BioWorld Today Contributing Writer

Despite a bumpy road that includes two FDA approvable letters, the amyloid A (AA) amyloidosis drug candidate Kiacta (eprodisate) has been given another chance to prove itself through a confirmatory Phase III study that was initiated this week by Bellus Health, of Laval, Quebec, and its development partner Celtic Therapeutics LLLP.

The study is designed to confirm the safety and efficacy of Kiacta in preventing renal function decline in patients with AA amyloidosis, a complication of chronic inflammatory conditions, such as rheumatoid arthritis, that normally progresses to end-stage renal failure and death.

The compound has received orphan drug status and fast-track designation from the FDA and orphan medicinal product designation by the European Medicines Agency (EMEA).

AA amyloidosis develops when proteolytic fragments of serum amyloid A protein are deposited in tissues as amyloid fibrils. Kiacta is designed to interfere with interactions between amyloidogenic proteins and glycosaminoglycans to prevent deposition of the fibrils in tissues.

The international, randomized, double-blind, placebo-controlled, event-driven confirmatory study will involve approximately 230 patients diagnosed with AA amyloidosis enrolled from approximately 90 sites in 30 countries. The primary endpoint of the study is based on patients reaching an event linked to the deterioration of their renal function, defined as a persistent decrease in creatinine clearance of 40 percent or more, a persistent increase in serum creatinine of 80 percent or more, or progression to end-stage renal disease. The primary efficacy analysis will be the time from baseline to the first renal deterioration event of the primary endpoint. The study is tentatively planned to end when approximately 104 renal events have occurred. The companies estimate that the study will be completed in 2014.

In 2005, the initial Phase II/III trial for Kiacta, then called Fibrillex, demonstrated a positive trend in AA amyloidosis patients but missed its primary endpoint. The international, randomized, double-blind, placebo-controlled and parallel-designed trial studied 183 AA amyloidosis patients at 27 sites around the world over a 24-month treatment period. The study's primary endpoint, which looked at kidney function measurements and death, required 20 percent more stabilized or improved patients in the treated group compared to placebo (p = 0.01). Instead, only 13.4 percent more treated patients reached the endpoint (p = 0.06). (See BioWorld Today, April 19, 2005.)

Based on the finding that Kiacta reduced the progression of AA amyloidosis-associated renal disease – albeit below the primary endpoint value – officials at Bellus, then known as Neurochem Inc., decided to pursue FDA approval. Neurochem had inked a $54 million partnership with Centocor Inc., giving the Malvern, Pa.-based company exclusive distribution rights for the compound in all markets except Canada, Switzerland, China, Japan, Taiwan and South Korea. Neurochem remained responsible for U.S. and European Union (EU) product approvals and global manufacturing activities. (See BioWorld Today, Dec. 23, 2004.)

In August 2006, Neurochem received an approvable letter from the FDA requesting more efficacy data and a safety update. The company hoped to resolve the FDA's questions without additional trials by pursuing an FDA-proposed alternative: additional analysis from a complete follow-up of patients in the double-blind study. (See BioWorld Today, Aug. 15, 2006.)

Nearly a year later, after addressing the FDA's concerns without conducting another clinical trial, the company found itself almost right back where it started, with a second approvable letter – this one requesting a new efficacy trial with a target "p" value of 0.05 as well as additional pharmacokinetic studies and plans for post-approval QT clinical study. At the time, analysts following the drug reacted with skepticism to prospects for Kiacta, with Jonathan Aschoff, analyst with Brean Murray, Carret & Co. LLC calling the program "dead in the water." (See BioWorld Today, July 19, 2007.)

Not surprisingly, shares of Bellus were hammered on the news, which was followed by disappointing Phase III results from a second compound, Alzhemed (tramiprosate), designed to treat Alzheimer's disease. In 2008, Bellus refunded $6 million of the up-front payment from Centocor and took back full ownership rights and control of Kiacta.

In 2009, Bellus significantly reduced its basic research, support and administrative functions and retooled its business model to focus on taking early stage product candidates that address unmet medical needs through proof-of-concept and Phase II studies. The company subsequently withdrew its marketing applications for Kiacta in the U.S., EU and Switzerland and initiated discussions with several potential partners to complete a confirmatory Phase III trial and move Kiacta toward commercialization. In April, the company inked an agreement giving Celtic worldwide rights for Kiacta for up-front payments of $10 million. Celtic is a private equity firm based in the U.S. Virgin Islands that was founded in 2007 when the U.S.-based partners of Celtic Pharma Management LP split from their London-based colleagues. Celtic, which acquires Phase II programs with convincing initial efficacy and seeks to bring them to the finish line, is funding the confirmatory Phase III study and other development activities for Kiacta, estimated to cost $20 million. Celtic hopes to secure regulatory approval for the drug, then auction the commercialization rights, with the proceeds from the auction process shared equally by Bellus and Celtic.

Celtic is "highly confident" that the study will succeed, company co-founder and general partner Stephen Evans-Freke told BioWorld Today. Kiacta's initial Phase III study demonstrated significant robustness, arresting or reversing renal decline by 42 percent (p = 0.025) compared to placebo over a two-year period, and showed an excellent safety profile.

"The problem was that [Bellus] had struck a Faustian bargain with both the FDA and the EMEA, requiring the 0.01 results in order to get approved with one study," Evans-Freke said. "Even though the trial failed by that criteria, by any normal criteria it was a successful trial."

Just as important, the first trial had a composite endpoint, including a scoring system, Evans-Freke added. The new trial – with the approval of the FDA and the EMEA – drops the composite to focus on a single, primary endpoint. "We have written agreement from the FDA and the EMEA that 0.05 statistical significance on the second trial will be sufficient for approval," Evans-Freke said.

In the meantime, Kiacta has been safe and well tolerated during chronic administration, with some AA amyloidosis patients exposed to the compound for more than eight years in the compassionate use program. And Celtic "believes strongly" that AA amyloidosis is underdiagnosed, Evans-Freke said, with a likely market opportunity of $500 million to $600 million.

For its part, Bellus is thrilled to see Kiacta advance quickly to a confirmatory Phase III study. "We still believe very strongly in this product," Roberto Bellini, the company's president and CEO, told BioWorld Today. He credits the "entrepreneurial" nature of Bellus and Celtic in creating the right combination to move the product forward. "The best kinds of partnerships are ones where you have similar kinds of cultures," Bellini said. "We've contributed our experience. Now, Celtic is funding this program and allowing us to push the project forward, bring it right to the point of approval, and maximize its value."

Bellus' stock (TSX:BLU) also was bolstered by news of the study, closing at C12 cents Wednesday, up 118 percent.