LONDON – Motif Bio Ltd. is to float on the Alternative Investment Market in London, aiming to raise at least £4 million (US$6 million) to revive the fortunes of iclaprim, an antibiotic against methicillin-resistant Staphylococcus aureus that was turned down by the FDA in January 2009.

The FDA's Anti-infective Drugs Advisory Committee voted 17 to 2 against approving iclaprim in the treatment of complicated skin and skin structure infections (SSSIs), saying the data did not demonstrate noninferiority to the comparator, Pfizer Inc.'s Zyvox (linezolid), and that three deaths in the two phase III trials were "possibly related" to the product.

That verdict, and the call for further phase III trials, signaled the end for then-owner Arpida AG, of Reinach, Switzerland, and the file was subsequently withdrawn from the EMA, too.

Now Motif has picked up the baton, and has plans for two further phase III trials, in acute bacterial skin and skin structure infections (ABSSSIs) and hospital-acquired bacterial pneumonia. Following the fundraising, the London-based company will confirm with the FDA and EMA that the development plan meets requirements, with the aim of starting the first study during 2015.

On the face of it, a vote of 17 to 2 against implies there is a fair bit to do, but Graham Lumsden, CEO of Motif, said iclaprim was a victim of circumstance. In 2007 - 2009, the FDA was in ultra-cautious mode after it became evident that another antibiotic, Sanofi SA's Ketek (telithromycin) approved in the U.S. in 2004, was causing liver toxicity.

"The anti-infectives division at the FDA wasn't going to let it happen again," Lumsden said. Along with iclaprim, other antibiotics caught in the crosshairs were oritavancin (Targanta Therapeutics Corp., later acquired by the The Medicines Co.), telavancin (Theravance Inc.), ceftobiprole (Basilea Pharmaceutica AG) and cethromycin (Advanced Life Sciences Inc.).

A new drug application by New York-based Pfizer Inc. for another antibiotic, dalbavancin, was pulled after the FDA asked for a new trial, and Pfizer spun the drug off into new company Durata Therapeutics Inc. (See BioWorld Today, Dec. 23, 2009.)

Amongst those products, dalbavancin, brand name Dalvance, was subsequently approved in May 2014, leading in October to Durata's acquisition by Actavis plc for up to $809 million. (See BioWorld Today, Oct. 7, 2014).

The Medicines Co. won approval for oritavancin, now branded Orbactiv, in August 2014.

As another sign that things are looking up for antibiotics, Lumsden cites Paratek Pharmaceutical Inc.'s initial public offering (IPO) in 2014, when it raised $100 million to take its antibiotic, omadacycline, into phase III. The product has had a particularly tortuous time in the hands of pharma, however, having been previously partnered with Novartis AG, Merck & Co. Inc. and Bayer AG. (See BioWorld Today, Oct. 1, 2012.)

For proof that the tide has turned and that pharma is newly engaged with antibiotics, Lumsden pointed to the acquisition in January of Cubist Pharmaceuticals Inc. by Whitehouse Station, N.J.-based Merck for $9.5 billion. (See BioWorld Today, Dec. 9, 2014.)

Evidently, attitudes toward antibiotics have shifted, with the Generating Antibiotics Incentives Now (GAIN) program, providing further momentum. Motif is confident that in this improved environment, iclaprim too, can get over the finishing line. Indeed, Lumsden said, "We did consider going back to the FDA with the same file, but thought we couldn't do that for political reasons."

GAIN[ING] A 'MUCH BETTER POSITION'

The designs of a 500- to 600-patient ABSSSI study and a trial in hospital-acquired bacterial pneumonia involving around 900 patients are now being drawn up. The FDA has confirmed a meeting for early April, and Motif is about to engage with the EMA to ensure the studies meet the needs of both regulators.

After Arpida was rebuffed by the FDA in 2009, iclaprim passed into the ownership of Acino Holding AG, of Aesch, Switzerland. The drug delivery specialist met the FDA in November 2010 after the agency updated the definition of SSSI to that of ABSSSI, and changed the endpoints.

The FDA agreed with Acino that with the existing data and some additional analysis, or possibly another trial, the file was suitable for resubmission. However, Acino did not progress iclaprim, and in 2014 it was acquired by Nuprim Inc., a U.S. company set up by the former CEO and chief scientific officer of Arpida.

Motif has made a conditional agreement, subject to completing the IPO before March 31, to merge with Nuprim.

In the meantime, the patents on iclaprim, which was discovered by Roche AG, have not been renewed. But with GAIN providing 10 years of market exclusivity, Lumsden, a veteran of Merck, is unconcerned about that. "I spent 25 years at Merck wasting my time on patents," he told BioWorld Today.

"GAIN, and similar exclusivity in Europe, puts us in a much better position. Generics companies can always work a way around patents."

Lumsden is in the middle of a roadshow, taking in Edinburgh, London, Zurich and Geneva, and said he has had "a unanimously enthusiastic reception. It's very favorable because antibiotics are in the news and we have a special situation, with a phase III asset," he said.