Durata Therapeutics Announces FDA’s Acceptance for Priority Review of NDA for Dalvance (dalbavancin hydrochloride)

CAS No.	171500-79-1
Chemical Name:	Dalbavancin
Synonyms:	MDL 63397;Dalbavancin
CBNumber:	CB41028737
Molecular Formula:	C88H100Cl2N10O28
Formula Weight:	1816.71

CHICAGO, Nov 26, 2013 (GLOBE NEWSWIRE via COMTEX) — Durata Therapeutics, Inc. DRTX +6.48% today announced that the New Drug Application (NDA) for its investigational drug, Dalvance (dalbavancin hydrochloride) for injection, has been accepted for priority review by the U.S. Food and Drug Administration (FDA) with an action date of May 26, 2014. Durata is seeking FDA approval of Dalvance(TM) for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible Gram-positive microorganisms, including MRSA (methicillin resistant Staphylococcus aureushttp://www.drugs.com/nda/dalbavancin_131126.html

Dalbavancin, V-Glycopeptide, VER-001, BI-397 factor B0, BI-397

Vicuron Pharmaceuticals (Originator)

5,31-Dichloro-38-de(methoxycarbonyl)-7-demethyl-19-deoxy-56-O-[2-deoxy-2-(10-methylundecanamido)-beta-D-glucopyranuronosyl]-38-[N-[3-(dimethylamino)propyl]carbamoyl]-42-O-alpha-D-mannopyranosyl-N15-methylristomycin A aglycone; (3S,15R,18R,34R,35S,48S,50aR

Dalbavancin, which is also referred to in the scientific literature as BI397 or VER001, is a semi=synthetic glycopeptide mixture, the properties of which have been reported in U.S. Pat. Nos. 5,606,036, 5,750,509, 5,843,679, and 5,935,238.

U.S. Publication No. 20040224908;

J Antibiot1995,48,(8):869

Drugs Fut1999,24,(8):839

Dalbavancin is prepared by chemical modification of the natural glycopeptide complex A-40,926 as described in Malabarba and Donadio (1999) Drugs of the Future 24(8):839-846. The predominant component of dalbavancin is Factor Bo, which accounts for >75% of the whole complex.

[0042] The amount of each of the components present in a dalbavancin composition is dictated by a variety of factors, including, for example, the fermentation conditions employed in the preparation of the natural glycopeptide complex A-40926, which is the precursor to dalbavancin (see, e.g., U.S. Pat. No.5,843,679), the conditions employed to recover A-40926 from the fermentation broth, the chemical reactions employed to selectively esterify the caxboxyl group of the sugar moiety of A-40926, the conditions employed to amidate the peptidyl carboxyl group, the conditions employed to saponify the ester of the carboxyl group of the N-acylaminoglucuronic acid function, the conditions employed to recover dalbavancin from the synthetic mixture, and the like.

the semisynthetic glycopeptide dalbavancin was synthesized from the natural antibiotic A 40926, originally isolated from an Actinomadura culture (Malabarba et al., 1998, U.S. Pat. No. 5,750,509). Dalbavancin has shown greater efficacy against various bacterial strains than vancomycin or the antibiotic linezolid and represents a promising new treatment for skin and soft tissue infections (see, e.g., Jabés et al., 2004, Antimicrob. Agents Chemother. 48:1118-1123). According to U.S. Pat. No. 5,750,509, dalbavancin is a glycopeptide antibiotic with a monomethyl moiety at its N¹⁵ amino (see FIG. 1 for numbering), and this N¹⁵-monomethyl amino could be free (i.e. —NHCH₃) or protected with an amino protecting group such as t-butoxycarbonyl, carbobenzyloxy, arylalkyl or benzyl. The method for making certain of the dalbavancin components reported in the ‘509 patent also produced N¹⁵,N¹⁵-dialkyl analogs of dalbavancin in minor-quantities, but these molecules were not characterized.

Dalbavancin (INN, trade name Zeven) is a novel second-generation lipoglycopeptideantibiotic. It belongs to the same class as vancomycin, the most widely used and one of the few treatments available to patients infected with methicillin-resistant Staphylococcus aureus (MRSA).^[1]

Dalbavancin (BI397) is a novel semisynthetic lipoglycopeptide that was designed to improve upon the natural glycopeptides currently available, vancomycin and teicoplanin.^[2]

It possesses in vitro activity against a variety of Gram-positive pathogens^[3][4] includingMRSA and MRSE.^[5] It is a once-weekly, two-dose antibiotic that Pfizer acquired when it bought Vicuron Pharmaceuticals in 2005.^[6]

Dalbavancin has undergone a phase III clinical trial for adults with complicated skin infections, but in Dec 2007 the FDA said more data was needed before approval.^[6] On September 9, 2008, Pfizer announced that it will withdraw all marketing applications in order to conduct another Phase 3 clinical trial.^[7] Durata Therapeutics acquired the rights to dalbavancin in December 2009 and has initiated two new Phase III clinical trials for treatment of acute bacterial skin and skin structure infections.^[8] Preliminary results in Dec 2012 looked good.^[9]

1.  Vicuron Pharmaceuticals Submits New Drug Application for Dalbavancin to U.S. Food and Drug Administration
2.  Scheinfeld NS. (May 2006). “Dalbavancin: A review for dermatologists.”. Dermatology Online Journal 12 (6). Unknown parameter |numero= ignored (help) PMID 17083861
3.  Chen AY, Zervos MJ, Vazquez JA (2007). “Dalbavancin: a novel antimicrobial”. Int. J. Clin. Pract. 61 (5): 853–63. doi:10.1111/j.1742-1241.2007.01318.x. PMC 1890846.PMID 17362476.
4.  Das B, Sarkar C, Biswas R, Pandey S (2008). “Review: dalbavancin-a novel lipoglycopeptide antimicrobial for gram positive pathogens”. Pak J Pharm Sci 21 (1): 78–88. PMID 18166524.
5.  Dalbavancin: A Novel Lipoglycopeptide Antibacterial
6.  UPDATE 1-Pfizer says US FDA wants more data on antibiotic. Dec 2007
7.  “Pfizer Will Withdraw Global Marketing Applications for Dalbavancin to Conduct a New Trial” (Press release). Pfizer Inc. 2008-09-09. Retrieved 2008-09-11.
8.  Durata Begins Dalbavancin Study Enrollment. Drug Discovery & Development – October 05, 2011.
9.  Durata Therapeutics Announces Phase 3 Clinical Trial Results for Dalbavancin in the Treatment of ABSSSI

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