New Drug Targets Enter Clinical Trials – OMA1, CAPN2, BTM-3566 & AMX-0114

Major Breakthrough! New Targets Entering Clinical Trials in February, Paving the Way for a New Era in Medicine

In the long journey of new drug development, the first entry of a drug into clinical trials is an immensely significant milestone. This signifies that the target has undergone extensive biological validation, including gene expression, protein structure, and function analysis, and is likely to play a key role in the pathogenesis of related diseases, bringing new hope for treatments. Today, let’s explore some important targets that made their clinical debut in February with Guideview.

OMA1: The "Guardian" of Mitochondrial Health and a New Therapeutic Target

OMA1 is a zinc metalloprotease located in the inner mitochondrial membrane and encoded by the OMA1 gene. It plays a crucial role in maintaining mitochondrial dynamics and stress response. When cells experience stress, such as loss of membrane potential or mitochondrial damage, OMA1 is activated. It cleaves the long isoform of the mitochondrial fusion protein OPA1, inhibiting fusion and promoting fission. Additionally, OMA1 degrades proteins such as DELE1 and PINK1, regulating mitophagy and apoptosis, thereby determining cell fate. For example, during apoptosis, Bax/Bak protein aggregation activates OMA1, triggering a cascade of reactions that lead to cell death.

OMA1 expression is closely linked to various diseases. In osteosarcoma, high OMA1 expression is associated with tumorigenesis and lung metastasis, and knocking it out can inhibit tumor growth. However, in lung adenocarcinoma, low OMA1 expression suppresses the PI3K/AKT pathway, reducing cancer cell proliferation. Additionally, OMA1-deficient mice exhibit obesity, metabolic disorders, and mitochondrial dysfunction, indicating its potential impact on metabolic diseases. Currently, the antifungal drug ciclopirox induces OMA1 self-cleavage to inhibit tumor growth, while certain kinase inhibitors may cause cardiotoxicity by activating OMA1. Thus, OMA1 is not only a key regulator of mitochondrial quality control but also a promising therapeutic target for multiple diseases.

BTM-3566: A Promising Anti-Cancer Drug Targeting OMA1

BTM-3566, developed by Bantam Pharma, is a small-molecule OMA1 agonist bringing new hope to cancer treatment. It induces OMA1 activation, leading to the cleavage of mitochondrial proteins OPA1 and DELE1, which subsequently activates HRI kinase and phosphorylates eIF2a. eIF2a regulates the Integrated Stress Response (ISR), which, depending on cellular conditions, either promotes adaptation or triggers apoptosis to combat cancer cells.

BTM-3566’s progress is highly anticipated. It was first presented at the 2021 ASH conference and is currently undergoing a Phase 1 clinical trial (NCT06792734) for relapsed/refractory mature B-cell lymphoma, with results expected in early 2026.

BTM-3566 has shown remarkable anti-cancer effects. In human DLBCL PDX models with high-risk genomic alterations (such as Myd88 mutations and MYC/BCL2 rearrangements), 100% of cell lines responded, with complete tumor regression observed in 6 out of 8 PDX models.

In mantle cell lymphoma, BTM-3566 inhibits proliferation and induces apoptosis, even in cells resistant to Ibrutinib and Venetoclax. In various animal models, including CDX and drug-resistant PDX mouse models, BTM-3566 nearly completely suppresses tumor growth.

Furthermore, BTM-3566 is not limited to hematologic malignancies; it also exhibits tumor-suppressive effects in solid tumors such as choriocarcinoma and esophageal cancer, though its efficacy is lower than in blood cancers.

From a commercial perspective, the diffuse large B-cell lymphoma market is expanding. In 2023, it was valued at $3.9 billion and is expected to reach $5.2 billion by 2034, with a CAGR of 2.7% from 2024 to 2034. Mantle cell lymphoma, a subtype of non-Hodgkin lymphoma, accounts for 6%–8% of cases. The global mantle cell lymphoma treatment market is projected to reach $2.53 billion in 2024 and grow at a CAGR of 8.6% from 2024 to 2034.

Currently, Bantam Pharma leads the development of OMA1-targeting drugs, with its BTM-3566 and BTM-3528 offering new hope for many patients.

CAPN2: A Versatile Target Hidden Deep in Cells

CAPN2 belongs to the calpain family and is a calcium-dependent, non-lysosomal cysteine protease. It plays multiple roles in cells, acting as a "regulator" of cytoskeletal remodeling and signal transduction by selectively cleaving key substrates to modulate cellular structure and function.

In neurons, CAPN2 is involved in activity-induced cleavage of CPEB3, affecting the translation of CPEB3-targeted mRNAs and influencing axonal degeneration. It also plays a key role in tumor development and metastasis. For instance, in pancreatic cancer, upregulated CAPN2 enhances epithelial-mesenchymal transition via the Wnt/β-Catenin pathway, promoting tumor cell proliferation, migration, and invasion.

AMX-0114: A CAPN2-Targeting Therapy Offering Hope for Neurological Diseases

AMX-0114, developed by Amylyx, is an antisense oligonucleotide targeting CAPN2. It binds to an exon within CAPN2’s protease-active domain, reducing CAPN2 mRNA levels via RNase H-mediated degradation, thereby lowering functional calpain-2 protein levels in cells.

Currently, AMX-0114 is undergoing a Phase 1 clinical trial (NCT06665165) in Canada for ALS (amyotrophic lateral sclerosis). In multiple studies, it has shown strong therapeutic potential. In induced pluripotent stem cell-derived motor neurons, AMX-0114 pre-treatment significantly reduced extracellular neurofilament light chain (NfL) levels, a biomarker of axonal damage in CNS diseases, suggesting its effectiveness in mitigating neuronal injury.

In iPSC-derived neurons carrying the ALS-associated TDP-43(M337V) mutation, AMX-0114 improved neuronal survival and reduced extracellular NfL levels. 

Additionally, in an oxidative stress-induced neurotoxicity model, AMX-0114 pre-treated neurons exhibited higher cell body retention under hydrogen peroxide exposure, effectively inhibiting CAPN2 activity and providing neuroprotection.

From a commercial standpoint, the recently approved ALS drug Tofersen (QALSODY) has achieved sales of $32 million in 2024. Experts predict that AMX-0114’s peak annual sales could reach $150 million. In 2023, the global ALS treatment market was valued at $667.3 million and is expected to grow at a CAGR of 5.8% from 2024 to 2030, with drug therapies accounting for 63.1% of the market while stem cell therapies rapidly develop.

Currently, only six drugs targeting CAPN2 are in development, presenting a relatively low competition landscape, which provides significant opportunities for AMX-0114’s future growth.

Conclusion

These newly introduced clinical targets—OMA1, CAPN2, and their associated drugs BTM-3566 and AMX-0114—show immense potential in their respective fields. They not only offer new directions for disease treatment but also inject fresh momentum into the pharmaceutical industry. We eagerly anticipate further breakthroughs from these targets and drugs, bringing new hope to patients worldwide.

References

[1]. Shammas MK, Huang X, Wu BP, et al. OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy. J Clin Invest. 2022;132(14):e157504. doi:10.1172/JCI157504
[2]. Bantam Pharma website
[3]. Coherent Market Insight
[4]. Grand View Research

[5]. Amylyx Website