Having promised to let Cardiome Pharma Corp. know about its NDA resubmission before the end of September, the FDA surprised the company by responding a month ahead, declaring the data package proposed for Brinavess (vernakalant hydrochloride) insufficient.

Shares of Vancouver, British Columbia-based Cardiome (NASDAQ:CRME) sank 32.8 percent Monday, or $1.27, to close at $2.60 on the news about Brinavess, an intravenous (I.V.) potassium channel blocker intended for rapid conversion of recent onset atrial fibrillation (AF).

Company officials could not be reached but said in a press release that talks would continue with the U.S. regulators. The drug is cleared for marketing in Europe, Canada and several other countries. In Europe, it won the nod for rapid conversion of recent onset AF to sinus rhythm in non-surgery adult patients with AF lasting fewer than seven days and for post-cardiac surgery patients with AF lasting fewer than three days.

In the most recent exchange with FDA gatekeepers, Cardiome proposed including in the new NDA package information from the original bid plus six years of safety data from sales of Brinavess in 33 countries, augmented by interim results from more than 1,100 patients enrolled in the SPECTRUM study, a prospective post-authorization EU safety study, as well as preclinical data from subsequent studies done by the company at the FDA's request.

Not enough, it turned out.

During Cardiome's second-quarter earnings call on Aug. 8, Cormark analyst David Novak asked for an update on Brinavess, recalling that the agency "encouraged you to submit a bunch of human data from the EU" and suggested another powwow 60 days after receipt of that package. Cardiome CEO William Hunter said the latest get-together with U.S. regulators "was converted into a type A meeting with a written response, and they have committed to getting back to us with their response before the end of September."

The agency acted even faster.

Cardiome has had its ups and downs with vernakalant. In the summer of 2011, Kenilworth, N.J.-based Merck & Co. Inc. took over rights for development and commercialization in North America from Astellas US LLC, a subsidiary of Astellas Pharma Inc., of Tokyo. Merck already had rights in other parts of the world. In August 2008, nearly seven months after Cardiome and Astellas had expected an approval decision from the FDA about the drug then known as Kynapid, the agency had responded with a request for more data. Merck's move came on the heels of an October 2010 setback, when Cardiome suspended enrollment in a clinical trial of the drug due to a case of cardiogenic shock at a South American clinical site. But then, in March 2012, Merck terminated development of the oral version. In September of the same year, the company returned rights to the oral and I.V. versions to Cardiome. (See BioWorld Today, Aug. 12, 2008, Oct. 22, 2010, July 27, 2011, March 20, 2012, and Sept. 27, 2012.)

Steadymed as she goes

With the latest edict from the FDA on Brinavess, "new product acquisitions are imperative to turn Cardiome cash flow-positive," in the view of Mackie Research analyst Andre Uddin, who pointed out in a report that the company has incurred a $300 million net operating loss to date. H.C. Wainwright analyst Swayampakula Ramakanth, reacting to second-quarter earnings, opined Aug. 9 that Cardiome's Xydalba (dalbavancin hydrochloride) will drive growth in the second half of this year. The compound is a second-generation, semi-synthetic lipoglycopeptide, which consists of a lipophilic side-chain added to an enhanced glycopeptide backbone. Xydalba shows bactericidal activity in vitro against a range of Gram-positive bacteria, such as Staphylococcus aureus (including methicillin-resistant strains) and Streptococcus pyogenes, as well as certain other streptococcal species.

"While Cardiome successfully launched Xydalba in select EU countries at the end of 2016, sales have been modest due to the significant time required for a new product to be added to hospital formularies," Ramakanth wrote. "To date, only about 10 percent of the 354 initially targeted hospitals have approved the drug for their formularies. However, according to management, 90 percent of target hospitals have scheduled drug committee meeting dates to review Xydalba between the second and fourth quarters of this year. Therefore, we expect the third quarter to be the first quarter of meaningful Xydalba revenues and expect the product to become Cardiome's main growth driver" this year and next. Ramakanth projected $4.5 million in revenues this year, growing to $36.5 million by 2025.

Approvals of another prospect in the hopper, Trevyent (tresprostinil sodium), could help, too. In July, Cardiome's partner, Rehovot, Israel-based Steadymed Ltd., submitted an NDA for the drug-device combination product that uses Steadymed's Patchpump technology to deliver the vasodilatory prostacyclin analogue to treat pulmonary arterial hypertension (PAH). Cardiome licensed the commercial rights to Trevyent for many international markets in June 2015 and expects to file for European Medicines Agency and Health Canada approvals by the end of this year. The current market leader in PAH is Remodulin (tresprostinil) for injection from United Therapeutics Corp., of Silver Springs, Md., which gained worldwide sales of $602 million last year.

"By using a pre-programmed, easy-to-use injector pump, we believe that Trevyent offers significantly improved convenience over Remodulin and could become the new standard of care for the treatment of PAH," Ramakanth said, adding that he expects Trevyent to win approval in the EU and Canada in early 2019 and projects the risk-adjusted, ex-U.S. revenues from the compound to grow to $74 million in 2025 from $5 million in 2019.