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Bioblast Announces Phase 2a Results of
Trehalose in Patients with Spinocerebellar Ataxia Type 3 (SCA3)
Patients Treated with Trehalose
Remained Stable According
to a Well-Established Clinical
A Recent Natural History Study
in The Lancet Neurology in Patients
with SCA3 Noted a Steady Disease
Progression Over Time
Tel Aviv, Israel, - January 18, 2017 - Bioblast Pharma
Ltd. (NasdaqGM: ORPN), a clinical-stage, orphan disease-focused biotechnology company, today announced results of a six-month open
label Phase 2a study that also included an additional six-month follow-up period investigating trehalose in patients with Spinocerebellar
Ataxia Type 3 (SCA3).
The objectives of the study were to establish
safety and tolerability of two doses of trehalose as well as to assess the effect of the drug on reducing the rate of clinical
decline in this progressively disabling disease.
This open label study evaluated 14 SCA3
patients over a six-month period; eight patients received a dose of 13.5 grams (g) of trehalose IV, and six patients received a
dose of 27g, both on a weekly basis. Investigators and patients were blinded to the dose administered.
The key findings of the study included:
SARA is a clinical scale that assesses a range of different
impairments in cerebellar ataxia. The scale is made up of eight measurements related to gait, stance, sitting, speech, finger-chase
test, nose-finger test, fast alternating movements and heel-shin test.1 A recently
published long-term natural history study in patients with SCA3 showed an average annual increase of 1.56 points on the SARA scale
score, denoting the disease progression.2
1 [Weyer A, Abele M, Schmitz-Hubsch T, Schoch B,
Frings M, Timmann D. Reliability and validity of the scale for the assessment and rating of ataxia: a study in 64 Ataxia patients.
Movement Disorders 2007;22:1633-7: (https://www.ncbi.nlm.nih.gov/pubmed/17516493)].
2 (Jacobi h, et. al. Long-term disease progression
in spinocerebellar ataxia types 1,2,3 and 6: a longitudinal cohort study. The Lancet Neurology 2015:14:1101-1108)
Warren Wasiewski, MD, Bioblast's Chief Medical Officer
said, "The stability of the patients in terms of their SARA scale scores during the 6-month study period was promising, given
the steadily worsening nature of the disease. It was also encouraging to see that patients who continued beyond the initial treatment
period maintained stable SARA scores as well.
"In a relentlessly deteriorating neurological disease
such as SCA3, one needs to show a slowing or halting of progression to be considered clinically meaningful. The outcomes from this
trial provide valuable information that will assist in the design of a second clinical trial using trehalose in SCA3 patients."
Susan Perlman, MD, Clinical Professor of Neurology and the Director,
Ataxia Center and HD Center of Excellence at the David Geffen School of Medicine at UCLA commented on the results, "Given
that the natural history controls would have predicted a worsening in the SARA score, the fact that the average of the patients
over 6-12 months did not show worsening is encouraging. Corroboration of this result in a double-blind, placebo-controlled
study in a larger number of patients would be an appropriate next step in determining the value of trehalose in SCA3."
Zohar Argov, MD, Professor (Emeritus) of Neurology at Hebrew
University Hadassah Medical School, and former President of the European Neurological Society and Special Medical Advisor to Bioblast
commented, "Hereditary ataxias - of which SCA3 is one out of a group that includes more than six others - have
various genetic defects with presumed different pathophysiologies. SCA3 is the typical and the most frequent form for those several
SCAs with a repeat expansion defect that causes protein aggregation.
"Any therapy development for these hereditary ataxias
should keep in mind the chronicity of the condition and its rate of progression over several years. Consequently, in order to truly
evaluate the effect of a drug on patients with these diseases, studies need to be conducted over a significant period of time but
in any case, not less than six months in order to get results that are robust."
The most common adverse event in the Phase 2a SCA3 study as
well as in the prior Phase 2a study in Oculopharyngeal Muscular Dystrophy (OPMD) was transient and benign glucosuria, lasting for
a few hours after infusion of trehalose. Glucosuria is the result of the metabolism of trehalose by the enzyme trehalase into two
glucose molecules and subsequent excretion in the urine.
Expanding the safety database of trehalose in people
The results of this study add to the increasingly valuable database
Bioblast has accumulated on trehalose's safety in progressive genetic neurological diseases as well as in healthy subjects.
A total of 57 people have been exposed to trehalose: 25 patients
with OPMD, 14 patients with SCA3, and 18 healthy subjects, with some patients having been on the drug for up to 24 months.
These patients and healthy volunteers have received a total of more than 2,100 doses of trehalose IV, representing a total of more
than 53,000g. Overall, trehalose has been well tolerated in all 57 people: no infusion reactions were reported and no safety signals
identified. No adverse event has led to discontinuation of study drug, or drug related death.
Proprietary position of trehalose
Bioblast has received a U.S. patent for administration of trehalose
to treat SCA3 (and OPMD) that is expected to expire in 2033. In addition, the company has secured Orphan Drug Designation for SCA3
and OPMD in the U.S. and in the EU.
Trehalose is a protein stabilizer that also activates
autophagy and crosses the blood-brain-barrier
Trehalose is a low molecular weight disaccharide (.342 kDa)
that protects against pathological processes in cells. It has been shown to penetrate muscle and cross the blood brain barrier.
In animal models of several diseases associated with abnormal cellular-protein aggregation, it has been shown to reduce pathological
aggregation of misfolded proteins as well as to activate autophagy pathways through the activation of Transcription Factor EB (TFEB),
a key factor in lysosomal and autophagy gene expression. Activation of TFEB is an emerging therapeutic target for a number of diseases
with pathologic accumulation of storage material.
Information on Trehalose in OPMD
Trehalose 90mg/mL IV solution is being developed as a treatment
for OPMD based on studies in cell and animal models of OPMD where it demonstrated the ability to reduce aggregation of the pathological
protein (PABPN1) in muscle cells, the hallmark of the disease, by stabilizing the protein, reducing the formation of protein aggregations,
and promoting clearance of abnormal proteins through activation of autophagy, thereby preventing muscle cell death.
In a Phase 2a open label study of patients with OPMD, trehalose
administered as a weekly infusion of 27g for six months showed an improvement in dysphagia as measured by the reduced time to consume
80 cc of cold water, nectar and honey. In the 12 month follow up of that study designed as a withdrawal study, those patients who
were randomized to stay on drug continued to have reduced drinking time and those who were withdrawn from drug had an increase
in the drinking time. These data suggest that the treatment effect is sustained in the those who continue to receive trehalose
and was lost in those who were withdrawn from treatment.
Beyond OPMD, Bioblast is currently conducting analyses to determine
the next orphan disease for which it will investigate the use of trehalose as a therapeutic agent. Bioblast intends to make such
a decision in the first half of 2017.
About Spinocerebellar Ataxia Type 3 (SCA3; Machado-Joseph
SCA3, also known as Machado-Joseph disease, is the most common
form of hereditary cerebellar ataxias, which are a group of genetic diseases characterized by ataxia, spasticity, difficulty with
speech and swallowing, weakness in arms and memory deficits. Symptoms can begin in early adolescence and get worse over time. Eventually
SCA3 leads to paralysis, and severe cases can lead to an early death in the fourth decade of life. SCA3 is currently considered
incurable, and there is no approved pharmacologic treatment for SCA3.
About Oculopharyngeal Muscular Dystrophy (OPMD)
OPMD is an inherited myopathy characterized by dysphagia (difficulty
in swallowing), eyelid drooping (ptosis) and the loss of muscle strength in multiple muscles of the limbs. Symptoms generally appear
in mid-life and get worse over time. As the dysphagia becomes more severe, patients may become malnourished, may lose significant