Rare Diseases

Ultragenyx More Than Meets The Eye?


Ultragenyx appears to be on the cusp of FDA and EMA approvals for rhGUS in patients with ultra-rare MPSVII.

Burosumab is generating promising data for rare genetic hypophosphatemia, with potential implications of bone pathology in cancer.

Candidate UX007 is generating promising data in studies of glucose and fatty acid metabolism disorders.

Rare disease pact with Takeda could result in six rare disease candidates entering its pipeline, including a $65 million investment.

Ultragenyx (RARE) is a $2.9 billion market cap biotechnology company focused on developing better medications for rare and ultra-rare debilitating genetic diseases. The company has completed phase 3 study of recombinant human beta-glucuronidase (rhGUS) in patients with mucopolysaccharidosis VII (MPSVII), a rare lysosomal storage disease, and submitted for regulatory approvals in the U.S. and EU. The company is also conducting a phase 3 study of aceneuramic acid extended release (Ace-ER) in patients with GNE myopathy, a progressive muscle-wasting disorder. In a promising study, Ultrgenyx is conducting phase 2 and phase 3 studies of burosumab, an anti-fibroblast growth factor 23 (FGF23) immunotherapy for patients with bone mineralization disorders X-Linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO). UX007 is being evaluated in a phase 3 studies for glucose transporter type-1 deficiency syndrome (Glut1 DS) and a phase 2 clinical study in patients with long-chain fatty acid oxidation disorders (LC-FAOD). Takeda (OTCPK:TKPYY) and Ultragenix have entered into a rare disease pact that could give Ultragenix a strong foothold in the rare disease space. In depth scientific publication information on RARE candidates can be found here on the company website.

RARE announced in May 2017 that its application (BLA) submitted to FDA and a Marketing Authorization Application (MAA) submitted to EMA for rhGUS, (UX003), an enzyme replacement therapy for MPS VII (Sly syndrome) were accepted for review. MPS VII is caused by beta-glucuronidase deficiency, required for glycosaminoglycan catabolism (dermatan sulfate, chondroitin sulfate, and heparan sulfate). Progressive accumulation of these moieties results in a multi-system disease that includes a severe form called non-immune hydrops fetalis. MPS VII currently has no approved treatments. Regulatory guidance decisions regarding the therapy are expected in late 2017 and early 2018. The phase 3 study involved only twelve patients for 24 weeks of treatment with rhGUS. FDA and EMA analysis of the totality of the data was granted given its difficulty to treat and rare demographic prevalence. According to the company, “EMA agreed that approval under exceptional circumstances could be possible based on the Phase 3 study with urinary GAG levels as a surrogate primary endpoint, provided the data are strongly supportive of a favorable benefit/risk ratio and that some evidence or trend in improvement in clinical endpoints is observed”. The condition is extremely rare, with only 1 in 250,000 being affected, and only 100 cases being reported in the U.S. Other FDA approved MPS enzyme replacement treatments have been successfully employed such as Aldurazyme for MPS I, Elaprase for MPS II, Vimizim for MPS IVA, and Naglazyme for MPS VI. Given the relaxed regulatory stance by FDA and pre-existing model for the therapeutic product, Strong Bio would expect high chance of approval on this candidate. However, sales cannot be expected to help the company maintain a market cap of $3 billion.

GNE myopathy is a Rare disorder caused by a defect in sialic acid biosynthesis leading to progressive muscle weakness and atrophy, usually with adult onset. RARE is testing sialic acid therapy to determine if it confers a meaningful clinical benefit based upon encouraging preclinical data. Sialic acid extended release (SA-ER) was shown to increase upper extremity muscle strength (10 Naïve subjects demonstrated a +3.47 kg improvement in UEC at week 24) with no effect on walk speed or stair climb test in a phase 2 GNE myopathy study. However, in extension studies lower extremity function seemed to resist deterioration, but did not increase in a statistically significant manner. It was well-tolerated with no serious adverse events reported, with most common being gastrointestinal types. A phase 3 study examining Ace-ER in GNE myopathy is fully enrolled with key readouts in 2H 2017, which will be necessary for EMA approval. The 89 patient double-blind placebo-controlled study is evaluating safety and efficacy of Ace-ER compared to placebo over 48 weeks, and if positive results are obtained, will be sufficient for NDA and MAA submission. GNE myopathy is ultra-rare as well, affecting about one out of one million people worldwide.

Burosumab (KRN23) is a monoclonal antibody specifically binding and inhibiting FGF23, implicated in bone deterioration. FGF23 is responsible for reduction in serum phosphorous levels by acting in the kidney to promote phosphaturia, as well as affecting vitamin D production. KRN23 was given FDA Breakthrough Therapy designation by FDA in June 2016 for patients only one…