Mitochondrial Disease

About Mitochondrial Disease

Numerous health problems, including neurological and muscular degeneration, cardiomyopathies, cancer, diabetes, and pathologies of aging can arise from mitochondrial dysfunction. Disorders such as Leigh syndrome, MELAS, NARP Syndrome and Freidrich’s Ataxia have been associated with mitochondrial defects. Severe mitochondrial defects can result in childhood disorders such as Leigh syndrome, for which there are no effective therapies and are often fatal.

Preclinical studies showed evidence that rapamycin, through inhibition of the mTOR signaling pathway, robustly enhances survival and attenuates disease progression in a mouse model of Leigh syndrome [1]. Administration of rapamycin to these mice, which are deficient in the mitochondrial respiratory chain subunit Ndufs4, delays onset of neurological symptoms, reduces neuroinflammation, and prevents brain lesions. Rapamycin induces a metabolic shift toward amino acid catabolism and away from glycolysis, alleviating the buildup of glycolytic intermediates, which could contribute to its therapeutic benefits. This approach of could be applicable for a broad range of mitochondrial diseases.

Due to the unique pharmacological profile of ABI-009, ABI-009 is well-suited for the treatment of certain mitochondrial diseases. AADi is conducting a phase 2a study to determine the optimal dose and utility of ABI-009 in pediatric patients with Leigh syndrome.

[1] Johnson et al (2013). Science. 342 (6165): 1524–1528

Mitochondrial Disease

January, 3 2019, Aadi Bioscience, Inc. (Aadi), a clinical stage biopharmaceutical company focused on treating diseases driven by mTOR activation, today announced that its drug TARZIFYX™ (sirolimus albumin-bound nanoparticles for injectable suspension, ABI-009) has received Breakthrough Therapy Designation status from the FDA for the indication of Advanced (metastatic or locally advanced) Malignant PEComa (perivascular epithelioid cell tumor). The designation was granted based on data provided to the FDA from Aadi’s ongoing phase 2 registration trial (NCT02494570) in Advanced Malignant PEComa. In October 2018, Aadi also received Fast Track Designation from the FDA for TARZIFYX™ for the same indication. Aadi received orphan drug designation for TARZIFYX™ for the treatment of PEComa in December 2017. Aadi’s Phase 2 registration trial for Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT), a rare form of sarcoma, has completed enrollment. Aadi previously received agreement from the FDA that this open label study in 30 efficacy evaluable patients with a primary endpoint of overall response rate could support the submission of an NDA for approval to treat this rare disease. mTOR inhibition is relevant in a number of disease states and has not been fully exploited in oncology, cardiovascular disease, CNS diseases, mitochondrial disease, diseases of ageing, etc. Due to the unique properties of Aadi’s drug including effective CNS penetration, it is being tested in nine ongoing clinical studies across these indications with encouraging results even outside of oncology in early studies in pulmonary hypertension and surgically refractory epilepsy. Aadi’s ongoing and planned clinical trials include Oncology (pediatric tumors, advanced sarcoma, first-line treatment of advanced colorectal cancer, newly diagnosed and recurrent glioblastoma, advanced neuroendocrine tumors), Cardiovascular indications (pulmonary arterial hypertension), CNS indications (surgically refractory epilepsy) and Mitochondrial disease (Leigh Syndrome). About Aadi and TARZIFYX™ (ABI-009) Aadi is a clinical stage biopharmaceutical company led by Dr. Neil Desai, an inventor of ABRAXANE®, TARZIFYX™ and the nab® technology platform. Aadi’s lead product TARZIFYX™ (sirolimus albumin-bound nanoparticles for injectable suspension, ABI-009) is an mTOR inhibitor complexed with human albumin that has significantly higher tumor accumulation and improved efficacy over other mTOR inhibitors in preclinical models. mTOR as a therapeutic target is well recognized in oncology, however Aadi aims to develop the full potential of albumin-bound sirolimus in therapeutic areas and diseases that are driven by mTOR activation and where the mTOR inhibitors have not or cannot be effectively exploited due to problems of pharmacology, effective drug delivery, safety or effective targeting to the disease site. These indications include oncology, cardiovascular, CNS, mitochondrial disease and diseases of ageing. About PEComa Perivascular epithelioid-cell tumors, defined by the World Health Organization as ‘mesenchymal tumors composed of distinctive cells that show a focal association with blood-vessel walls and usually express both melanocytic and smooth muscle markers,’ are a rare subset of soft-tissue tumors, with an undefined cell of origin. The PEComa family of tumors include lymphangioleiomyomatosis (LAM), angiomyolipoma (AML), clear-cell ‘sugar’ tumor of the lung (CCST), and a variety of morphologically and immunophenotypically similar tumors, which may arise in almost any body site (typically the uterus, retroperitoneum, genitourinary, and gastrointestinal tract), collectively termed PEComa-NOS. Malignant PEComas can have an aggressive clinical course including distant metastases and ultimate death. They have been shown to frequently harbor mutations in the TSC1 and/or TSC2 genes that result in the activation of mTORC1 pathway. Therefore, mTORC1 signaling is a promising therapeutic target for malignant PEComa, and anecdotal case reports have suggested clinical benefits of mTOR inhibitors in patients with malignant PEComas.   See original News Broadcast here: Businesswire.com/Aadi