BioWorld Today Contributing Writer

Rib-X Pharmaceuticals Inc. hooked a big fish for its first partnership, inking an exclusive worldwide research collaboration and licensing option with Sanofi SA, of Paris, for antibiotics resulting from its RX-04 program for the treatment of resistant Gram-positive and resistant Gram-negative pathogens.

Rib-X will receive $10 million in an up-front payment and is eligible to receive up to an additional $9 million in near-term research-based milestones. The big payoff could come downstream, with development and regulatory milestones of up to $86 million and commercial milestones potentially exceeding $100 million for each product derived from the RX-04 program, according to Mark Leuchtenberger, president and CEO of New Haven, Conn.-based Rib-X.

The research plan involves a minimum of four target product profiles, "so that implies at least four different target products in the development program," Leuchtenberger told BioWorld Today, confirming potential development and commercialization milestones of $744 million.

"But there is no upper limit on the number of products that could come out of the collaboration," he added. "For a preclinical-stage [compound], it's a very good deal."

Rib-X retained a co-promotion option in the U.S. on one molecule coming from the collaboration that could earn royalty rates in the low double digits on net sales. The company also retained the rights to its core discovery platform and earlier-stage programs, including RX-05 and RX-06, which are targeting different portions of the ribosome.

"Essentially, this is a drilling collaboration," Leuchtenberger said, with the "drilling site" including only one section of the peptidyl transferase center of the ribosome.

Using technology based on the work of co-founder Thomas A. Steitz, who shared the 2009 Nobel Prize for chemistry for studies of the structure and function of the ribosome, the RX-04 program targets bacterial ribosomes, an internal cell component where proteins are synthesized from amino acids and RNA.

The program exploits the peptidyl transferase region of the 50S subunit – the catalytic region of the ribosome and a well-known binding site of many classes of antibiotics, including oxazolidinones, lincosamides, phenyl propanoids, pleuromutilins, macrolides/ketolides and sparsomycin.

"There is no commercial antecedent for the binding site or the development program that we have at RX-04," Leuchtenberger said.

After synthesizing fewer than 200 compounds, the company has created five completely novel series of compounds targeting two sites that have shown good antibacterial activity against a number of clinically important multidrug-resistant Gram-negative pathogens. In a poster presentation at the 21st European Congress of Clinical Microbiology and Infectious Diseases in May, Rib-X presented data demonstrating that RX-04 directly affected ribosome function and exerted antibacterial activity by interfering with protein synthesis.

Rib-X isn't alone in the antibiotics space. Trius Therapeutics Inc., of San Diego, is developing drugs against Gram-positive infections, and Achaogen Inc., of South San Francisco, is advancing candidates against Gram-negative bacteria. Like Rib-X, Tetraphase Pharmaceuticals Inc., of Watertown, Mass., is developing antibiotics that can target both Gram-positive and Gram-negative pathogens. (See BioWorld Today, June 2, 2010.)

However, in "less than three years from a standing start," RX-04 has achieved what Leuchtenberger called "best-in-class coverage" of not only all Gram-positive pathogens but also the three worst existing classes of drug-resistant Gram-negative organisms, including Acinetobacter and New Delhi metalol-beta-lactamase. (See BioWorld Today, Sept. 15, 2010.)

"We've pioneered uncharted territory," Leuchtenberger said, noting that Rib-X is the only company to marry X-ray crystallography with computational chemistry to explore and define all binding sites of the ribosome. "It's taken us a little while to industrialize that discovery engine, but now we're hitting our stride," he added.

The unmet need is enormous, Leuchtenberger said, and noted that methicillin-resistant S. aureus (MRSA) kills more than 19,000 in the U.S. each year – more than HIV. Nevertheless, the antibiotic pipelines have slowed over the past 10 years. In fact, the National Institutes of Health has awarded some $69,000 in grants for every U.S. death from AIDS, but only $570 for every death from MRSA, he said, citing research published on Tuesday in Wired.

Sanofi was one of at least six potential suitors for RX-04, added Leuchtenberger, who joined Rib-X from Targanta Therapeutics Corp., where he led the company's 2007 initial public offering and 2009 acquisition by The Medicines Co.

Rib-X scientists will immediately begin to collaborate with Sanofi's research and development team, added Leuchtenberger, who flew to Toulouse, France, on Wednesday for a kickoff meeting with Sanofi.

And the Sanofi collaboration may not be the last for the company this year. Leuchtenberger confirmed Rib-X has been in active discussions with potential partners for delafloxacin, a broad-spectrum fluoroquinolone antibiotic candidate currently in a Phase IIb study that is expected to report in the fourth quarter. "We hope to get a Phase III development partnership for [delafloxacin] later this year, following the data," he said.

The company's other clinical-stage candidate, radezolid, is a second-generation oxazolidinone with broader spectrum of coverage than conventional oxazolidinones and increased activity against Gram-positive organisms. The compound has completed two Phase II trials "so it will be Phase III ready next year," Leuchtenberger said, adding that the company also will entertain development partnerships for the earlier-stage programs RX-05 and RX-06.

Privately held Rib-X has managed to attract outside funding even during the depths of the recession, garnering a $20 million private equity round last year. Previously, the company raised $50 million in a Series C financing, $63.5 million in a Series B preferred stock placement and $22 million in two Series A tranches. (See BioWorld Today, Jan. 4, 2002, May 3, 2003, and June 21, 2006.)

The up-front payment from Sanofi, combined with the company's existing cash, extends Rib-X's financial runway into the second half of 2012. Later this year or early next year, the company may explore another financing, "whether it's the public market or another private financing," Leuchtenberger said.