Iclaprim is an
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
drug candidate that is active against
Gram positive organisms.
It is administered intravenously.
''
In vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'', iclaprim is active against
methicillin-resistant ''Staphylococcus aureus'' (MRSA),
vancomycin-resistant ''Staphylococcus aureus'' (VRSA), strains of ''
Streptococcus pneumoniae
''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They are ...
'' resistant to several common antibiotics, and some
Gram-negative bacteria
Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
.
It is of the
diaminopyrimidine
Diaminopyrimidines (DAP) are a class of organic chemical compounds that include two amine groups on a pyrimidine ring.
They include many dihydrofolate reductase inhibitor drugs (such as pyrimethamine, trimetrexate, and piritrexim and the ant ...
dihydrofolate reductase
Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as an electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In ...
(DHFR)-
inhibiting type.
History
Iclaprim is an optimized analog of
trimethoprim
Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for ''Pneumocystis'' pneumonia in peop ...
that was discovered by scientists at
Roche
F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX S ...
.
[ Arpida was spun out of Roche in 1998,] and acquired iclaprim from Roche in 2001.[ Arpida held an initial public offering on the Swiss stock exchange in 2005.
Arpida ran two Phase III clinical trials for complicated ]skin and skin structure infection Skin and skin structure infections (SSSIs), also referred to as skin and soft tissue infections (SSTIs), or acute bacterial skin and skin structure infections (ABSSSIs), are infections of skin and associated soft tissues (such as loose connective ti ...
s that were completed by 2008, but as of 2017, had not been published in the medical literature
Medical literature is the scientific literature of medicine: articles in journals and texts in books devoted to the field of medicine. Many references to the medical literature include the health care literature generally, including that of denti ...
.[ A new drug application was filed with the ]United States Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
based on these trials, and was rejected due to failure to show non-inferiority and due to safety concerns, especially drug-induced QT prolongation QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (ECG). Excessive QT prolo ...
.[. ] The FDA advisory committee said that the drug "should not be developed further" based on the results presented. A parallel application for marketing approval to the European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
was withdrawn in 2009; in the announcement of the withdrawal, the EMA said that there was insufficient data from clinical studies to justify the dosage proposed by the company and that resistance to the drug had already been seen in the clinical trial data.
Arpida collapsed after the rejection by the FDA and the EMA withdrawal.[ Arpida and the privately owned Swiss company Evolva began discussing an acquisition of Arpida by Evolva, which would allow Evolva to go public via a ]reverse merger
A reverse takeover (RTO), reverse merger, or reverse IPO is the acquisition of a public company by a private company so that the private company can bypass the lengthy and complex process of going public. Sometimes, conversely, the public compan ...
in September 2009. Arpida sold off iclaprim to Acino Pharma in November 2009, and in December 2009, Arpida and Evolva completed their transaction.
Acino sold the rights to iclaprim, its data and regulatory filings, and manufactured drug to a group called Life Sciences Management Group of Bethesda, Maryland
Bethesda () is an unincorporated, census-designated place in southern Montgomery County, Maryland. It is located just northwest of Washington, D.C. It takes its name from a local church, the Bethesda Meeting House (1820, rebuilt 1849), which in ...
, in September 2013 and that company assigned its rights to a company called Nuprim, which had been formed by the former chief executive officer, chief science officer, and US agent of Arpida in 2014. In December 2014, Motif BioSciences and Nuprim signed an agreement allowing Motif to acquire the iclaprim assets, and the transaction was completed in April 2015.[ In 2015, the FDA granted ]qualified infectious disease product
The Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) is a piece of American regulatory legislation signed into law on July 9, 2012. It gives the United States Food and Drug Administration (FDA) the authority to collect user ...
status for iclaprim.[
In September 2017, the FDA granted orphan drug status to iclaprim for the treatment of ''Staphylococcus aureus'' lung infections in people with cystic fibrosis. Iclaprim was non-inferior to ]vancomycin
Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, ...
when it was studied in two phase III studies of acute skin and skin structure infections published in 2018. As of February 2019, it is still not approved.
Chemistry
Iclaprim contains a stereocenter and is a racemate
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
, a 1: 1 mixture of (''R'')- and (''S'')-enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
s:
Names
During its development, other names for the drug have included AR-100, MTF-100, RO-48-2622, and the brand name Mersarex.[ It received its INN name in 2003.]
References
External links
Iclaprim at UK Speciality Pharma Service
Further reading
*
{{Sulfonamides and trimethoprim
Bacterial dihydrofolate reductase inhibitors
Aminopyrimidines
Benzopyrans
Phenol ethers
Cyclopropanes
Experimental drugs