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Earlier this week, Matinas BioPharma Holdings, Inc. (MTNB) announced the company commenced dosing in a Phase 1 clinical study of MAT2501, an orally administered encochleated formulation of the broad spectrum antibiotic, amikacin. The initial indication for MAT2501 is for the treatment of nontuberculous mycobacterium (NTM) infections, a potentially serious and life-threatening disease that affects nearly 90,000 individuals in the U.S.
On December 8, 2016, the company announced it has received a research contract award from Cystic Fibrosis Foundation Therapeutics Inc. (CFFT), the non-profit drug discovery and development affiliate of the Cystic Fibrosis Foundation, to study MAT2501 for the treatment of NTM in pre-clinical models of cystic fibrosis (CF). The award provided by CFFT will support a collaborative research program between Matinas and Colorado State University to study the efficacy of MAT2501 in NTM infection in a CF lung model developed by the university.
Amikacin is a powerful antibiotic with limited resistance. Unfortunately, tolerability is poor and adverse events, including severe nephrotoxicity and ototoxicity, is common. This greatly limits uptake of the drug and relegates use to last-resort indications. Additionally, Amikacin must be delivered via intramuscular or intravenous injection. Nebulized and inhaled formulations are under late-stage development, but to date, no oral formulation has been approved by the U.S. FDA. Matinas MAT2501 has important differentiating characteristics that could make the drug a tremendous commercial success. Below is a quick review of MAT2501 and why I believe the initiation of a Phase 1 study is an important milestone for Matinas.
Quick Background On Amikacin
Amikacin is an aminoglycoside antibiotic used to treat serious bacterial infections. The drug is highly potent with broad-spectrum antibiotic activity (1). Amikacin works by binding to the bacterial 30S ribosomal subunit, interfering with mRNA translation and synthesis of important proteins vital to bacterial growth and survival. Amikacin has synergistic effects with beta-lactam antibiotics and although antibiotic resistance to aminoglycosides exists and is increasing, resistance to amikacin is less common due to the drugs conserved moiety (attached to N-1) and inhibition of multiple biological mechanisms, including acetylation, phosphorylation, and adenylation (2).
The most common uses in the U.S. are in treating severe, hospital-acquired infections with multidrug-resistant Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter, and Enterobacter. Amikacin can also be used to treat non-tubercular mycobacterium (NTM) infections and tuberculosis (if caused by sensitive strains) when first-line drugs fail to control the infection. NTM is the initial focus for Matinas with MAT2501.
Despite powerful efficacy and low resistance, Amikacin use in the U.S. is limited due to severe nephrotoxicity (3). Drug-induced acute kidney injury with amikacin is common, with roughly 20% incidence, and exacerbated by the presence of previous kidney damage, diabetes, and hypertension (4). Because of this risk, blood levels of the drug and markers of kidney function (i.e. creatinine) should be monitored and dose adjusted if necessary. Ototoxicity (hearing loss) is another remarkably significant side effect of amikacin use, with incidence rates found to be as high as 70% in some studies (5). The toxic side-effect profile of the drug relegates its use to a position as an antibiotic of last resort.
Amikacin may be administered 1-3 times a day but is only available as an intravenous or intramuscular injection or via nebulization. There is no oral formulation available as amikacin is not absorbed orally in its free form. In people with kidney disease, dosage must be adjusted according to the creatinine clearance, usually by reducing the dosing frequency. An orally bioavailable formulation of amikacin that improves ease of administration and reduces nephrotoxicity would be highly desirable to the infectious disease medical community.
Matinas Cochleate Technology
MAT2501 utilizes its cochleates technology to encapsulate and protect amikacin so that the drug can be dosed orally. Cochleates are stable, crystalline phospholipid-cation delivery vehicles that are composed of soybean phosphatidylserine (PS) and calcium. Calcium is used to create a calcium-phospholipid anhydrous crystal structure that traps the active pharmaceutical ingredient (API) inside the nano-crystalline structure. Once formed, the compound has a unique multilayered structure and no internal aqueous space. Cochleate drugs can be taken orally because the high calcium concentration inside the digestive tract keeps the cochleate structure in crystalline form. This protects the API even though the outer layers of a cochleate crystal may be exposed to harsh environmental conditions or enzymes found in the digestive tract.
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