Ultragenyx plans to halt development of aceneuramic acid (sialic acid) extended release (Ace-ER) after the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) myopathy (GNEM) candidate failed a Phase III trial.

According to topline results disclosed by Ultragenyx yesterday, Ace-ER did not achieve its primary endpoint of demonstrating a statistically significant difference in the upper extremity muscle strength composite score (UEC) compared to placebo in adults with GNEM following 48 weeks of treatment.

Without disclosing details, Ultragenyx added that the Phase III study also did not meet its three key secondary endpoints—lower extremity muscle strength composite score as measured by hand-held dynamometry (HHD), physical functioning using the Mobility domain of the GNE Myopathy-Functional Activity Scale (GNEM-FAS), and muscle strength in knee extensors.

The Phase III Ace-ER study enrolled 89 adults with GNEM who were able to walk 200 or more meters in the six-minute walk test. Patients were randomized 1:1 to Ace-ER at a dose of 6 grams/day or placebo for 48 weeks. The Ace-ER patients showed a +0.74 kg improvement in UEC score compared with placebo patients (–2.25 kg versus –2.99 kg), which Ultragenyx said was not statistically significant.

Ace-ER is designed to bypass the genetic block in the sialic acid pathway and provide continuous exposure over 24 hours. Ultragenyx and the drug’s developers reasoned that the muscles would pick up increased amounts of sialic acid from the serum, incorporate it into proteins and fats, and potentially improve muscle strength and function over time.

Ultragenyx licensed rights to Ace-ER and its potential use in treating GNEM from Nobelpharma, AAIPharma, and the HIBM Research Group.

There are no approved therapies for GNEM, also called hereditary inclusion body myopathy (HIBM). Approximately 2000 patients in the developed world have GNEM, Ultragenyx stated last year.


“We are disappointed by these results, as we had hoped that Ace-ER would offer a new option for GNEM patients,” Ultragenyx CEO and president Emil D. Kakkis, M.D., Ph.D., said in a statement.

Ultragenyx said it would work with investigators and patient groups to make study data and tools available for the development of other therapies, as well as craft a “reasonable” transition plan for patients still on Ace-ER.

“This outcome does not affect our overall strategy, as the company moves forward with multiple preclinical and clinical programs and regulatory filings,” Dr. Kakkis added.

The trial failure was the second significant clinical setback for Ultragenyx this year.

In March, the company acknowledged that its glucose transporter type-1 deficiency syndrome (Glut1 DS) candidate UX007 failed a Phase II trial by missing its primary endpoint of reducing the frequency of total number of observable and absence seizures among patients following 8 weeks of treatment with UX007 compared to placebo.

However, the study also showed that UX007 did reduce absence seizures captured via electroencephalogram, though not observable seizures captured by diary. The synthetic triglyceride compound remains in development for long-chain fatty acid oxidation disorders (LC-FAOD).

Ultragenyx has seen better clinical results from burosumab (KRN23), which the company is co-developing under a collaboration and license agreement signed in 2013 with Kyowa Hakko Kirin, which discovered the drug.

In April, the companies announced positive Phase III results in adults with X-linked hypophosphatemia (XLH). Patients treated with burosumab showed a statistically significant improvement in serum phosphorus levels, with 94% of patients achieving normal levels compared to 8% on placebo. Patients treated with burosumab also achieved a statistically significant improvement in stiffness and strong trends in improvements in physical function and pain.

Announcing second-quarter results last month, Ultragenyx said a Biologics License Application, or BLA, for burosumab was scheduled to be filed with the FDA this month. Burosumab is also in Phase II development for tumor-induced osteomalacia (TIO).

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