Orphan Drug Weekly Report: Amgen, Novartis, Ascentage Pharma Among Nine Therapies Granted Orphan Drug Designation by FDA

Last week, the FDA granted a total of nine orphan drug designations, including seven small-molecule chemical drugs, one cell therapy, and one gene therapy. Among them were an AAV vector-based gene therapy developed by Novartis Gene Therapies, a subsidiary of Novartis, and a lymphoid T progenitor cell therapy derived from CD34+ hematopoietic stem cells developed by Smart Immune. Ascentage Pharma’s Bcl-2 selective small-molecule inhibitor, APG-2575, secured its fifth orphan drug designation. In this article, WuXi AppTec’s content team will review some of these therapies.

Drug: AVXS-401

R&D Company: Novartis Gene Therapies

Indication: Friedreich’s Ataxia (FA)

Introduction: Friedreich’s ataxia (FA) is caused by a trinucleotide repeat expansion in the FXN gene, which encodes frataxin. This genetic alteration leads to a significant reduction in frataxin protein levels. Frataxin deficiency results in iron accumulation in tissues, affecting cells with high energy demands, such as those in the heart and brain. AVXS-401 is a gene therapy developed by Novartis Gene Therapies that uses an adeno-associated virus serotype 9 (AAV9) vector to deliver a functional copy of the FXN gene, thereby restoring frataxin production in tissues severely affected by FA.

Early toxicity studies in healthy mice demonstrated that AVXS-401 has a favorable safety and tolerability profile. Efficacy studies showed that a single intracerebroventricular (ICV) injection of low-dose AVXS-401 improved behavior and promoted gliogenesis in Friedreich’s ataxia (FA) mouse models with frataxin deficiency in the central nervous system. In mouse models lacking frataxin in the heart, AVXS-401 restored cardiac function, more than tripled median survival, and prevented the onset of cardiovascular disease. When the therapeutic dose was scaled up and administered to non-human primates, AVXS-401 achieved sustained frataxin expression in both the central nervous system and the heart, with effects remaining significant six months post-treatment.

Drug: Carfilzomib

R&D Company: Amgen

Indication: Acute Lymphocytic Leukemia (ALL)

Introduction: Carfilzomib has been approved by the FDA for use in combination with other therapies to treat relapsed or refractory multiple myeloma. As a proteasome inhibitor, it targets the proteasome-dependent degradation of excess proteins in myeloma cells, a process that allows these cells to recycle amino acids for continued growth and proliferation. By blocking the proteasome, carfilzomib causes an accumulation of proteins within the cells, ultimately leading to myeloma cell death.

Drug: ATI-450

Developer: Aclaris Therapeutics

Indication: Cryopyrin-Associated Periodic Syndrome (CAPS)

Introduction: ATI-450 is an oral small-molecule inhibitor targeting the p38α mitogen-activated protein kinase-activated protein kinase 2 (MK2) inflammatory signaling pathway. This pathway drives the expression of various inflammatory mediators, including cytokines, chemokines, and matrix metalloproteinases. Key pro-inflammatory cytokines regulated by this pathway include tumor necrosis factor-alpha (TNFα), interleukin-1 alpha and beta (IL-1α and IL-1β), and interleukin-6 (IL-6). Based on this mechanism, Aclaris is developing ATI-450 as a potential therapeutic agent for immune-mediated inflammatory diseases.

Drug: APG-2575

R&D Company: Ascentage Pharma

Indication: Follicular Lymphoma (FL)

Introduction: Follicular lymphoma is the second most common type of non-Hodgkin lymphoma (NHL), an indolent lymphoma that accounts for approximately 22% of NHL cases. Although treatments are available to improve overall survival, follicular lymphoma is considered an incurable malignancy, characterized by a disease course marked by repeated relapses and remissions.

APG-2575 is a novel oral Bcl-2 selective small-molecule inhibitor under development by Ascentage Pharma. It restores the programmed cell death mechanism (apoptosis) in tumor cells by selectively inhibiting the Bcl-2 protein, thereby killing tumor cells, and is intended for the treatment of various hematologic malignancies. Previously, it has received four orphan drug designations for the treatment of Waldenström’s macroglobulinemia (WM), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and acute myeloid leukemia (AML). Meanwhile, APG-2575 has obtained approvals for multiple Phase 1b/2 clinical trials in the United States, China, and Australia, with clinical development for multiple hematologic oncology indications advancing simultaneously worldwide.

Drug: Uttroside B

R&D Company: Q BioMed

Indication: Hepatocellular Carcinoma (HCC)

Introduction: Uttroside B is a saponin derived from *Streptomyces niger*, classified as a natural small-molecule compound. It modulates signaling pathways associated with cell survival and apoptosis by affecting JNK phosphorylation and caspase activity. Uttroside B exhibits cytotoxicity against various types of liver cancer cells and has demonstrated favorable therapeutic efficacy in preclinical studies.

Drug: T-lymphoid progenitor cells derived from CD34+ hematopoietic stem cells

R&D Enterprise: Smart Immune

Indication: Enhancing Cell Engraftment in Patients Undergoing Hematopoietic Stem Cell Transplantation

Introduction: Smart Immune’s proprietary technology is based on a biomimetic ex vivo thymus platform that differentiates CD34+ stem cells, purified from umbilical cord blood or peripheral blood hematopoietic stem cells, into T-lymphoid progenitor cells. When these T-lymphoid progenitor cells are infused into the human body, they migrate to the patient’s thymus, where they rapidly mature and acquire the ability to kill viruses and cancer cells without attacking healthy cells. This significantly reduces the risk of graft-versus-host disease (GVHD). This cell therapy acts synergistically with thymic epithelial cells by expressing cytokines that facilitate the reorganization and regeneration of the thymic epithelium, thereby significantly accelerating cell engraftment.

Drug: AVR-48

R&D Company: AyuVis Research

Indication: Prevention of bronchopulmonary dysplasia (BPD)

Introduction: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that primarily affects premature infants, who often require oxygen therapy. AyuVis is developing AVR-48, a novel small-molecule immunomodulator administered intravenously to enhance the body’s ability to resist inflammation and restore lung function, thereby helping to reduce or prevent BPD in premature infants and shorten hospital stays. Unlike current steroid therapies, AVR-48 does not suppress normal immune function and acts synergistically with these treatments due to its distinct anti-inflammatory properties.

Note: This article aims to introduce medical and health research and does not constitute a recommendation for treatment plans. For guidance on treatment options, please consult a qualified healthcare provider at a reputable hospital.

References:

[1] Novartis Gene Therapies. Retrieved Jan 22, 2021，from https://avexis.com/research-and-development.html

[2] Amgen. Retrieved Jan 22, 2021，from https://www.kyprolis.com/

[3] Aclaris. Retrieved Jan 22, 2021，from https://www.aclaristx.com/drugdiscovery/

[4] Ascentage Pharma Secures 9th FDA Orphan Drug Designation, Setting a Record Among Chinese Pharmaceutical Companies. Retrieved Jan 22, 2021, from https://www.ascentagepharma.com/news/press-releases/?lang=zh-hant

[5] Q BioMed. Retrieved Jan 22, 2021，from https://www.qbiomed.com/pipeline/uttroside

[6] Smart Immune. Retrieved Jan 22, 2021，from https://www.smart-immune.com/our-platform/

[7] Ayuvis. Retrieved Jan 22, 2021，from https://www.ayuvis.com/bronchopulmonary-dysplasia-bpd

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