Solithromycin Explained

Solithromycin (trade name Solithera) is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia[1] and other infections.[2]

Solithromycin exhibits excellent in vitro activity against a broad spectrum of Gram-positive respiratory tract pathogens,[3] [4] including macrolide-resistant strains.[5] Solithromycin has activity against most common respiratory Gram-positive and fastidious Gram-negative pathogens,[6] [7] and is being evaluated for its utility in treating gonorrhea.

Pre-clinical studies

An in vivo pre-clinical study performed by Jeffrey Keelan done in sheep may provide a prophylactic approach for intrauterine infections during pregnancy. This study was carried out by administering solithromycin to pregnant sheep, resulting in effective concentrations greater than 30 ng/ml in the fetal plasma, maternal plasma and amniotic fluid. A single maternal dose maintained these concentrations for over 12 hours.[8]

Clinical trials

Structure

X-ray crystallography studies have shown solithromycin, the first fluoroketolide in clinical development, has a third region of interactions with the bacterial ribosome,[15] as compared with two binding sites for other ketolides.

The only previously marketed ketolide, telithromycin, suffers from rare but serious side effects. Recent studies[16] have shown this to be likely due to the presence of the pyridine-imidazole group of the telithromycin side chain acting as an antagonist towards various nicotinic acetylcholine receptors. Solithromycin differs from telithromycin because the side chain does not significantly antagonize nicotinic acetylcholine receptors.[17] Instead of the pyridine-imidazole group used on telithromycin, this molecule has a triazole-phenylamine moiety.

Mechanism of action

Solithromycin inhibits bacterial translation by binding to the 23S ribosomal RNA, preventing the offending bacteria from synthesizing proteins.[18]

Side effects

During a clinical study some patients presented with elevated liver enzyme which may or may not be indicative of hepatotoxicity. This prompted the FDA Antimicrobial Drugs Advisory Committee to vote that the risk to the liver has not been adequately characterized and that further studies need to be conducted. To this extent, the FDA requests a 9,000 patient safety trial as well as restricting the drug.

Development

In 2008, investigational new drug applications for solithromycin capsules and an intravenous formulation were submitted. From studies of pharmacokinetics, safety, and efficacy several issues were found. There is variable absorption which can result in subtherapeutic drug concentrations and even therapy failure. Additionally, there are significant drug-drug interactions affecting solithromycin concentrations as well the concentrations of the offending drugs. There is also a narrow therapeutic margin which can make this drug challenging to dose.[19]

Commercial aspects

Cempra's general plan is to develop solithromycin develop products through late stage clinical trials and sell them to their hospital based sales force or through partnerships, which would need negotiations with larger pharmaceutical companies.[20] There are several manufacturing plants used such as Wockhardt Limited and Hospira Incorporated manufacturing facilities as well as Uquifa Laboratories, an alternative GMP facility.[21]

Intellectual property

Due to the fact that bringing new products to the market takes a significant investment of time and money, companies place considerable importance on patent protection for new products. Solithromycin is a new chemical entity from the macrolide library of compounds that were licensed by Optimer. It is covered by a series of patents and patent applications which claim the composition of matter of solithromycin.[22] There are also patents surrounding the synthesis and purification of this substance. For example, patent EP3190122 A1 presents a novel, efficient route of synthesis that bypasses the need for chromatographic purification which saves time.[23]

Notes and References

  1. Reinert RR . Clinical efficacy of ketolides in the treatment of respiratory tract infections . The Journal of Antimicrobial Chemotherapy . 53 . 6 . 918–927 . June 2004 . 15117934 . 10.1093/jac/dkh169 . free .
  2. Web site: Solithromycin . Cempra . https://web.archive.org/web/20120318061805/http://www.cempra.com/research/antibacterials/. 18 March 2012 .
  3. Woosley LN, Castanheira M, Jones RN . CEM-101 activity against Gram-positive organisms . Antimicrobial Agents and Chemotherapy . 54 . 5 . 2182–2187 . May 2010 . 20176910 . 2863667 . 10.1128/AAC.01662-09 . Mariana Castanheira .
  4. Farrell DJ, Sader HS, Castanheira M, Biedenbach DJ, Rhomberg PR, Jones RN . Antimicrobial characterisation of CEM-101 activity against respiratory tract pathogens, including multidrug-resistant pneumococcal serogroup 19A isolates . International Journal of Antimicrobial Agents . 35 . 6 . 537–543 . June 2010 . 20211548 . 10.1016/j.ijantimicag.2010.01.026 .
  5. McGhee P, Clark C, Kosowska-Shick KM, Nagai K, Dewasse B, Beachel L, Appelbaum PC . In vitro activity of CEM-101 against Streptococcus pneumoniae and Streptococcus pyogenes with defined macrolide resistance mechanisms . Antimicrobial Agents and Chemotherapy . 54 . 1 . 230–238 . January 2010 . 19884376 . 2798494 . 10.1128/AAC.01123-09 .
  6. Putnam SD, Castanheira M, Moet GJ, Farrell DJ, Jones RN . CEM-101, a novel fluoroketolide: antimicrobial activity against a diverse collection of Gram-positive and Gram-negative bacteria . Diagnostic Microbiology and Infectious Disease . 66 . 4 . 393–401 . April 2010 . 20022192 . 10.1016/j.diagmicrobio.2009.10.013 .
  7. Putnam SD, Sader HS, Farrell DJ, Biedenbach DJ, Castanheira M . Antimicrobial characterisation of solithromycin (CEM-101), a novel fluoroketolide: activity against staphylococci and enterococci . International Journal of Antimicrobial Agents . 37 . 1 . 39–45 . January 2011 . 21075602 . 10.1016/j.ijantimicag.2010.08.021 .
  8. Keelan JA, Kemp MW, Payne MS, Johnson D, Stock SJ, Saito M, Fernandes P, Newnham JP . 6 . Maternal administration of solithromycin, a new, potent, broad-spectrum fluoroketolide antibiotic, achieves fetal and intra-amniotic antimicrobial protection in a pregnant sheep model . Antimicrobial Agents and Chemotherapy . 58 . 1 . 447–454 . 4 November 2013 . 24189250 . 3910757 . 10.1128/AAC.01743-13 .
  9. News: Intravenous (IV) Administration of Cempra Pharmaceutical's Solithromycin (CEM-101) Demonstrates Excellent Systemic Tolerability in a Phase 1 Clinical Trial . 7 May 2011 .
  10. News: Cempra antibiotic compound as effective, safer than levofloxacin . 15 Sep 2011 .
  11. http://investor.cempra.com/releasedetail.cfm?ReleaseID=889300. 4 Jan 2015
  12. http://investor.cempra.com/releasedetail.cfm?ReleaseID=920866. 7 July 2015
  13. Web site: Cempra Announces Positive Topline Phase 3 Clinical Results for Intravenous Solithromycin in the Treatment of Community-Acquired Bacterial Pneumonia (NASDAQ:CEMP) . 2016-03-03 . https://web.archive.org/web/20160105072945/http://investor.cempra.com/releasedetail.cfm?ReleaseID=936994 . 2016-01-05 . dead .
  14. Web site: Cempra Announces FDA Acceptance of Solithera™ New Drug Applications in the Treatment of Community-Acquired Bacterial Pneumonia (NASDAQ:CEMP) . 2016-07-09 . https://web.archive.org/web/20160709221252/http://investor.cempra.com/releasedetail.cfm?ReleaseID=978096 . 2016-07-09 . dead .
  15. Llano-Sotelo B, Dunkle J, Klepacki D, Zhang W, Fernandes P, Cate JH, Mankin AS . Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis . Antimicrobial Agents and Chemotherapy . 54 . 12 . 4961–4970 . December 2010 . 20855725 . 2981243 . 10.1128/AAC.00860-10 .
  16. Bertrand D, Bertrand S, Neveu E, Fernandes P . Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors . Antimicrobial Agents and Chemotherapy . 54 . 12 . 5399–5402 . December 2010 . 20855733 . 2981250 . 10.1128/AAC.00840-10 .
  17. Fernandes P, Martens E, Bertrand D, Pereira D . The solithromycin journey-It is all in the chemistry . Bioorganic & Medicinal Chemistry . 24 . 24 . 6420–6428 . December 2016 . 27595539 . 10.1016/j.bmc.2016.08.035 . free .
  18. Owens B . Solithromycin rejection chills antibiotic sector . Nature Biotechnology . 35 . 3 . 187–188 . March 2017 . 28267725 . 10.1038/nbt0317-187 . 3648650 .
  19. Web site: FDA Briefing Document Solithromycin Oral Capsule and Injection Meeting of the Antimicrobial Drugs Advisory Committee (AMDAC). www.fda.gov. 31 October 2017.
  20. Web site: Cempra Annual Report. investor.cempra.com. en. 2017-10-30. https://web.archive.org/web/20151005211456/http://investor.cempra.com/secfiling.cfm?filingID=1193125-13-96011. 2015-10-05. dead.
  21. Web site: Cempra Receives Complete Response Letter From FDA For Solithromycin NDAs (NASDAQ:CEMP) . investor.cempra.com . en . 2017-10-31 . https://web.archive.org/web/20170704154336/http://investor.cempra.com/releasedetail.cfm?ReleaseID=1005708 . 2017-07-04 . dead .
  22. Web site: Cempra, Inc. - Annual Report. investor.cempra.com. en. 2017-10-30. https://web.archive.org/web/20151005211456/http://investor.cempra.com/secfiling.cfm?filingID=1193125-13-96011. 2015-10-05. dead.
  23. A novel synthetic pathway towards solithromycin and purification thereof . 2017-07-12 . EP . 3190122.

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