BMN-349: An Investigational Oral Chaperone for Alpha-1 Antitrypsin Deficiency-Associated Liver Disease

1. Executive Summary

BMN-349 is an investigational, orally bioavailable small molecule therapeutic candidate currently under development by BioMarin Pharmaceutical.[1] This agent is designed to function as an Alpha-1 Antitrypsin (A1AT) modulator and protein folding stabilizer, specifically acting as a molecular chaperone. Its primary pharmacological target is the misfolded Z-mutant A1AT (Z-AAT) protein, the accumulation of which is central to the pathogenesis of Alpha-1 Antitrypsin Deficiency (AATD)-associated liver disease.[1] Consequently, the principal therapeutic indication for BMN-349 is AATD-associated liver disease.[2]

As of early 2025, BMN-349 has progressed into Phase 1 clinical development. An ongoing clinical trial, identified as NCT06738017, is actively evaluating the safety, tolerability, and pharmacokinetic profile of BMN-349 in adult participants who are either homozygous for the Z mutation (PiZZ genotype) or heterozygous (PiMZ genotype) with concurrent metabolic dysfunction-associated steatohepatitis (MASH).[4] Preclinical investigations have provided encouraging results, particularly studies conducted in the PiZ mouse model of AATD. These studies have demonstrated the potential of BMN-349 to reduce the accumulation of Z-AAT polymers within hepatocytes and to enhance the secretion of Z-AAT into the circulation.[5]

AATD-associated liver disease represents a significant unmet medical need, characterized by progressive liver damage stemming from the intrahepatic accumulation of misfolded Z-AAT. Current therapeutic options for the liver manifestations are limited, with liver transplantation being the only definitive treatment for end-stage disease. BMN-349's mechanism of action, which targets the fundamental protein misfolding and polymerization defect at its hepatic source, offers a novel therapeutic strategy. The successful development of an orally administered small-molecule chaperone like BMN-349 could represent a substantial advancement, potentially providing the first targeted therapy for the liver complications of AATD.

The progression of BMN-349 to Phase 1 clinical evaluation, following promising preclinical data, signifies BioMarin's strategic investment in this novel chaperone mechanism for an orphan disease that has historically presented considerable therapeutic challenges. The specific development of an oral small molecule formulation also points towards a strategic objective of improving patient convenience and potentially long-term adherence compared to existing protein augmentation therapies (which address lung disease) or more complex therapeutic modalities such as gene therapy currently under investigation by other entities. Pharmaceutical companies typically advance drug candidates to Phase 1 human trials only after substantial preclinical evidence suggests a favorable risk-benefit profile and a scientifically plausible mechanism of action. The positive preclinical findings for BMN-349, particularly its effects on Z-AAT polymerization and secretion [5], provide this foundational support. Given the current lack of approved pharmacological treatments that directly address the underlying Z-AAT proteinopathy in the liver, BMN-349 addresses a clear unmet need. Furthermore, oral small molecules [1] are generally preferred for chronic conditions due to their ease of administration, which can foster better long-term patient compliance compared to parenteral therapies or the inherent complexities of gene therapies. BioMarin's consistent emphasis on BMN-349 in its pipeline updates and strategic communications [2] further underscores its perceived value and strategic importance within the company's research and development portfolio.

2. Introduction to Alpha-1 Antitrypsin Deficiency (AATD)

Pathophysiology of AATD

Alpha-1 Antitrypsin Deficiency (AATD) is an autosomal co-dominant genetic disorder primarily caused by mutations in the SERPINA1 gene, located on chromosome 14. This gene encodes Alpha-1 Antitrypsin (A1AT), a 52-kDa glycoprotein that is a prominent member of the serine protease inhibitor (serpin) superfamily.[5] A1AT is predominantly synthesized and secreted by hepatocytes, with smaller amounts produced by other cell types such as monocytes and alveolar macrophages. Its principal physiological role is the inhibition of neutrophil elastase, a potent protease released by neutrophils during inflammation. By neutralizing neutrophil elastase, A1AT protects tissues, particularly the delicate elastin matrix of the lungs, from proteolytic degradation.[5]

The most common and clinically severe form of AATD arises from the "Z" mutation, a single nucleotide polymorphism (SNP) resulting in a glutamic acid to lysine substitution at position 342 of the A1AT protein (Glu342Lys, also known as the Pi*Z allele).[5] Individuals homozygous for this mutation (PiZZ genotype) produce the Z-AAT protein, which is prone to misfolding within the endoplasmic reticulum (ER) of hepatocytes. This misfolding exposes a region of the protein that allows for a loop-sheet insertion mechanism, leading to the formation of ordered, stable Z-AAT polymers.[5]

These Z-AAT polymers are inefficiently secreted and instead accumulate within the hepatocyte ER, forming characteristic eosinophilic, Periodic Acid-Schiff positive after diastase digestion (PAS-D+) inclusion bodies.[5] The intracellular accumulation of these polymers is believed to be the primary driver of liver disease in AATD. This "proteotoxic" gain-of-function mechanism triggers chronic ER stress, activates pro-inflammatory pathways (such as NF-κB), and promotes apoptosis and autophagy in hepatocytes. Over time, these processes can lead to progressive liver injury, neonatal cholestasis, chronic hepatitis, fibrosis, cirrhosis, and an increased lifetime risk of developing hepatocellular carcinoma.[5]

Concurrently, the impaired secretion of Z-AAT from the liver results in profoundly low serum levels of functional A1AT, typically 10-15% of normal levels in PiZZ individuals.[5] This systemic deficiency creates an imbalance between proteases (primarily neutrophil elastase) and anti-proteases in the lower respiratory tract. In the presence of inflammatory stimuli, such as cigarette smoke or infections, unopposed neutrophil elastase activity leads to the progressive destruction of alveolar walls and the development of early-onset panacinar emphysema and chronic obstructive pulmonary disease (COPD).[16] Thus, AATD manifests as a "loss-of-function" disease in the lungs (due to A1AT deficiency) and a "gain-of-toxic-function" disease in the liver (due to Z-AAT polymer accumulation).

Unmet Medical Needs in AATD-Associated Liver Disease

Despite the significant burden of AATD-associated liver disease, there are currently no approved pharmacological therapies that specifically target the underlying molecular defect of Z-AAT polymerization and accumulation within hepatocytes. Current management strategies for AATD liver disease are largely supportive, focusing on monitoring liver function, managing complications of portal hypertension and cirrhosis (such as varices and ascites), and screening for hepatocellular carcinoma. For patients who progress to end-stage liver disease, liver transplantation remains the only curative option, as it replaces the source of the mutant Z-AAT protein. However, transplantation is a major surgical procedure with associated risks, limited availability, and the need for lifelong immunosuppression.[16]

Intravenous A1AT augmentation therapy, which involves regular infusions of pooled human plasma-derived A1AT, is an established treatment for individuals with severe AATD and evidence of emphysema. This therapy aims to increase circulating A1AT levels to protect the lungs from further elastolytic damage.[20] While beneficial for the pulmonary manifestations, augmentation therapy does not address the intrahepatic accumulation of Z-AAT polymers and therefore has no direct impact on the progression of AATD-associated liver disease. This highlights a critical unmet need for therapies that can specifically target the liver pathology in AATD.

The biphasic nature of liver disease presentation in PiZZ individuals, with a notable peak in early childhood and another in adulthood (typically around age 40) [16], suggests that the window for therapeutic intervention may be broad. However, it also implies that early intervention, before the establishment of irreversible liver damage, could be crucial for maximizing therapeutic benefit. If a therapy like BMN-349 proves safe and effective, its application could potentially extend to younger populations to prevent or mitigate the early onset of liver injury. The current Phase 1 trial for BMN-349 is focused on adults [8], but successful outcomes in this population could pave the way for future pediatric investigations, given the lifelong nature of the protein defect and the early liver involvement in a subset of patients.

3. BMN-349: Profile and Mechanism of Action

BMN-349 is an investigational therapeutic agent developed by BioMarin Pharmaceutical, Inc..[1] It is characterized as an orally bioavailable small molecule.[1] While the specific chemical structure, molecular formula, and CAS number for BMN-349 are not explicitly detailed in the provided documentation, related patent information [18], which appears to underpin the scientific basis for this therapeutic approach [17], describes a class of A1AT polymerization inhibitors characterized by a central β-hydroxyamide moiety. It is highly probable that BMN-349 belongs to this chemical class of compounds.

The primary mechanism of action of BMN-349 is as an Alpha-1 Antitrypsin (A1AT) modulator and a protein folding stabilizer.[1] More specifically, it functions as a molecular chaperone. The therapeutic intent of BMN-349 is to target the misfolded Z-AAT protein within hepatocytes, the primary cell type responsible for A1AT synthesis. The Z mutation (Glu342Lys) in A1AT predisposes the protein to misfolding and subsequent polymerization within the endoplasmic reticulum (ER) of liver cells. BMN-349 is designed to interact with this misfolded Z-AAT, aiming to correct its conformation or stabilize it in a state that is less prone to polymerization.[5]

The class of compounds to which BMN-349 likely belongs is reported to bind to a novel, "cryptic" binding site on the A1AT protein. This binding site is not readily apparent in the structure of unbound, wild-type A1AT but is formed or becomes more accessible upon interaction with the compound. This site is strategically located at the "breach" region of β-sheet A, an area critical for the conformational changes involved in both the normal inhibitory function of serpins and their pathological polymerization. Significantly, this region includes the site of the Z-mutation (E342Lys).[18] The binding of the chaperone molecule to this cryptic site is thought to stabilize β-sheet A, thereby interfering with the transition of Z-AAT to the highly polymerization-prone M* intermediate state.[18]

Compounds within this class have demonstrated high affinity for Z-AAT [18] and show selectivity for the mutant Z-AAT over the wild-type M-AAT. This selectivity appears to be primarily driven by a faster rate of association with the Z variant.[18] BMN-349 itself has been described as preferentially sequestering the mutant Z-AAT protein.[13]

The intended therapeutic consequences of BMN-349's engagement with Z-AAT are twofold:

1. Reduction of Liver Polymer Burden: By inhibiting the polymerization of Z-AAT, BMN-349 aims to decrease the accumulation of toxic protein polymers within the ER of hepatocytes. This reduction in intracellular polymer load is expected to alleviate ER stress, reduce hepatocyte injury, and thereby mitigate the progression of AATD-associated liver disease, including fibrosis and cirrhosis.[5]
2. Increased Secretion of Monomeric A1AT: By stabilizing Z-AAT in a more native-like, non-polymerogenic conformation, BMN-349 is also designed to facilitate the correct processing and secretion of monomeric A1AT from hepatocytes into the bloodstream.[5] An increase in circulating functional A1AT could potentially offer systemic benefits, including enhanced lung protection, although the primary focus of BMN-349 development is liver disease.

The pharmacological strategy of targeting a cryptic binding site that is preferentially accessible or formed in the mutant Z-AAT [18] is a sophisticated approach. This suggests that BMN-349 may not merely act as a general stabilizer but could actively induce or select for a non-polymerogenic conformation of Z-AAT. Such a targeted interaction, specific to the disease-causing protein variant, holds the potential for a higher therapeutic index. This is because the drug would preferentially engage with the pathological Z-AAT, minimizing off-target interactions with correctly folded wild-type M-AAT or other unrelated cellular proteins. This specificity, combined with the direct intervention in the polymerization pathway by stabilizing β-sheet A and preventing the M* transition, could translate into a more profound and sustained correction of the Z-AAT defect with a potentially more favorable side effect profile compared to less specific proteostasis modulators. The observed high affinity and faster association rate with Z-AAT for related compounds lend further support to this concept of targeted engagement.[18]

4. Preclinical Development of BMN-349

The preclinical development of BMN-349 has relied significantly on the PiZ mouse model. This transgenic model expresses the human SERPINA1 gene carrying the Z mutation, leading to the accumulation of Z-AAT polymers in hepatocytes and the subsequent development of liver pathology that mirrors key aspects of human AATD-associated liver disease. This makes the PiZ mouse a relevant in vivo system for evaluating the efficacy of potential therapeutic agents like BMN-349.[5]

A summary of a key preclinical study design, as presented at the International Liver Congress (ILC) 2022 by BioMarin authors (Handyside, Wang, Bunting, Lomas, Irving, Ronzoni), is outlined below [5]:

• Animal Cohorts: The study utilized both young (5-6 weeks old) and adult (11-12 weeks old) female heterozygous PiZ mice. The inclusion of different age groups allows for the assessment of the drug's effect at potentially different stages of polymer accumulation and liver disease.
• Treatment Regimen: BMN-349 was administered twice daily (BID) via oral gavage at doses of 50 mg/kg or 100 mg/kg. The treatment duration was 30 days.
• Outcome Measures and Analyses:
• Plasma samples were collected at baseline and at several time points during the treatment period (days 5, 20, and 30) for the quantification of total Z-AAT and Z-AAT polymer levels using ELISA.
• At the end of the 30-day treatment period, liver tissue was harvested. Histopathological analysis, including Periodic Acid-Schiff with Diastase (PAS-D) staining, was performed to evaluate the extent of Z-AAT polymer accumulation (globules) within hepatocytes.
• In the adult cohort, liver and plasma samples were also subjected to mass spectrometry-based proteomics to identify and quantify pharmacodynamic biomarkers.
• Untreated wild-type (WT) mice and untreated PiZ mice served as control groups for comparison.

The key preclinical efficacy findings from these studies, particularly as reported in the ILC2022 abstract [5] and supported by patent literature for the compound class [17], are summarized in Table 1.

Table 1: Summary of Key Preclinical Efficacy Data for BMN-349 and Related Compounds

Parameter	Model System	BMN-349 Dose / Compound Details	Key Result	Source Snippet(s)
Liver Z-AAT Polymer Load	PiZ Mouse (young & adult)	BMN-349: 50 or 100 mg/kg PO BID for 30 days	Reduction in Z-AAT polymer globules in hepatocytes (PAS-D staining)	5/5
Intracellular Z-AAT Polymers	CHO-TET-ON-Z-A1AT cells	Compound 1 (from patent): Concentration-dependent	Complete blockage of intracellular Z-AAT polymer formation (pIC50​ = 6.3)	18/18
Plasma Total Z-AAT	PiZ Mouse (young & adult)	BMN-349: 50 or 100 mg/kg PO BID for 30 days	Increased plasma levels of total Z-AAT	5/5
Secreted Z-AAT	CHO-TET-ON-Z-A1AT cells	Compound 1 (from patent): Concentration-dependent	Approx. 3-fold increase in secreted Z-AAT (pEC50​ = 6.3)	18/18
Secreted Z-AAT	iPSC-hepatocytes (ZZ A1AT genotype)	Compound 1 (from patent): Concentration-dependent	Approx. 3-fold increase in secreted Z-AAT (pEC50​ = 6.5)	18/18
Circulating Monomeric Z-AAT	Transgenic Mouse Model (Z-A1AT)	Compound 1 (from patent): 10, 30, 100 mg/kg PO	6- to 7-fold increase with 100mg/kg; significant dose-dependent increases with 10 & 30mg/kg. Robust target engagement in liver demonstrated.	18/18
Plasma Z-AAT Polymers	PiZ Mouse (young & adult)	BMN-349: 50 or 100 mg/kg PO BID for 30 days	Assessed (specific change not detailed in snippet)	5/5
Pharmacodynamic Biomarkers	PiZ Mouse (adult)	BMN-349: 50 or 100 mg/kg PO BID for 30 days	Assessed by proteomics in liver and plasma (specific changes not detailed)	5/5

These preclinical results provided crucial in vivo validation for BMN-349's proposed mechanism of action. The data indicated that BMN-349 could effectively modulate the processing of mutant Z-AAT in the liver, leading to a reduction in the accumulation of pathogenic polymers—the primary driver of liver injury in AATD—and concurrently increasing the secretion of A1AT into the circulation. This strongly supported the advancement of BMN-349 into human clinical trials.

The consistent efficacy of BMN-349 observed in both young and adult PiZ mice [5] is a particularly noteworthy aspect of the preclinical findings. This suggests that the therapeutic potential of BMN-349 may extend across different stages of AATD-liver disease. The ability to show effects in adult mice, which would have a more established polymer burden and potentially more advanced liver pathology compared to younger animals, implies that BMN-349 might not only prevent the de novo formation of polymers but could also contribute to the reduction of existing polymer loads or mitigate ongoing liver damage. This is clinically significant as many AATD patients are diagnosed after some degree of liver injury has already occurred. A therapy capable of intervening effectively even in the presence of established pathology would hold considerable promise.

5. Clinical Development Program for BMN-349

Following the promising preclinical data, BioMarin Pharmaceutical advanced BMN-349 into human clinical trials. The initial phase of clinical development focuses on establishing the safety, tolerability, and pharmacokinetic (PK) profile of BMN-349 in individuals with AATD.

Phase 1 Clinical Trial (NCT06738017)

The cornerstone of the early clinical development for BMN-349 is a Phase 1 study registered under NCT06738017. Key details of this trial, compiled from multiple sources [4], are summarized in Table 2.

Table 2: Overview of the Phase 1 Clinical Trial for BMN-349 (NCT06738017)

Parameter	Details
Official Title	A Randomized, Double-Blind, Placebo-Controlled, Single Oral Dose Study Evaluating the Safety and Pharmacokinetics of BMN 349 in Homozygous for the Z Mutation of Alpha 1 Antitrypsin Gene (PiZZ) and Heterozygous for the Z Mutation (PiMZ/MASH) Adult Participants
NCT ID	NCT06738017
Phase	Phase 1
Status	Recruiting (as of March 2025)
Sponsor	BioMarin Pharmaceutical
Primary Indication	Alpha-1 Antitrypsin Deficiency (AATD)
Study Design	Randomized, Double-Blind, Placebo-Controlled. Includes Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) components. The SAD portion has been reported as completed.
Key Objectives	To assess the safety and tolerability of BMN-349. To evaluate the pharmacokinetics of BMN-349.
Primary Endpoints	Incidence of any adverse events (AEs), including serious adverse events (SAEs), dose-limiting toxicities (DLTs), and adverse events of special interest (AESIs). Incidence of laboratory test abnormalities. Incidence of lung function test abnormalities. 12-lead ECG parameters.
Secondary Endpoints (Anticipated)	Pharmacokinetic parameters (e.g., Cmax​, Tmax​, AUC, half-life). Exploratory pharmacodynamic markers (e.g., serum Z-AAT levels, Z-AAT polymer levels).
Target Population	Adults (18-64 years) with confirmed PiZZ genotype, or PiMZ genotype with evidence of Metabolic Dysfunction-Associated Steatohepatitis (MASH).
Number of Participants	Approximately 12
Intervention	Single oral dose of BMN-349 or placebo (SAD). Repeated oral doses of BMN-349 or placebo (MAD).
Key Inclusion Criteria	Confirmed PiZZ or PiMZ genotype. Age 18-64 years. Nonsmokers (no tobacco/nicotine use for ≥6 months prior to screening).
Key Exclusion Criteria	International Normalized Ratio (INR) > 1.2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 125 U/L. Current or recent A1AT augmentation therapy. Recent (last 3 months) diagnosis of pneumonia.
Study Start Date	February 21, 2025 (listed on some registries); MAD phase reported to have started Dec 2024.
Estimated Primary Completion Date	August 2025
Key Recruitment Locations	University of California, San Diego (CA, USA); Saint Louis University (MO, USA); Medpace Clinical Pharmacology Unit (Cincinnati, OH, USA); The Medical University of South Carolina (Charleston, SC, USA).

Reported Timelines and Future Clinical Plans

BioMarin has consistently communicated its plans for BMN-349. Initial announcements indicated an intent to initiate a global clinical program in 2024 [7], with the first-in-human study expected to commence later that year.[2] The formal study start date for NCT06738017 is listed as February 21, 2025 [8], although an update from BioMarin in February 2025 mentioned that the single-ascending dose (SAD) phase was complete and the multiple-ascending dose (MAD) phase had begun in December 2024.[7] This suggests a phased initiation or early cohort enrollment.

Clinical proof-of-concept (POC) for BMN-349 was initially anticipated in 2025.[7] BioMarin's presentation at the J.P. Morgan Healthcare Conference in January 2025 included "BMN 349 (A1AT) Study Start" as a milestone anticipated over the next 18 months, reinforcing the ongoing early-phase activities.[11] The company continues to feature BMN-349 in its earlier-stage development portfolio updates, underscoring its strategic commitment to this program.[6]

The inclusion of participants with a PiMZ genotype who also have MASH in this first-in-human study [7] is a strategically significant decision. While the PiZZ genotype is associated with the most severe A1AT deficiency and highest risk of liver disease, individuals heterozygous for the Z allele (PiMZ) can also develop liver complications, particularly if other co-existing risk factors for liver disease, such as MASH, are present. Evaluating BMN-349 in this PiMZ/MASH population from an early stage allows BioMarin to gather safety and PK data in a more heterogeneous patient group. Positive findings in this cohort could broaden the potential applicability of BMN-349 beyond individuals with the PiZZ genotype. It may provide early insights into the drug's utility in scenarios where Z-AAT polymerization contributes to, but is not the sole driver of, liver pathology. This could inform future development strategies, potentially including combination therapies or applications in a wider spectrum of AATD-related liver conditions, thereby expanding the drug's market potential and addressing an under-recognized segment of the AATD population.

6. Regulatory Status and Outlook

BMN-349 is currently in Phase 1 of clinical development.[1] To conduct clinical trials in the United States, BioMarin Pharmaceutical submitted an Investigational New Drug (IND) application to the Food and Drug Administration (FDA), which was subsequently cleared, permitting the initiation of human studies. BioMarin had previously indicated its intention to file the IND for BMN-349 in 2023 [23], and the commencement of the Phase 1 trial in early 2025 confirms this regulatory step was successfully completed.[8]

Orphan Drug Designation (ODD)

Alpha-1 Antitrypsin Deficiency (AATD) is a well-recognized rare genetic disorder, making therapies developed for this condition eligible for Orphan Drug Designation (ODD) by regulatory authorities such as the FDA in the United States and the European Medicines Agency (EMA) in Europe.[16] ODD provides various incentives to encourage the development of drugs for rare diseases, including periods of market exclusivity upon approval, tax credits for qualified clinical testing, and reductions in regulatory fees.[21]

Several other investigational therapies for AATD have successfully obtained ODD. For instance, INBRX-101 received FDA ODD for AATD treatment in March 2022, and alvelestat was granted US ODD for AATD in October 2021. Additionally, ARO-AAT received FDA Breakthrough Therapy Designation for AATD-associated liver disease in July 2021.[21]

Despite AATD being a qualifying condition, the AdisInsight drug profile for BMN-349, a generally reliable source for such regulatory information, explicitly states "No" under the Orphan Drug Status category as of September 2024.[1] None of the other provided research snippets indicate that BMN-349 has received ODD from either the FDA or EMA.[3]

The current absence of a reported ODD for BMN-349 is noteworthy, particularly given BioMarin's strategic focus on rare diseases and the precedents set by other AATD therapies. This situation could arise from several possibilities: BioMarin may not have formally applied for ODD for BMN-349 yet; an application might be under review by regulatory agencies and not yet publicly disclosed; the initial ODD application might not have been granted for reasons not detailed in the available information; or there could be a specific strategic rationale for delaying or not pursuing ODD at this early stage of development. Given the significant advantages conferred by ODD, especially for a company specializing in orphan diseases, this lack of designation is an important aspect of BMN-349's current regulatory landscape. Further clarification from BioMarin or regulatory agencies would be needed to ascertain the precise reasoning behind this status.

7. Therapeutic Potential and Strategic Context

BMN-349 holds considerable therapeutic potential due to its novel mechanism of action, which directly targets the core molecular pathology of Z-AAT accumulation in the liver—the primary cause of liver disease in AATD.[5] This approach is fundamentally different from existing A1AT augmentation therapies, which are designed to address the serum deficiency of A1AT for lung protection and do not impact the progression of liver disease.[20]

The development of BMN-349 as an orally bioavailable small molecule represents a significant potential advancement in patient convenience and treatment adherence compared to intravenously administered protein therapies or the more complex and invasive gene therapy strategies currently being explored.[2] BioMarin Pharmaceutical has expressed ambitions for BMN-349 to become a best-in-class treatment for AATD-associated liver disease, indicating a high level of confidence in its potential efficacy and safety profile.[2]

BMN-349 is a key component of BioMarin's early-stage development pipeline and aligns with the company's overarching strategy of focusing on innovative therapies for genetically defined rare diseases.[2] The company has articulated a commitment to concentrating its resources on programs with the highest potential for patient impact, and BMN-349's continued advancement reflects this strategic prioritization.[2]

The scientific foundation for this class of small molecule chaperones appears robust, originating from academic research led by Professor David Lomas at University College London (UCL) and involving early collaborative development efforts with GlaxoSmithKline (GSK). BioMarin has subsequently licensed and further developed this technology.[17] This lineage suggests a strong scientific rationale and a considerable period of foundational research supporting the BMN-349 program.

The successful clinical development of an effective oral small molecule chaperone like BMN-349 could revolutionize the management of AATD-associated liver disease. Currently, patients with progressive liver disease due to AATD have limited options, with liver transplantation being the only definitive treatment for end-stage complications.[16] By targeting the root cause of Z-AAT polymerization within hepatocytes [5], BMN-349 offers the prospect of not only halting disease progression but also potentially facilitating the clearance of existing toxic polymers and promoting hepatocyte recovery. If BMN-349 can achieve this, it could significantly reduce the morbidity associated with chronic liver disease, delay or prevent the development of cirrhosis and its complications, and ultimately decrease the number of AATD patients requiring liver transplantation. Such an outcome would represent a major clinical breakthrough and address a substantial unmet medical need, offering a far less invasive and more broadly accessible therapeutic option for a significant portion of the AATD patient population affected by liver disease.

8. Conclusion and Future Perspectives

BMN-349, an investigational oral small molecule chaperone developed by BioMarin Pharmaceutical, is currently in Phase 1 clinical trials for the treatment of Alpha-1 Antitrypsin Deficiency (AATD)-associated liver disease. Its mechanism of action, which involves modulating the folding of the mutant Z-A1AT protein to prevent its polymerization within hepatocytes and enhance its secretion, is supported by encouraging preclinical data from cell and animal models. If successfully developed, BMN-349 could offer a novel, targeted, and convenient oral therapy for a condition with significant unmet medical needs.

The ongoing Phase 1 study (NCT06738017) will be critical in establishing the safety, tolerability, and pharmacokinetic profile of BMN-349 in individuals with PiZZ and PiMZ/MASH genotypes. Future research will likely focus on demonstrating pharmacodynamic effects in humans, such as changes in serum Z-A1AT levels (both total and monomeric forms), Z-A1AT polymer levels, and markers of liver injury and function. Successful outcomes in Phase 1 would pave the way for Phase 2 and 3 trials designed to assess the efficacy of BMN-349 in halting or reversing the progression of AATD-associated liver disease, potentially using histological improvements, non-invasive imaging, and clinical outcomes as endpoints. Furthermore, if BMN-349 leads to a significant and sustained increase in functional circulating A1AT, its potential to confer lung protection might also be explored, although the primary development focus remains on liver disease.

Several challenges lie ahead for the BMN-349 program. A key hurdle will be the successful translation of preclinical efficacy—particularly the extent of Z-AAT polymer reduction and the increase in functional A1AT secretion—into clinically meaningful benefits for patients with established liver disease. Ensuring long-term safety and tolerability will also be paramount for a chronically administered oral therapy, especially in a patient population that may have varying degrees of pre-existing liver compromise. The identification and validation of sensitive, non-invasive biomarkers to monitor liver disease progression and therapeutic response will be important for guiding clinical development and patient management. Moreover, BMN-349 enters an evolving therapeutic landscape for AATD, with other modalities such as gene therapies and RNA interference (RNAi) strategies also under investigation by various entities.[21] BMN-349 will need to demonstrate a competitive and compelling profile in terms of efficacy, safety, and patient convenience.

Despite these challenges, BMN-349 represents an innovative and scientifically rational approach to treating the liver manifestations of AATD. Its development as an oral small molecule chaperone is a significant endeavor that, if successful, could provide a much-needed, targeted, and more convenient therapeutic option for individuals affected by this debilitating orphan disease, potentially transforming the standard of care.

Works cited

1. BMN 349 - AdisInsight - Springer, accessed May 27, 2025, https://adisinsight.springer.com/drugs/800066713
2. BioMarin continues pipeline clearout by halting preclinical gene therapy for heart condition, accessed May 27, 2025, https://www.fiercebiotech.com/biotech/biomarin-continues-pipeline-clearout-halting-preclinical-gene-therapy-heart-condition
3. Under new leadership, BioMarin axes 4 candidates and centers on 3 assets - Fierce Biotech, accessed May 27, 2025, https://www.fiercebiotech.com/biotech/under-new-leadership-biomarin-axes-4-candidates-and-centers-3-assets
4. BMN-349 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 27, 2025, https://synapse.patsnap.com/drug/58c8e84906f14220ae572e78aeaf8276
5. www.postersessiononline.eu, accessed May 27, 2025, https://www.postersessiononline.eu/173580348_eu/congresos/ILC2022/aula/-FRI_285_ILC2022.pdf
6. BioMarin Pharmaceutical Inc. - cloudfront.net, accessed May 27, 2025, https://d18rn0p25nwr6d.cloudfront.net/CIK-0001048477/7fa8d9a9-c624-4ab2-8eef-ca445b3478b8.pdf
7. A Randomized, Double-Blind, Placebo-Controlled, Single Oral Dose ..., accessed May 27, 2025, https://adisinsight.springer.com/trials/700367121
8. UCSD Alpha-1 Antitrypsin Deficiency Trial → BMN 349 Single Dose in (PiZZ) and (PiMZ) Adult Participants, accessed May 27, 2025, https://clinicaltrials.ucsd.edu/trial/NCT06738017
9. Study of BMN 349 Single Dose in (PiZZ) and (PiMZ) Adult Participants, accessed May 27, 2025, https://clinicaltrials.biomarin.com/clinical-trial/study-of-bmn-349-single-dose-in-pizz-and-pimz-adult-participants/
10. BioMarin looks to up pace of new drug filings - Fierce Biotech, accessed May 27, 2025, https://www.fiercebiotech.com/biotech/biomarin-rd-head-talks-2-new-pipeline-additions-strategy-sustain-best-pipeline-company
11. BioMarin Pharmaceutical Inc., accessed May 27, 2025, https://s203.q4cdn.com/846063244/files/doc_events/2025/BioMarin_JPM-2025_FINAL.pdf
12. Form 10-Q, accessed May 27, 2025, https://s203.q4cdn.com/846063244/files/doc_financials/2025/q1/f478cb3e-f0b5-444e-9711-87419d9931e9.pdf
13. BioMarin Announces Strong Third Quarter 2023 Results, Including Continued Profitability, and 15% Total Revenue Growth Year Over Year, accessed May 27, 2025, https://investors.biomarin.com/news/news-details/2023/BioMarin-Announces-Strong-Third-Quarter-2023-Results-Including-Continued-Profitability-and-15-Total-Revenue-Growth-Year-Over-Year-11-01-2023/default.aspx
14. Alpha-1 Antitrypsin Deficiency - BioMarin Clinical Trials, accessed May 27, 2025, https://clinicaltrials.biomarin.com/areas-of-clinical-research/alpha-1-antitrypsin-deficiency/
15. BioMarin Pharmaceutical Inc., accessed May 27, 2025, https://clinicaltrials.biomarin.com/
16. Alpha-1 antitrypsin deficiency-associated liver disease: From understudied disorder to the poster child of genetic medicine - PMC, accessed May 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11999460/
17. Structural and cellular basis of alpha-1-antitrypsin (AT) deficiency and the serpinopathies, accessed May 27, 2025, https://gtr.ukri.org/projects?ref=MR%2FV034243%2F1&pn=0&fetchSize=50&selectedSortableField=firstAuthorName&selectedSortOrder=ASC
18. WO2019243841A1 - Novel compounds - Google Patents, accessed May 27, 2025, https://patents.google.com/patent/WO2019243841A1/en
19. High-resolution characterization of ex vivo AAT polymers by solution-state NMR spectroscopy - PMC - PubMed Central, accessed May 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12057664/
20. PHARMACY POLICY STATEMENT - CareSource, accessed May 27, 2025, https://www.caresource.com/documents/marketplace-in-policy-pharmacy-medical-benefit-1142022.pdf
21. Global Alpha-1 Antitrypsin Deficiency Augmentation Therapy Market Report 2025, accessed May 27, 2025, https://www.thebusinessresearchcompany.com/report/alpha-1-antitrypsin-deficiency-augmentation-therapy-global-market-report
22. BioMarin Announces Fourth Quarter and Full Year 2021 Financial Results and Corporate Updates, accessed May 27, 2025, https://investors.biomarin.com/news/news-details/2022/BioMarin-Announces-Fourth-Quarter-and-Full-Year-2021-Financial-Results-and-Corporate-Updates-02-23-2022/default.aspx
23. BioMarin Announces Record Revenues in First Quarter 2022, accessed May 27, 2025, https://www.biomarin.com/news/press-releases/biomarin-announces-record-revenues-in-first-quarter-2022/
24. A1AT - Drugs, Indications, Patents - Patsnap Synapse, accessed May 27, 2025, https://synapse.patsnap.com/target/9155cbec4f2e4936872c83853dd23b1e
25. Alpha 1 Antitrypsin Deficiency Pipeline Drugs Market Stages, Target, Molecule Type and Key Players - GlobalData, accessed May 27, 2025, https://www.globaldata.com/store/report/alpha-1-antitrypsin-deficiency-a1ad-drugs-in-development-analysis/
26. FORM S-1/A - SEC.gov, accessed May 27, 2025, https://www.sec.gov/Archives/edgar/data/1273636/000119312514094588/d615962ds1a.htm
27. Orphan designation: Overview | European Medicines Agency (EMA), accessed May 27, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/orphan-designation-overview
28. BioMarin Pharmaceutical, Inc. - Drug pipelines, Patents, Clinical trials - PatSnap Synapse, accessed May 27, 2025, https://synapse.patsnap.com/organization/945a78962ce6ae24be3fc455ea813669
29. EU/3/23/2816 - orphan designation for treatment of primary membranous nephropathy, accessed May 27, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-23-2816
30. Gene, Cell, & RNA Therapy Landscape Report Q1 2025 Quarterly Data Report - ASGCT, accessed May 27, 2025, https://www.asgct.org/global/documents/asgct-citeline-q1-2025-report.aspx