package developed by Mabwell, highlight the robustness and international acceptability of the early research. This facilitates a more streamlined and parallel global development strategy, as the foundational data supporting safety and rationale are recognized across key markets, reducing the likelihood of needing substantially different preclinical work for different regions.

B. Orphan Drug Designation (ODD)

The FDA granted Orphan Drug Designation to 9MW3011 (MWTX-003/DISC-3405) in February 2024 for the treatment of patients with polycythemia vera.[1] ODD is conferred upon investigational therapies intended for rare medical diseases or conditions affecting fewer than 200,000 individuals in the United States.[1] The drug is also anticipated to qualify for orphan status for its other proposed indications, such as β-thalassemia, which are also classified as rare diseases.[4]

C. Fast Track Designation (FTD)

In September 2023, the FDA granted Fast Track Designation to 9MW3011 for polycythemia vera.[1] FTD is designed to expedite the development and review process for drugs that aim to treat serious conditions and address unmet medical needs.

The sequence of obtaining FTD in September 2023, prior to ODD in February 2024, for polycythemia vera in the US, points to a deliberate, stepwise regulatory strategy by Disc Medicine. Securing FTD, which acknowledges the drug's potential to fill a significant void in treating a serious condition, likely provided a stronger foundation for the subsequent ODD application. This methodical approach demonstrates a strategic engagement with the FDA, potentially fostering a more collaborative review process and leveraging each successful designation to build a more compelling overall profile for 9MW-3011.

D. Implications of Regulatory Designations

These designations carry significant benefits:

• Orphan Drug Status: Provides advantages such as assistance from the FDA in the drug development process, tax credits for qualified clinical trial costs, exemption from certain FDA application fees, and, importantly, seven years of market exclusivity in the US upon approval for the designated indication (PV).[1]
• Fast Track Designation: Allows for more frequent interactions with the FDA throughout the development process, eligibility for Accelerated Approval and Priority Review if relevant criteria are met, and the possibility of a rolling review of the New Drug Application (NDA), where completed sections of the NDA can be submitted and reviewed by the FDA on an ongoing basis rather than waiting for all sections to be completed.[1]

Table 4: Key Regulatory Milestones and Designations for 9MW-3011

Regulatory Agency	Milestone/Designation	Date Granted/Achieved	Indication (if specific)	Key Implications/Benefits	Citations
NMPA (China)	Clinical Trial Application Accepted	Oct 2022	PV, β-thalassemia (proposed)	Enabled clinical trials in China.	4
FDA (US)	IND Approval	Nov 2022	Polycythemia Vera	Enabled clinical trials in the US.	4
FDA (US)	Fast Track Designation	Sep 2023	Polycythemia Vera	More frequent FDA meetings, potential for Accelerated Approval/Priority Review, rolling NDA review.	1
FDA (US)	Orphan Drug Designation	Feb 2024	Polycythemia Vera	Development assistance, tax credits, fee exemptions, 7-year post-approval market exclusivity for PV in the US.	1

VI. Commercial and Intellectual Property Landscape

The commercial strategy and intellectual property rights for 9MW-3011 are shaped by a key licensing agreement and an emerging patent portfolio.

A. Licensing and Collaboration Agreements (Mabwell and Disc Medicine)

In January 2023, Mabwell, through its wholly-owned subsidiary Mabwell Therapeutics, entered into an exclusive licensing agreement with Disc Medicine, Inc. for 9MW-3011.[6]

• Territories: Disc Medicine obtained exclusive rights to develop and commercialize 9MW-3011 in the United States, Europe, and other territories excluding Great China and Southeast Asia. Rights for Great China and Southeast Asia are retained by Mabwell.[1]
• Financial Terms: The agreement stipulates that Mabwell is eligible to receive up to a total of $412.5 million, comprising an upfront payment and subsequent milestone payments contingent on development, regulatory, and commercial achievements.[1]
• Upfront Payment: Disc Medicine made a one-time, non-refundable down payment of $10 million to Mabwell.[6]
• Royalties: In addition to milestone payments, Mabwell is entitled to receive tiered royalties on net sales of the licensed products, described as being "close to two digit percentage".[6]

The substantial potential deal value of $412.5 million plus royalties for a drug that was, at the time of the agreement, in early clinical development (INDs recently approved, prior to completion of Phase 1 healthy volunteer studies) signifies a high perceived value and considerable interest in the TMPRSS6 target for iron-related disorders. This reflects positively on the innovation stemming from Mabwell's R&D and the therapeutic promise of 9MW-3011. Such a deal provides Mabwell with significant non-dilutive funding and potential future revenue, while Disc Medicine secures a promising clinical-stage asset to bolster its hematology pipeline. This level of investment may also stimulate broader research and development activities around the TMPRSS6 pathway by other entities.

Mabwell's retention of rights in "Great China and Southeast Asia," coupled with its established GMP-compliant manufacturing capabilities, positions the company to independently serve these significant markets. This could lead to a distinct regional brand and revenue stream for Mabwell, operating in parallel with Disc Medicine's commercialization efforts in Western markets, thereby maximizing global market penetration.

Table 5: Summary of Mabwell-Disc Medicine Licensing Agreement for 9MW-3011

Aspect	Details	Citations
Licensor	Mabwell (via Mabwell Therapeutics)	6
Licensee	Disc Medicine, Inc.	6
Licensed Product	9MW-3011 (MWTX-003/DISC-3405)	1
Disc Medicine's Territories	United States, Europe, other territories excluding Great China and Southeast Asia	1
Mabwell's Retained Territories	Great China and Southeast Asia	1
Upfront Payment	$10 million	6
Total Potential Deal Value (to Mabwell)	Up to $412.5 million (including upfront and milestone payments)	1
Royalty Rate (to Mabwell)	Tiered, "close to two digit percentage" of net sales	6
Date of Agreement Announcement	January 19-20, 2023	6

B. Intellectual Property: Patent Portfolio

The intellectual property surrounding 9MW-3011 is anchored by patent applications covering the antibody and its uses.

• A key patent application is WO2021207072A1, filed by Mabwell Therapeutics Inc., with inventors Xin Du, Buxin CHEN, and Yu Jean WANG, and a priority date of April 7, 2020.[8] This international patent application discloses anti-TMPRSS6 antibodies and antigen-binding fragments thereof that bind to TMPRSS6 on the cell surface and increase hepcidin expression. The claims encompass the antibodies themselves, including specific heavy chain (HC) and light chain (LC) variable region sequences and complementarity determining regions (CDRs) (e.g., specific SEQ ID NOs for various antibody constructs are detailed), as well as methods for treating disorders of iron metabolism, such as β-thalassemia, by administering these antibodies.[8] The patent describes antibodies capable of modulating components involved in iron metabolism, inhibiting TMPRSS6 suppression of hepcidin, and potentially leading to beneficial hematological effects.[8]
• PatSnap Synapse indicates the existence of "100 Patents (Medical) associated with 9MW-3011," although specific details require a subscription to access.[7] This suggests a broader patent estate beyond the foundational WO2021207072A1 application. Such a portfolio likely includes national phase entries of the PCT application in various countries, as well as potentially divisional or continuation applications covering different aspects like composition of matter, specific formulations, methods of use for various indications, and possibly manufacturing processes. This comprehensive IP strategy is crucial for securing long-term market exclusivity for both Mabwell and Disc Medicine in their respective territories.

C. Manufacturing and Supply Chain Considerations

Mabwell has invested in significant manufacturing capabilities. Its Taizhou factory is described as possessing robust in-house manufacturing capacity compliant with international Good Manufacturing Practice (GMP) standards, as recognized by the NMPA, FDA, and EMA. The facility has also passed an EU Qualified Person (QP) Audit.[1] Additionally, a new large-scale manufacturing base is currently under construction in Shanghai.[1] These facilities are vital for producing 9MW-3011 for clinical trials and, eventually, for commercial supply, at least within Mabwell's retained territories. They could also potentially serve as a source of supply for Disc Medicine, particularly in the earlier stages of development, creating an additional point of collaboration or revenue.

VII. Therapeutic Potential and Market Context

9MW-3011 is being developed to address significant unmet medical needs in hematologic disorders characterized by dysregulated iron homeostasis.

A. Target Indications and Unmet Medical Needs

• Polycythemia Vera (PV): PV is a rare myeloproliferative neoplasm leading to the overproduction of red blood cells, which increases blood viscosity and elevates the risk of thrombotic events (e.g., stroke, heart attack), and can cause debilitating symptoms such as fatigue, pruritus, and splenomegaly.[1] Current treatments include phlebotomy to reduce red cell mass, low-dose aspirin, and cytoreductive therapies like hydroxyurea, pegylated interferon-alpha, or the JAK inhibitor ruxolitinib (for hydroxyurea-intolerant/resistant patients).[16] However, these therapies have limitations: phlebotomy is burdensome and does not address underlying disease activity; hydroxyurea can have long-term toxicities; interferons have tolerability issues; and while ruxolitinib offers benefit, not all patients respond optimally, and some may lose response or experience side effects. There is a clear need for novel therapies with different mechanisms of action that can provide better disease control, symptom improvement, and a more favorable long-term safety profile. 9MW-3011, by restricting iron availability essential for erythropoiesis, offers a novel approach to controlling red blood cell production in PV.
• β-Thalassemia: This group of inherited hemoglobinopathies results from deficient β-globin chain synthesis, leading to chronic anemia, ineffective erythropoiesis (destruction of red blood cell precursors in the bone marrow), and systemic iron overload.[1] Iron overload occurs due to increased intestinal iron absorption (driven by chronically low hepcidin in response to ineffective erythropoiesis) and, in transfusion-dependent thalassemia (TDT), from repeated blood transfusions. Even in non-transfusion-dependent thalassemia (NTDT), iron overload is a significant concern.[17] Current management involves blood transfusions for severe anemia, iron chelation therapy to manage iron overload, and potentially hematopoietic stem cell transplantation for eligible patients. However, these approaches have challenges, including transfusion complications, chelation side effects and compliance issues, and transplant-related risks. 9MW-3011 aims to increase hepcidin levels, thereby reducing pathological iron absorption and potentially improving the efficiency of erythropoiesis by mitigating iron-induced oxidative stress and apoptosis of erythroid precursors.[8]
• Other Iron-Related Disorders: The mechanism of 9MW-3011 holds promise for other conditions. Preclinical work in sickle cell anemia has been noted [3], and general statements about "other diseases related to iron homeostasis" or "iron overload conditions" suggest a broader therapeutic horizon.[3]

B. Positioning Relative to Current Standard of Care

A recurrent theme in communications about 9MW-3011 is that "At present, there are no mature and effective macromolecular drug for relevant indications" such as PV and β-thalassemia.[1] 9MW-3011 is consistently positioned as a potential "first-in-class macromolecular drug to regulate iron homeostasis in vivo".[4] This deliberate positioning highlights its novel mechanism of action, distinguishing it from existing small molecule drugs (e.g., JAK inhibitors, iron chelators) or supportive care measures. Monoclonal antibodies, as macromolecular drugs, often provide high target specificity, which can translate to improved efficacy and potentially more favorable tolerability profiles by minimizing off-target effects. This differentiation could be a significant clinical advantage, particularly for patients who have not responded adequately to, or cannot tolerate, current therapies.

The focus on iron restriction via hepcidin upregulation offers a more physiological approach to managing conditions like PV. By limiting iron, a crucial nutrient for hemoglobin synthesis and thus for excessive red blood cell production, 9MW-3011 directly addresses a key driver of erythrocytosis in PV. This "iron-starvation" strategy for erythropoiesis is distinct from broadly cytotoxic agents like hydroxyurea or less specific pathway inhibitors such as JAK inhibitors. This targeted approach could potentially lead to better control of hematocrit levels, a reduced need for phlebotomies, and an improved symptom burden with a more favorable safety profile compared to existing options.

C. Future Outlook and Potential Impact

If clinical development proves successful, 9MW-3011 could emerge as a significant targeted, disease-modifying therapy for a range of disorders linked to dysregulated iron homeostasis. The potential for a convenient once-monthly subcutaneous injection, as suggested by early PK/PD data from healthy volunteer studies, would represent a substantial improvement in chronic disease management for patients, enhancing adherence and quality of life.[11] The drug's development addresses clear and pressing unmet medical needs in both PV and β-thalassemia, and its fundamental mechanism of action holds considerable promise for broader applications in other hematologic conditions where iron metabolism is perturbed.

VIII. Expert Conclusion and Forward Look

9MW-3011 (DISC-3405) stands out as a promising investigational agent with a novel, first-in-class mechanism targeting TMPRSS6 to modulate iron homeostasis. The preclinical rationale is sound, demonstrating that inhibition of TMPRSS6 leads to increased hepcidin and subsequent reductions in serum iron, with efficacy shown in relevant animal models of polycythemia vera and β-thalassemia. Early clinical data from Phase 1 studies in healthy volunteers have been encouraging, providing proof-of-mechanism with dose-dependent hepcidin elevation and iron reduction, along with a generally good safety and tolerability profile. The pharmacokinetic properties, particularly the long half-life supporting potential for infrequent subcutaneous dosing, add to its attractiveness for chronic conditions.

The ongoing patient cohort studies in China for PV and NTDT β-thalassemia, spearheaded by Mabwell, and the planned Phase 2 trial in PV by Disc Medicine in Western territories, are critical next steps. These trials will provide the first insights into the clinical efficacy and safety of 9MW-3011 in individuals affected by these debilitating disorders. The unmet medical needs in both PV and β-thalassemia remain substantial, with current therapies often falling short in terms of long-term efficacy, safety, or patient convenience. 9MW-3011, with its distinct mechanism, has the potential to offer a valuable new therapeutic option.

The dual development pathway adopted by Mabwell and Disc Medicine presents both opportunities for accelerated global data generation and inherent challenges related to strategic alignment, timely data sharing, and global regulatory harmonization. The ultimate success of this collaborative model will heavily depend on the effective execution of the framework established in their licensing agreement. Smooth coordination will be paramount to maximizing the drug's global potential.

Looking ahead, key catalysts will include initial data readouts from the ongoing patient trials and the successful initiation and recruitment for Disc Medicine's Phase 2 study in PV. Beyond the lead indications of PV and β-thalassemia, the fundamental ability of 9MW-3011 to modulate systemic iron levels via the master regulator hepcidin suggests a "pipeline-in-a-product" potential. If safety and efficacy are firmly established, exploration into other anemias or iron overload conditions where iron metabolism is dysregulated (such as sickle cell disease or potentially certain types of anemia of chronic disease/inflammation where iron restriction or redistribution could be beneficial) is a logical and exciting prospect. This could significantly expand its market potential and solidify its role as a versatile tool in managing a spectrum of hematologic and iron-related disorders. The journey of 9MW-3011 from bench to bedside will be closely watched by the medical and scientific communities.

IX. References

1 PR Newswire. (2024, February 20). FDA Grants Orphan Drug Designation to 9MW3011.

2 BioSpace. (2024, February 20). FDA Grants Orphan Drug Designation to 9MW3011.

6 PR Newswire. (2023, January 19). $412.5 million! Mabwell Announces Exclusive Licensing Agreement with DISC MEDICINE, INC. for Innovative Drug Candidates of Hematologic Diseases.

22 Mabwell. (2023, January 20). $412.5 Million Mabwell Announces Exclusive Licensing Agreement with DISC MEDICINE, INC. for Innovative Drug Candidates of Hematologic Diseases.

3 AdisInsight - Springer. (2025, January 17). 9MW 3011 Drug Profile.

4 Mabwell. (2022, November 21). Mabwell Announces the U.S. FDA approval of 9MW3011 (FIC) for IND.

5 PR Newswire. (2023, March 14). Mabwell Launched First in Human Clinical Trial of Its Iron Homeostasis Regulating Macromolecular Drug 9MW3011.

17 MediFind. A Randomized, Double-blind, Placebo-controlled, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of 9MW3011 in Patients With Non-transfusion-dependent β- Thalassemia. (Trial ID: NCT06772766).

16 CenterWatch. (2024, December 22). A Study of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of 9MW3011 in Patients With Polycythemia Vera. (Trial ID: NCT06752746).

2 BioSpace. (2024, February 20). FDA Grants Orphan Drug Designation to 9MW3011..2

18 CenterWatch. (2025, January 8). A Multiple Ascending Dose Study of 9MW3011 in Patients With Non-transfusion-dependent β-thalassemia. (Trial ID: NCT06772766).

7 PatSnap Synapse. 9MW-3011 Drug Profile. (Accessed May 2025, refers to CTR20242945).

15 Disc Medicine. (2025, January 10). Disc Medicine Highlights Recent Achievements Across Hematology Portfolio and Key Business Objectives and Milestones for 2025.

19 GlobeNewswire. (2025, May 7). Disc Medicine Reports First Quarter 2025 Financial Results and Provides Business Update.

11 Disc Medicine. (2024, June). Phase 1 Healthy Volunteer Study of DISC-3405, a Recombinant Humanized Antibody Targeting TMPRSS6, Demonstrates >50% Serum Iron Suppression and Sustained Hepcidin Induction. (EHA 2024 Poster, NCT06050915).

14 Thalassaemia International Federation. MWTX-003 (DISC-3405) Clinical Trial Update. (Refers to NCT06050915).

20 StockTitan. (2025, January 10). Disc Medicine Highlights Recent Achievements Across Hematology Portfolio and Key Business Objectives and Milestones for 2025.

21 Disc Medicine Investor Relations. (2025, January 10). Disc Medicine Highlights Recent Achievements Across Hematology Portfolio and Key Business Objectives and Milestones for 2025.

8 Google Patents. WO2021207072A1 - Anti-tmprss6 antibodies and uses thereof. (Mabwell Therapeutics Inc.).

23 Disc Medicine. (2023, October 4). Disc Medicine Initiates Phase 1 Study of DISC-3405, an Anti-TMPRSS6 Monoclonal Antibody Designed to Increase Hepcidin and Decrease Iron.

10 Riva, E., et al. (2022). Does Hepcidin Tuning Have a Role among Emerging Treatments for Thalassemia? Journal of Clinical Medicine, 11(17), 5119.

9 Giannini, S., et al. (2024). Pharmacological Inhibition of TMPRSS6 Decreases Hemoglobin Concentration and Red Blood Cell (RBC) Hemolysis in a Mouse Model of Sickle Cell Disease. Blood, 144 (Supplement 1), 3863. (ASH 2024 Abstract, refers to Chen, 2023 & Chen, 2021).

12 Mabwell. (2023, March 13). Mabwell Launched First in human Clinical Trial of Its Iron Homeostasis Regulating Macromolecular Drug 9MW3011. (Refers to CTR20230046).

13 Larvol Sigma. Mabwell Company Profile - NewsTrac. (Accessed May 2025, refers to EHA2024EHA_4101 and trial completions).

1 PR Newswire Snippet Summary..1

6 PR Newswire Snippet Summary..6

3 AdisInsight Snippet Summary..3

4 Mabwell Website Snippet Summary..4

5 PR Newswire Snippet Summary..5

18 CenterWatch Snippet Summary..18

16 CenterWatch Snippet Summary..16

7 PatSnap Synapse Snippet Summary..7

11 EHA 2024 Poster Snippet Summary..11

8 Google Patents Snippet Summary..8

9 ASH Abstract Snippet Summary..9

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