Horizon Pharma plc reported an all-around failure of its phase III trial, STEADFAST (Safety, Tolerability and Efficacy of Actimmune Dose Escalation in Friedreich’s Ataxia study), which missed its primary and secondary endpoints in evaluating Actimmune (interferon gamma-1b) to treat Friedreich’s ataxia (FA). As a result, the Dublin-based company will wind down the FA development program, including a 26-week extension study and long-term safety study.

The randomized, double-blind, placebo-controlled STEADFAST study enrolled 92 patients across four U.S. sites. Participants were treated with subcutaneous doses of Actimmune or placebo three times a week for 26 weeks.

The primary endpoint was a statistically significant change from baseline in the modified Friedreich’s Ataxia Rating Scale at week 26 compared to placebo. The exam-based rating scale measures disease progression based on functional parameters such as speech, ability to swallow, upper and lower limb coordination, gait and posture.

The trial also missed statistical significance on its secondary endpoints, which included observed mean change from baseline to week 26 in activities of daily living, timed 25-foot walk test, Friedreich’s Ataxia Rating Scale scores and other neurologic measures.

No additional safety findings were identified on initial data review outside those noted in the Actimmune prescribing information in its two FDA-approved rare indications: to reduce the frequency and severity of serious infections associated with chronic granulomatous disease, a genetic disorder that affects the functioning of some cells of the immune system, and to delay disease progression of severe, malignant osteopetrosis, a genetic disorder that affects normal bone formation.

Horizon officials said they discussed the trial results with the independent data safety monitoring board, the principal investigator (PI) and the Friedreich’s Ataxia Research Alliance (FARA) Collaborative Clinical Research Network before deciding to yank the Actimmune program in FA. Horizon will continue to work with FARA and the PI to analyze the data, which could help inform future research efforts, and to seek to present or publish the data.

On a conference call with analysts, Timothy Walbert, Horizon’s president and CEO, was glum but forthright, refusing to blame a placebo effect or to suggest the therapy might work in a subset of patients. Instead, he characterized the failure as a reflection of the inherent risk of drug development and the cost of innovation.

“We believe the development of Actimmune in FA was based on strong scientific and clinical rationale and that we designed the right trial in conjunction with the FDA, the principal investigator, as well as FARA,” Walbert said. “Unfortunately, it didn’t work.”

Although Horizon’s shares (NASDAQ:HZNP) were hit – slumping $4.36, or 22.5 percent, to close at $15.03 – greater pain likely was felt in the FA community, which still finds itself without an approved therapy. Of 25 disclosed drugs targeting FA pipeline, 17 remain in discovery, according to Cortellis Clinical Trials Intelligence (CTI). Actimmune was the only agent in an active phase III program.


FA is a neuromuscular disorder caused by a mutation to the FXN gene that limits the production of the protein frataxin, which functions in the mitochondria of the cell. Presenting between childhood and adulthood, FA affects an estimated 4,000 to 6,000 people in the U.S. The disease causes progressive loss of strength and coordination, scoliosis and diminished vision, hearing and speech as well as increased risk of diabetes and serious heart conditions. Most of those diagnosed as children require the use of a cane, walker or wheelchair by the time they are teenagers or young adults.

On the call, Walbert praised the involvement of the FA community, which he credited for the trial’s rapid patient enrollment.

“It has been a humbling experience for me personally and for our entire organization to work with the FARA organization, and we are hopeful that ongoing research leads to a treatment for people living with FA,” he said. “The FA community touched many people at our company and for that we are truly grateful.”

Analysts, while disappointed were not surprised by the outcome. Most had ascribed little value to Actimmune in FA, along with a low chance of success. In a flash note, Jefferies Group LLC analyst David Steinberg wrote, “While we were of the view that positive data would have been transformative ($500M+ peak opportunity on a $1.0B+ current [revenue] run rate, multiple expansion etc.), we had not included FA in our forecast due its high risk nature.”

That said, “Our confidence in the FA program had grown in recent months based on discussions with several FA experts,” he added. “As such, today’s news is somewhat surprising – particularly as all endpoints were missed.”

Nonetheless, Horizon’s growth outlook remains solid, “and we like the continued shift to higher margin, longer duration orphan assets,” Steinberg pointed out. “And the company continues to move forward aggressively in securing label expansion opportunities for its current assets – including the ongoing Actimmune oncology program.”

Last year, Horizon, in collaboration with Fox Chase Cancer Center Temple Health, initiated a phase I study of Actimmune in combination with nivolumab (Opdivo, Bristol-Myers Squibb Co.) in advanced solid tumors. The first two cohorts of that trial are complete and a third is enrolling, according to Jeff Sherman, Horizon’s executive vice president of R&D and chief medical officer, who pointed out that “the mechanism and the whole focus of that program is very different from FA.”

Moreover, Walbert indicated that the FA setback does not affect the company’s appetite for development-stage assets that could help grow its rare disease business. Actimmune was the product of just such a deal, when Horizon acquired Dublin-based Vidara Therapeutics International Ltd. in a 2014 reverse merger valued at about $660 million, adding the marketed product to its pipeline and shifting its headquarters to Ireland. (See BioWorld Today, March 20, 2014.)

“Though the negative outcome is certainly a disappointment, it does not in any way obscure what in our view are favorable dynamics surrounding the base business: namely rare disease assets that are largely durable and relatively young in their commercial lives, and a primary care business that is on relatively sound longer term footing due to increased payer contracting,” Piper Jaffray’s David Amsellem wrote in a hot comment.

Attention in the FA space may shift to vatiquinone (EPI-743), which Edison Pharmaceuticals Inc., of Mountain View, Calif., and Japanese partner Sumitomo Dainippon Pharma Co. Ltd. are advancing in a handful of orphan indications, including FA, characterized as inherited respiratory chain diseases of the mitochondria. The para-benzoquinone oral coenzyme Q10 analog has FDA orphan drug and fast track designation in FA, according to Cortellis CTI. (See BioWorld Today, Feb. 3, 2014.)

Horizon said its full-year 2016 adjusted net sales or adjusted EBITDA guidance were not affected by the FA program halt. Walbert insisted the company is well-positioned for growth in 2017 and beyond, based on its existing portfolio. Last month, the company reported third-quarter 2016 net sales of $208.7 million and said its rare disease medicines – including Actimmune, Ravicti (glycerol phenylbutyrate), Krystexxa (pegloticase) and Buphenyl (sodium phenylbutyrate) – represented 35 percent of total non-GAAP adjusted net sales, an increase from 29 percent of total net sales in the third quarter of last year. The company had cash and cash equivalents of $549.3 million as of Sept. 30.