Three years after creating its RX-04 discovery platform, Rib-X Pharmaceuticals Inc. has vetted 1,400 compounds, tuned them for efficacy against multi-drug resistant bacteria, and is in the process of selecting a handful of candidates to prep for an IND in 2012.

“The finalists essentially have great coverage across the board, and we’re really tuning for safety,” Rib-X CEO Mark Leuchtenberger said in an interview Sept. 18 at the Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.

Privately held discovery specialist is close to partnering search for two compounds.

Rib-X, in New Haven, Conn., recently inked a development deal with Sanofi SA. Leuchtenberger maintains it was the young firm’s rapid progress toward “what we think is best in class coverage of all the Gram negative bugs” that caught the French pharma’s eye (Also see "Rib-X Teams With Sanofi To Develop Novel, Broad-Spectrum Antibiotics" - Pink Sheet, 6 July, 2011.). The development team had to step up from monthly to weekly meetings “because we’re pushing or knocking down previous barriers that rapidly,” he stressed.

The Rib-X Approach To Rational Design

Rib-X created RX-04 by using crystallography to characterize a 20-angstrom-wide binding site on the ribosome, the cellular mechanism responsible for protein synthesis, and applying computational design tools and crystallography to create and test virtual antibiotic candidates that can fit that “pocket,” which is naïve to antibiotic activity and thus has no native antibiotic resistance mechanisms.

The actual candidates are then characterized biochemically as ribosomal inhibitors and through crystallography to demonstrate that they bind where they are intended.

The company was founded in 2002 based on technology licensed from Yale University – a high-resolution crystal structure of the ribosome developed by company co-founders Thomas Steitz and Peter Moore, and a structure-based drug design software application from co-founder William Jorgensen. Steitz won a Nobel prize in chemistry in 2009 for his work identifying the atomic structure of the ribosome. All three are still at Yale and involved with the company.

In the ensuing 10 years, however, Rib-X “has industrialized the model to the point where we now have several logs greater resolution in the model,” Leuchtenberger said. “It’s just become much more high resolution than the original academic discovery.”

To provide development options, Rib-X scientists created three entirely different small molecule discovery scaffolds under the RX-04 program, creating three new classes of antibiotics, Chief Scientific Officer Erin Duffy explained during a Sept. 17 presentation highlighting the compounds/technologies selected by ICAAC planners as most likely to become drugs (see related story, Also see "Novel Antibiotics At ICAAC Spur Optimism On Resistance Front" - Pink Sheet, 1 October, 2011.).

As created, the three scaffolds “in and of themselves really didn’t have impressive, or for that matter, any good and productive Gram negative activity,” but through iterations in design, Rib-X scientists “looked for properties to drive penetration into cell membranes and to avoid eflux out of them,” she said.

Gram negative bacteria have an inner and outer cell wall and an eflux mechanism to flush out antibiotics that penetrate either or both walls.

At the time Rib-X started talking to Sanofi and some other companies in the spring of 2011, “there was some skepticism that we would ever solve the eflux problem,” Leuchtenberger acknowledged, adding that “of course we now have great coverage,” particularly against the three most clinically important Gram negative pathogens: Acinetobacter baumannii, Pseudomonas aeruginosa and NDM-1-producing Enterobacteriaceae.

“Nobody we know of has come up with a drug in the Gram-negative space that targets the three toughest bugs, responsible for the biggest mortality, except for us,” he said.

Rib-X also has two other anti-infective discovery programs. RX-06 creates antifungal candidates and RX-05 generates antibiotics from a class entirely differentiated from the three that are part of RX-04 and is aimed at binding sites away from the 20-angstrom-wide pocket that defines the Sanofi deal for RX-04 candidates. “So that leaves this very rich, uncharted, unlicensed physical territory for us to develop novel anti-infectives – the entire rest of the ribosome,” Leuchtenberger said.

A Patent On The Whole Ribosome

Through the Yale patent, Rib-X has exclusive freedom to operate on the whole ribosome, Leuchtenberger explained. “The Yale patent is very, very far-reaching. It prevents anyone from working on any aspect of the ribosome at all, the entire ribosome, with the intention of rational drug design.”

Specifically, the area of the ribosome where most drug interaction activity is aimed is the 50S subunit. “Old drugs can bind there, but new drugs can’t be developed using rational drug design; they have to do traditional screening,” he said.

Making Rational Changes To Older Drugs

By visualizing where existing antibiotics bind on the ribosome, Rib-X can improve on their resistance profile. A case in point is Pfizer Inc.’s Zyvox (linezolid), the only marketed oxazolidinone antibiotic.

A billion-dollar drug already, no one had any idea where Zyvox bound to the ribosome, Leuchtenberger said. “We understood within not six months of founding the company where it was because we developed the crystal structure. In fact, we understand the actual bindings of all our competitor drugs much better than the companies themselves because we see the target interaction.”

That understanding led Rib-X to develop radezolid, a next-generation oxazolidinone the company says has an improved safety profile that allows for long-term treatment options, as well as better binding ability to thwart mutations.

Visualizing linezolid’s binding site allowed Rib-X scientists to see the mutation that occurs in the bacterial ribosome at a point where that binding is weakest, rendering the antibiotic ineffective, Leuchtenberger explained. They then created radezolid so that it would bind both in the same pocket as linezolid and in a second one “around the corner.” Even if that mutation occurs, it does nothing to change the essential binding. “It’s immovable; it can’t be blasted out of there by the mutation that Zyvox is subject to.”

Radezolid has completed Phase II trials in community-acquired pneumonia and uncomplicated skin and skin structure infections and is now in Phase I to evaluate an I.V. formulation, with the goal of providing an I.V. to oral step-down option to test in Phase III. That trial should read out in October.

At the European Congress of Clinical Microbiology and Infectious Disease in May, Rib-X reported that in a test against 90 strains of oxazolidinone-resistant Gram positive bacteria, both radezolid and torezolid, a Phase III oxazolidinone in development by San Diego-based Trius Therapeutics Inc., bested linezolid, but that radezolid had 2-16 times greater potency against the resistant strains compared to torezolid.

Another of Rib-X’s rational design programs, RX-02, is focused on remediating the macrolide class of antibiotics by engineering novel molecules that overcome known bacterial resistance modifications to that historically very safe class.

Lead Candidate Doesn’t Fit The Paradigm

Like many start-ups, Rib-X licensed in a candidate early on to get the pipeline flowing. In this case, the molecule, delafloxacin, first went through clinical trials at Abbott Laboratories Ltd. as a community antibiotic, Leuchtenberger said.

Rib-X determined through its 3-D examination of the molecule that it had “much more potential” as an anti-methicillin-reistant Staphylococcus aureus (MRSA) agent and “that it was going to have better safety than a lot of quinolones.” And, so far, it has shown no QT prolongation, dysglycemia, hepatic toxicity or phototoxicity in over 1,200 patients, he said.

The program will be Phase III-ready by the end of 2011, Leuchtenberger said. The candidate is nearly finished accrual in a Phase IIb trial comparing it against linezolid and vancomycin for treatment of acute bacterial skin and skin structure infections (ABSSSI), including MRSA. That should read out in December.

The goal is to position delafloxacin as a front-line empirical treatment in the ER, Leuchtenberger said. “At a point where it would be relatively attractive pricing, you’d have front-line treatment [and] solve most of your MRSA problems before you even have to go to the expensive drugs.”

The Drug Of Choice Right Off The Bat

Though delafloxacin also covers most of the Gram negatives, it doesn’t hit the most difficult to treat, Leuchtenberger acknowledged. Still, according to existing guidelines, physicians have to begin antibiotic therapy within six hours of seeing the infected patient – long before laboratory identification of the pathogens comes back in 24-48 hours.

In that situation, Rib-X is hoping physicians can end the practice of treating patients empirically with cocktails of antibiotics that aim to treat a broad spectrum of pathogens and instead treat them with delafloxacin monotherapy. Further, the company is hoping the antibiotic’s efficacy and benign safety profile will lead physicians to continue their patients on it even after the pathogens in play are identified.

FDA’s new endpoint for ABSSSI is to show efficacy in 48-72 hours, and Leuchtenberger said Rib-X is seeing improvement in that time period in its trials.

The new responder efficacy endpoint is for cessation of lesion spread and fever resolution at 48-72 hours after enrollment in the clinical trial (Also see "FDA Skin Infections Guidance Spurs Debate On Endpoint Relevance" - Pink Sheet, 6 September, 2010.).

In the future, predicted Leuchtenberger, “it’s only the second- and third-line patients that are going to have the narrow-spectrum therapies, whether Gram negative or Gram positive. That will sort itself out down the line. What we want to be is the drug that gets used right off the bat.”

The majority shareholder in privately held Rib-X is Warburg Pincus. “They’ve been great to work with,” Leuchtenberger said. The private equity firm anted $100 million of the $190 million invested in the company so far.

Other investors include ABS Ventures, Axiom Venture Partners LP, Cardinal Partners, Connecticut Innovations, EuclidSR Partners, MedImmune Ventures Inc., Saints Capital, Radius Ventures LLC, SR One Venture Investments and Vox Equity Partners I & II, LP.

The company’s runway should extend into late 2012, with the prospect of partnering delafloxacin and/or radezolid based on those pending read-outs.

By Shirley Haley

Rib-X Counting On Rational Drug Design To Outsmart Resistant Bacteria

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