Despite the impressive impact in antibacterial treatment in the middle of last century, infectious diseases are far from conquered. On a global scale, illnesses caused by microorganisms continue to be one of the biggest killers. New diseases like West Nile encephalitis and SARS seem to emerge constantly. Many infectious diseases like herpes, hepatitis B, and most notably, HIV can still not be cured. Often available treatments have a low responder rate and/or unbearable side effects, such

as the interferons and drugs used to treat hepatitis C infections.  Even conditions once thought well under control like community acquired pneumonia are now less easily treated due to the emergence of drug resistant pathogens.  Unfortunately, the global drug industry generated just two new classes of antibacterials during the past four decades,  making the need for new drugs and treatment options even more desperate.  

Antibacterials
The efforts are directed towards the discovery of antimicrobial drugs that act by completely new mechanism of action, to minimize cross-resistance to currently used antibiotics. As an example, in close collaboration with Vicuron Pharmaceuticals, Novartis researchers have developed peptide deformylase (PDF) inhibitors, a promising new class of antibiotics targeting an essential bacterial enzyme. The preclinical research team could convincingly demonstrate activity against all drug resistant pathogens tested. This approach has already yielded a first clinical candidate: LBM-415, for which Phase I studies have been initiated at the end of 2003.

Antivirals
Current in-house research efforts are focused on hepatitis C, an area of desperate need for more effective and better tolerated treatments. Scientific approaches include well-known viral targets such as the NS3 serine protease, as well as other Novartis-specific compound opportunities. 

The Infectious Diseases Disease Area (DA) is headed by Tom Evans and is located in Cambridge. Infectious Diseases research is also conducted at the Novartis Institute for Tropical Diseases (NITD) in Singapore.

Chen D, Hackbarth C, Ni ZJ, Wu C, Wang W, Jain R, He Y, Bracken K, Weidmann B, Patel DV, Trias J, White RJ, and Z. Yuan. Identification of Proline-3-Alkylsuccinly Hydroxamate VRC3375 as a Peptide Deformylase Inhibitor Through Integrated Combinatorial and Medicinal Chemistry. Antimicrobial Agents and Chemotherapy 48:250-261.

Jain R, Sundram A, Lopez S, Neckermann G, Wu C, Hackbarth C, Chen D, Wang W, Ryder NS, Weidmann B, Patel D, Trias J, White R, Yuan Z. Alpha-Substituted hydroxamic acids as novel bacterial deformylase inhibitor-based antibacterial agents. Bioorg Med Chem Lett. 13:4223-8 (2004). 

Favre B, Hofbauer B, Hildering K-S, Ryder NS. Comparison of in vitro activities of 17 antifungal drugs against a panel of 20 dermatophytes using a microdilution assay. J Clin Microbiol.   41:4817-4819. (2003).

Goessnitzer E, Malli R, Schuster S, Favre B, Ryder NS. Novel high energy intermediate analogues with triazasterol-related structures as inhibitors of ergosterol biosynthesis. Part I synthesis and antifungal activity of N-alkyl-N'-(phenethyl- and cyclohexenylethyl)guanidines and N2-substituted 2-Imidazolinamines. Arch Pharm (Weinheim)   335:535-546 (2002).

Arvidsson PI, Frackenpohl J, Ryder NS, Liechty B, Petersen F, Zimmermann H, Camenisch GP, Woessner R, Seebach D On the antimicrobial and hemolytic activities of amphiphilic b-peptides. ChemBioChem 2:771-773 (2001). 

Gautier-Lefebvre I, Behr J-B, Guillerm G, and Ryder NS. Synthesis of new (difluoromethylphosphono) azadisaccharides designed as bisubstrate analogue inhibitors for GlcNAc:b-1,4 glycosyltransferases. Bioorganic and Medicinal Chemistry Letters 10:1483-1486 (2000).

Ryder NS. Activity of terbinafine against serious fungal pathogens.  Mycoses 42 (Suppl. 2):115-9 (1999).

Famvir®  (famciclovir) is a potent antiviral agent that is active against a range of herpes viruses such as herpes zoster (shingles) and genital herpes.

Coartem®/Riamet® (artemether + lumefantrine) is a highly effective antimalarial indicated for the treatment of the most dangerous form of malaria, falciparum malaria. Novartis is making Coartem available to malaria-endemic developing countries, through a collaboration with the World Health Organization (WHO).

Lamprene® (clofazimine) and Rimactane® (rifampicin) are two anti-leprosy drugs developed in the 1950s and 1960s. These are two key products of Multiple Drug Therapy (MDT), the cornerstone of the leprosy elimination strategy.  Novartis is making MDT available free of charge to all leprosy patients worldwide through a collaboration with the WHO.

Denavir® (penciclovir) is a non-prescription topical antiviral cream against cold sores.

LDT600 (hepatitis B - phase III) may take efficacy to a next level in the treatment of hepatitis B. Data shows that LTD600 reduces serum hepatitis B DNA levels significantly more than standard therapy lamivudine, suggesting that it could become the best-in-class treatment.