Escala Therapeutics
ManNAc Program Overview
2017
Escala Therapeutics, Inc.
Focus
Leadership
Current
Status
Market
Opportunity
• Focused on the clinical development and commercialization of N-acetyl-D-mannosamine (ManNAc), a
naturally-occurring monosaccharide and precursor to sialic acid
• Under investigation as a bid oral agent for the treatment of GNE Myopathy (HIBM) & primary podocyte
disorders (nephropathies)
• Active business development to grow pipeline in rare metabolic, neurologic & neuromuscular disorders
• Lindsay Rosenwald, MD, Executive Chairman
• Hootan Khatami, MD, CEO
4 clinical trials led by the NIH (NHGRI, NCATS, NIDDK):
https://clinicaltrials.gov/ct2/results?term=MAnnac&Search=Search
• GNE Myopathy: Phase 1 study (completed); Natural History & phase 2 studies ongoing
• Primary podocyte nephropathy: Phase 1 trial in progress (recruiting)
• Orphan designation granted in US & EU
• SME Status granted by CHMP
• New Zealand Pharmaceuticals Ltd manufactures ManNAc and will be the exclusive global supplier
• GNE myopathy: ~400 patients diagnosed in USA; Up to 2,000 patients expected in USA & ~40,000
worldwide based on GNE gene mutation prevalence
• Nephropathy: Steroid resistant/dependent MCD ~1500; FSGS: 6,000 children diagnosed; up to 20,000
patients have end stage kidney disease due to MCD/FSGS
• Diabetic nephropathy: ~200,000 patients
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Strategic Advisory Board
Marlene Haffner, MD
Dr. Haffner is an internist and hematologist who graduated from the George Washington University School of Medicine and did further training at the
Columbia University School of Medicine and the Albert Einstein College of Medicine, in New York City. Marlene received her Masters of Public Health from
the Johns Hopkins Bloomberg School of Public Health in Baltimore. For more than twenty years, Dr. Haffner was the Director of the Office of Orphan
Products Development at the FDA.
Philippe Monteyne, MD, PhD
Trained as a Medical Doctor and Neurologist, and holder of a Ph.D. in Immunology from UCL Belgium (Catholic University of Louvain), Dr.
Monteyne started his career in the academic field with the public research foundation of Belgium and as Neurologist at Saint Luc Univ
Hospital Brussels, and as post doctoral fellow with the Pasteur Institute in Paris. Dr. Monteyne is a VC Partner with the newly created
investment ‘FUND+’, an open-ended fund for long-term equity investment in innovative life sciences companies with a focus on
Belgium. Philippe is also visiting Professor of Neurosciences at UCL, Catholic University of Louvain in Belgium.
Grannum R. Sant, MD, F.R.C.S., F.A.C.S.
Dr. Sant holds a Bachelor’s degree and an M.D. degree from Trinity College, Dublin. He also did a general surgery residency at the Albert Einstein College
of Medicine of Yeshiva University and a general surgery fellowship at the Royal College of Surgeons, Edinburgh, Scotland, UK. He then went on to do a
urology residency at Tufts University School of Medicine. He has served as Head of U.S. Oncology and Urology Medical Affairs at Sanofi US and its legacy
companies (Sanofi-Synthelabo, Sanofi-Aventis) and Head of US and Global Medical Affairs for Rare Orphan Diseases at Genzyme. He spearheaded six
product launches in urology, oncology and rare orphan diseases; and has led six disease state Registries (two in urology/oncology in the U.S. and four
Global Registries for Lysosomal Storage Diseases). He has served on publication and scientific communication teams across multiple therapeutic areas
and built Medical Scientific Liaison (MSL) and Medical Affairs teams in Urology, Oncology and Rare Orphan Diseases at Sanofi and Genzyme.
Dick H. A. Meijer
International Executive with more than 30 years of experience in commercial development and operations in the medical and
(bio)pharmaceutical industry in North and Central-Eastern European countries, Benelux, Greece and Portugal. He is President and
Founder of Bioneur, a boutique consultancy company specializing in rare diseases – orphan drugs. Bioneur conducts rare disease-specific
market research about, but not limited to, pre-commercial pathways and timelines, provides strategic advice to market entry and hands-on
operational support to emerging biopharmaceutical companies interested in expanding their commercial footprint in countries around the
world.
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Sialic Acid Synthesis Pathway and Role of ManNAc
• Sialic acids are negatively charged,
acidic sugars; part of membrane
glycoprotein in many tissues (figure
below)
• ManNAc is the 1st committed step in
sialic acid biosynthetic (figure right)
GNE
Myopathy
• Mice treated with ManNAc were
rescued from from death & kidney
pathology, restoring protein
sialylation & motor function1,2,3,4
1 Galeano, Huizing
3
2 Malicdan
et al. J Clin Invest 117 (2007) 1585-94
et al. Nat Med 15 (2009) 690-5
4Huizing,
4
Varki. Trends Mol Med 14 (2008) 351-60
Malicdan et al. Scriver’s OMMBID (2014)
GNE Myopathy: Clinical Features
• Rare muscular dystrophy caused by bi-allelic
mutations in GNE gene
• Presents in early adulthood with foot drop
• Progresses slowly from distal to proximal
weakness, although rate & severity of progression
varies
• Eventually progresses to severe weakness and
atrophy of all muscle groups; quadriceps relatively
spared
• Marked disability, wheelchair-bound, dependent
care ~10-20 years after disease onset
• Although exact pathophysiology is unknown,
clinical features are likely due to hyposialylation
Huizing, Malicdan et al. Scriver’s OMMBID (2014)
5
ManNAc Effects in GNE Myopathy Mice
EM
Pt/CSA (mN/mm2)
Muscle Contraction
Littermate
Gne D176V
-/-
-/- (with
ManNAc)
Motor Performance
Rimmed Vacuoles
Autophagosomes
• Mouse Model recapitulates human muscle
phenotype1
• ManNAc therapy prevents muscle decline in mice1
• ManNAc therapy restores muscle sialylation in
mutant mice2
1Malicdan
et al. Nat Med (2009)
et al. Mol Genet Metab (2012)
2Niethamer
6
*
Distance Run (m)
GNE-M mouse model
GNE-M patient
Gomori Trichrome
Littermate
-/-
-/- (with
ManNAc)
6
ManNAc Rescued Newborn Mice from Death due to
Podocytopathy
Gne M712T Knock-In (-/-) mice:
• Died between birth and postnatal day 3 (P3)
due to severe glomerular disease
• GNE mutant mice had podocyte
effacement, loss of foot processes
• Oral ManNAc replacement restored
podocyte morphology, & were rescued from
nephropathy
-/-
-/-
+/-
Age P2
Survivors at P21
ManNAc
untreated
(1g/kg/day)
50
48
27
26
12
1
+/+
+/-
total: 101 mice
-/-
+/+
+/-
-/-
total: 104 mice
7
Galeano*, Klootwijk*et al. J Clin Inv (2007) 117:1585
+/+
ManNAc Clinical Program Overview
Escala Therapeutics is in collaboration with NIH 3 clinical studies led by NIH (NHGRI, NCATS and NIDDK)
underway in GNE Myopathy and glomerulopathies
GNE Myopathy
•
Natural History Study ongoing
•
Ph1a SAD (completed): Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of DEX-M74
(ManNAc) in Subjects With GNE Myopathy/HIBM
• ManNAc was safe and well-tolerated up to 10g; No serious AEs
• ManNAc resulted in sustained released free sialic acid in plasma
• PK supported twice-daily ManNAc administration
•
Phase 2 open label (ongoing): 12 patients followed for 90 days & extension to 24 months
• Dosing to validate biological effect, biomarkers, muscle biopsies and clinical measurements to support
QOL based pivotal study.
• ManNAc safe & well-tolerated; 3-month data confirmed sustained SA increase
• 1-year interim data suggest ManNAc efficacy - presented at World Muscle Society congress, Oct 2016
•
Pivotal phase 3 study endpoint under discussion with FDA
Nephropathy
•
Phase 1 SAD and MAD ManNAc in patients with glomerulopathy (recruiting): 12 patients SAD followed
by 5 day MAD dosing, to Evaluate the Safety, Tolerability, and Pharmacokinetics and early
Pharmacodynamics in patients with glomerulopathy (FSGS, MCD, MN)
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Phase 1 PK Results: ManNAc + Neu5Ac
9
Preliminary Data Total Muscle Strength at 1 year:
ManNAc vs. Natural History Study (NHS)
Preliminary Data from Open Label Phase 2 Study, presented at World Muscle Society, Oct 2016
Findings were not statistically significant
LSMean (SE) Change in Total QMA (kg)
20
Natural History Study
Phase 2
10
N =12*
-3 kg
0
*The 12 subjects
on ManNAc were
also previously in
the NHS
N =17
-10
-20
-30
-28 kg
-40
0
3
6
Month
10
9
12
ManNAc Opportunity & Development Timeline
Indication
GNE myopathy
Patient number estimate
US: 400 diagnosed
~up to 2000*
WW: ~2000 diagnosed
Up to 40000*
Estimated
Business
Potential ($)
48M
MCD glomerulopathy
1,500
180M
FSGS glomerulopathy
20,000
2B
Diabetic nephropathy
200,000
10B
*Calculated prevalence estimate based on frequency of mutation
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Competition
• GNE myopathy has no approved therapy
• Ultragenyx had conducted a Phase 3, randomized, double-blind,
placebo-controlled study of SA-ER in ~89 subjects
– Anticipating approval in US & EU by end 2018 or early 2019
– Study limited to a subset of patients with preserved lower extremity
strength
– TID design vs. ManNAc BID (possibly once daily under investigation
– Prevalence likely large enough to sustain both products
• Escala is the only company developing nephropathy indications
12
ManNAc Intellectual Property
Patent or Application
Number
Country
Title
Status
Expiration
8,410,063
US
N-acetyl mannosamine as a therapeutic agent (Kidney disease,
myopathies)
Granted
2028
9,095,597
US
N-acetyl mannosamine as a therapeutic agent
(Kidney disease via specific administration)
Granted
2028
14/775,507
US
N-acetyl mannosamine as a therapeutic agent
(muscular atrophy/dystrophy, diabetes, high blood pressure)
Pending
2,680,842
Canada
N-acetyl mannosamine as a therapeutic agent (kidney disorders)
Granted
2,903,133
Canada
N-acetyl mannosamine as a therapeutic agent (muscular
atrophy/dystrophy, diabetes, high blood pressure)
Pending
08767999.9
No assigned Number yet
Europe
Europe
2028
Pending
N-acetyl mannosamine as a therapeutic agent (myopathy and liposomal
administration)
Pending
(Kidney disorders)
200872
Israel
N-acetyl mannosamine as a therapeutic agent
(Kidney disease)
Granted
245026
Israel
N-acetyl mannosamine as a therapeutic agent
(additional kidney disorders, muscular atrophy/dystrophy, diabetes, high
blood pressure )
Pending
13
2028
Summary & Program Next Steps
• Escala Therapeutics is in collaboration with NIH under 3 CRADAs for
the evaluation of ManNAc as potential treatment for GNE Myopathy
(orphan indication) and glomerular disorders
• 3 clinical studies led by NIH (NHGRI, NCATS and NIDDK) underway
in GNE Myopathy and glomerulopathies
– Significant unmet medical need in both indications
– Preliminary data in GNE myopathy at 1 year suggest ManNAc
effect in slowing decline in muscle strength
• Potential for several additional indications including Diabetic
nephropathy
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