Orphazyme Pioneering the heat shock protein response for neurodegenerative orphan diseases
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Orphazyme
Pioneering the
heat shock protein
response for
neurodegenerative
orphan diseases
1
Company Update – April 2020
Important notice
This presentation contains forward-looking statements. All statements other than statements of
historical facts contained in this presentation, such as statements regarding our future results of
operations and financial position, including our business strategy, prospective products, availability
of funding, clinical trial results, product approvals and regulatory pathways, collaborations, timing
and likelihood of success, plans and objectives of management for future operations, and future
results of current and anticipated products, are forward-looking statements. These forward-looking
statements are based on our current expectations and beliefs, as well as assumptions concerning
future events. These statements involve known and unknown risks, uncertainties and other factors
that could cause our actual results to differ materially from the results discussed in the forward-
looking statements. Any forward-looking statement made by us in this presentation speaks only as
of the date of this presentation and represents our estimates and assumptions only as of the date of
this presentation. Except as required by law, we assume no obligation to update these statements
publicly, whether as a result of new information, future events or otherwise after the date of this
presentation. Orphazyme is a trademark that we own. Other trademarks appearing in this
presentation are the property of their respective holders.
2
Significant progress in 2019 and early 2020
Clinical Clinical Regulatory / Access Company
–Reported positive data –Breakthrough Therapy –Raised ~$110M in Feb. 2020
from phase 2/3 trial with Designation granted NPC –Expanded senior management
arimoclomol in NPC –Pre-filing meetings with FDA team focused on commercial
–Enrolment completed in –Initiated Early Access
phase 2/3 sIBM, phase 3 Program in US in NPC
ALS and phase 2 PoC –Fast Track designation
Gaucher trial granted in sIBM
✓Arimoclomol in Niemann-Pick disease Type C getting closer to patients
✓ Pipeline advancing with trials in additional indications underway
✓ Team and capital resources in place to execute
3
Pro-actively addressing challenges of Covid-19
Regulatory Clinical
Preparing to submit marketing applications in Letter to investigators and patient organizations
the US and EU for NPC as planned
Scale up of patient-forward approaches
• Home nursing service
• Reimbursement
Patients • Direct to patient study drug shipments
Virtual data monitoring and scientific steering
US Early Access Program in NPC continues as committee meetings
planned
Protocol addendum
• Flexibility on use of local laboratories
• Adjustment to visit schedule
Employees
• Patient observation / assessment by phone
Working from home arrangements for all staff Drug supply
Shift work for laboratory staff required to attend • Provide patients with sufficient drug for study
company premises completion
4
Arimoclomol: Potential game-changer for
neurodegenerative diseases
- Protein
aggregates
Protein
First-in-class heat shock protein (HSP) amplifier
degradation
Folded &
Nascent
protein
functional
protein
HSPs are a natural cellular stress defense mechanism
Small molecule, oral/nasogastric, crosses BBB
Lysosome
Favorable safety profile observed to date in >540 patients
Misfolding
5
Arimoclomol: prolific late stage pipeline focused on
neurodegenerative diseases
Designations
Break- Key
Orphan Fast through
Neuropathic lysosomal diseases Drug Track Therapy milestone
✓
Submit
Niemann-Pick disease type C*
✓ ✓ Ph 2/3 (data reported) US H1 2020/
Europe H2 2020
Ph 2 results
Neurological Gaucher disease Ph 2 H1 2020
GCase-Parkinson’s disease** Pre-clinical
Neuromuscular disorders
✓
Ph 2/3 results
Sporadic inclusion body myositis
✓ Ph 2/3 H1 2021
Ph 3 results
Amyotrophic lateral sclerosis
✓ Ph 3
H1 2021
6 *Rare Pediatric Disease Designation (RPD) for arimoclomol in NPC **Arimoclomol / NME; glucocerebrosidase (Gcase)
NPC: addressing high unmet patient and physician
needs in an attractive ultra-orphan market
WW: ~ 3,000 patients Market opportunity
US/EU: ~ 1,000 patients Price range WW sales
diagnosed & treated 300K - 600K MPS I: 100M USD
USD/year MPS VI: 350M USD
Current estimate: only ~ 40%
diagnosed MPS II: 600M USD
Managed in highly
Lack of current Rx/competitors
specialized centers
US: no approved Rx ~ 25-50 centers in US and EU
Specialist pediatric neurologists
EU: generic miglustat only
Specialist metabolic centers
7
Key focus: get to approval, get to patients
US EU RoW
Regulatory • March 2020: BTD meeting • H1 2020: Pre-submission meeting
with EMA
filing • Q2’ 20: pre-NDA meeting
• H2 2020: Pre-submission meeting
• US submission H1’ 20
with rapporteur and co-rapporteur
• Covid-19 mitigation plan in place
• H2 2020: MAA Submission
Patients • ~ 300 patients diagnosed • >700 patients diagnosed • ~ 400 patients diagnosed
• Early Access program since Jan • Early Access Programs focused on • Early Access Programs where
2020 France via ATU and Italy via Law possible
643
• Patient group collaboration
Physicians • US thought-leader advisory board • European KOL Advisory Board
Q3/Q4 2020
• Build medical education program
Company • US President appointed • Focus on key EU markets • Finalize partnering for key
especially Germany & France countries: Japan, Canada, Turkey
• Building Medical Affairs and MSL
teams • Build lean in-country and cluster
organization
• Building Market and Patient
Access capabilities
8
US Early Access Program for NPC is now operational
Feb Feb Mar
Jan May
14th 24th 14th
Dedicated Protocol Sites agreed Protocol live, GOAL: First
US program submitted budget and posted to patient on
to FDA protocol sent clinicaltrials.gov treatment
Boston
Children’s
~45 patients already
Mayo Clinic Hospital-
Rush NYU
Children’s
under consideration for UCSF/Benioff Children’s
Hospital
Hospital
Philadelphia
Children’s
EAP before sites are open Oakland Cincinnati Children’s
Hospital
Pittsburgh
Children’s
50%
Hospital Emory
pediatric Orange
County
University
50% adult
9
Arimoclomol in NPC: unlocking huge potential in
neurodegenerative orphan diseases
Neurodegenerative market potential
Neurological Gaucher I & III /
sIBM / ALS GCase PD
NPC • Neurological Gaucher I & III:
• sIBM and ALS in pivotal trials
• Ph 2 results H1 2020
• No current effective disease-
• Filing preparations ongoing modifying Rx • GCase PD: PoC evaluation
• US EAP roll out • NME: Next gen HSP amplifier
• Significant market potential
• Lean go-to-market
strategy
• No approved Rx in US
~ 3K patients ~ 100K patients ~ 500K patients
2020+ 2022+ 2025+
Phased neurodegenerative platform
10Orphazyme at a glance
2019 Financials Capital Increase 2020 Outlook
R&D expense: February 2020 Operating loss1:
~USD 43M USD1 Raised gross 74M USD – 82 M USD
Year-end cash: proceeds of Year-end cash1:
~18M USD1 ~ 110M USD
> 45M USD
Footprint Shareholders2 Analysts
HQ Copenhagen, DK LSP (10.0%) Carnegie
Boston, US Novo (7.5%) Danske
Zug, Switzerland Consonance3 (7.0%)
Sunstone (6.7%) Oddo
Nasdaq Copenhagen Aescap I (6.5%) Redeye
ORPHA.CO
1R&D spend DKK 285.4M; year-end cash 2019: DKK 123.6M; Outlook operating loss 2020: DKK 500-550M; Outlook year-end cash 2020: >DKK 300M; USD figures
11 are for reference only; FX rate 1 DKK / 0.15 USD; 2major shareholders per recent disclosures, figures rounded, 3Consonance Capman GP LLC.Key priorities and anticipated milestones
Get to approval in NPC Submit NDA in US H1 2020
Submit MAA in EU H2 2020
Get to patients in NPC US early access program (EAP) roll-out 2020
Preparations for US launch 2020
Lean go-to market rollout US 2020
Lean go-to market roll out EU/ROW H2 2020 - 2021
Expand beyond NPC Gaucher disease Ph 2 results H1 2020
sIBM Ph 2/3 results H1 2021
ALS Ph 3 results H1 2021
12 NDA: new drug application; MAA: marketing authorization applicationNiemann-Pick
disease type C
Clinical overview
13NPC is an ultra-rare, devastating genetic disorder:
a life-limiting condition with high unmet need
• An ultra-orphan disease
• Epidemiology incidence: 1/100,000 live-births
• ~ 2,000 patients across US and EU • A progressive lysosomal
storage disorder
characterized by the
accumulation of lipids
US EU
• Affects cells of the brain,
liver, spleen and lungs
• Loss of 5 domains: ambulation, fine motor
skills, swallowing, cognition, speech
• When diagnosed in childhood, unlikely to
survive beyond teenage years
• ~ 300 patients diagnosed • ~ 600 patients diagnosed
• Managed in ~ 25-50 and treated in EU
• Adult-onset NPC is increasingly diagnosed
specialist centers by • Centralized approach to
pediatric neurologists patient management:
• No approved treatment ~ 25-50 metabolic centres
• Only approved treatment
is miglustat (used in 80%
of patients)
14Arimoclomol clinical development in NPC
Oct 2015 – May 2017 Jun 2016 – Jun 2018 Jun 2017 – Dec 2019
NPC-001: observational study NPC-002: phase 2/3 study NPC-002
1 year blinded + 1 year
36 patients enrolled: 31 completed – of these, 50 patients enrolled: 42 completed – 34 treated 41 enrolled from core study: interim of 35
27 continued to NPC-002 with arimoclomol, 16 with placebo completed (1 year blinded + 1 year OLE)–
22 on continuous arimoclomol, 13 with
placebo–arimoclomol
Trial design Inclusion/exclusion Key endpoints
• NPC 1/2 patients, n = 50 Inclusion Primary
• 12 months + 1 year OLE • NPC 1/2 patients 2–18 years • 5-domain NPC-CSS (ambulation, fine motor
• Minimum 1 neurological symptom skills, swallowing, speech and cognition)
• 2:1 arimoclomol to placebo
• Ability to walk with assistance Co-primary (US only)
• Arimoclomol max. 200 mg t.i.d. (bodyweight
dosed) • If on miglustat, stable for 6 months • CGI-I, only 8/50 patients with baseline
assessment
• Routine care permitted, incl. miglustat allowed Exclusion Biomarkers
• Participation in other trials • HSP70, oxysterols, unesterified cholesterol
• Epilepsy, liver/renal insufficiency
Subgroup analyses
• Patients ≥ 4 years
• Routine miglustat
• Excluding double functional null mutations
(post hoc analysis upon FDA request)
15 1563% reduction (observed) in disease progression
after 12 months with arimoclomol versus placebo
BIOMARKERS
CHANGE FROM BASELINE TO 12 MONTHS
5-domain NPC-CSS Change from baseline
• Mean treatment difference of -1.34 (95% CI -
Arimoclomol, n = 34
Increasing NPC
Placebo, n = 16 severity
2.71 to 0.02; p = 0.0536) in 5-domain NPC-CSS
score in favor of arimoclomol versus placebo
• Considered meaningful by clinicians, and
individualsFAVORABLE
with NPC and caregivers
SAFETY PROFILE
• Corresponds to a 63% reduction (baseline
adjusted, same as observed) in disease
progression
• Significance not reached owing to individuals with
double functional null mutations (n = 3) in
arimoclomol treatment group
16
34
16 1680% reduction (observed) in disease progression when
individuals with double functional null mutations are
excluded
BIOMARKERS
DOUBLE FUNCTIONAL NULL MUTATIONS
5-domain NPC-CSS Change from baseline
• Presence of double functional null mutations are
rare in individuals with NPC and strongly predictive
Arimoclomol, n = 31
Increasing NPC of early-onset and rapid disease progression
severity
Placebo, n = 16
• Post hoc analysis excluding individuals with double
functional FAVORABLE
null mutations (n =PROFILE
SAFETY 3) in arimoclomol
treatment group
CHANGE FROM BASELINE TO 12 MONTHS
• Significant mean treatment difference of -1.56
(95% CI -2.90 to -0.21; p =0.024) in 5-
domain NPC-CSS score in favor of arimoclomol vs
16 placebo
31
• Corresponds to 77% reduction (baseline
adjusted) in disease progression
17 17Arimoclomol has a benefit over standard of care 95%
reduction (observed) in disease progression
5-domain NPC-CSS Change from baseline
SUBGROUP ANALYSIS – BACKGROUND TREATMENT
Arimoclomol, n = 26
Increasing NPC
• Arimoclomol treatment benefit in individuals
Placebo, n = 13 severity
with miglustat as background treatment
(39 of 50 patients)
CHANGE FROM BASELINE TO 12 MONTHS
• Significant mean treatment difference of -2.01
(95% CI -3.44 to -0.58; p = 0.0073) in 5-
domain NPC-CSS score in favor of arimoclomol
versus placebo
13
• Corresponds to a 101% reduction (baseline
26 adjusted) in disease progression
18 18Arimoclomol has a favorable safety profile
Arimoclomol has an adverse
event (AE) rate similar to • In the phase 2/3 study, a similar AE rate was observed
between arimoclomol (88.2%) and placebo (81.3%)
placebo and a
2.5-fold higher serious AE
• Fewer SAEs occurred with arimoclomol (14.7%) than with
(SAE) rate for placebo
placebo (37.5%)
compared with arimoclomol
19 *SAE stands for serious adverse event5 domain NPC-CSS: 85% of NPC patients and caregivers stated
in a web survey that a difference of 1 point is meaningful
Score
0 1 2 3 4 5
Domain
Normal Clumsy, Ataxic, gait wider, Assisted Wheelchair
bangs into things poor balance ambulation – only dependent
Ambulation walk short
distance indoor
Normal Slight dysfunction Mild dystonia Limited skills, Unable to use
Fine motor but able to handle Require little unable to use hands. Assistance
skills cutlery assistance, able to pencil or eat needed for all
feed without help independently activities
Normal Cough while Intermittent Constant and Constant feeding Dependent
Swallow eating problems with intermittent problems or use feeding by tube
drink or food feeding problems of tube
Normal Mild learning Moderate learning Severe delay – Loss of cognitive
delay, still in delay – need Constant function
Cognition normal class special support in supervision, not Unable to
school and able to learn new understand day-
kindergarten skills to-day events
Normal Mild slurring / Severe dysarthria Non verbal Absence of
slower speech Very slow, difficult communication, communication
Speech to understand Uses simple signs
/ pictures
20 Ref study: OR-SRV-NPC-01sIBM
ALS
Neurological
GaucherArimoclomol: a novel approach for the treatment of sIBM,
directly targeting muscle degeneration
sIBM is a rare neuromuscular disease in adults Phase 2/3 Trial
• Most common idiopathic inflammatory myopathy in people over • 20-months 1:1 randomized, placebo-controlled
50 years • 152 patients (2 more randomized; over enrolled); fully enrolled
• Average time to walking stick: 5 years in May 2019
• Average time to wheelchair: 10-15 years • Randomization:
• Significant morbidity: propensity to fall, motor disability, • Arimoclomol 400mg (TID): n=75
swallowing failure and poor quality of life • Placebo TID: n= 75
• Death is related to falls and aspiration pneumonia
sIBM disease pathway Phase 2/ 3 Endpoints
• US & EU: up to 40,000 patients • Primary endpoint: IBM functional rating scale (IBMFRS)
• No approved treatment • Secondary endpoints:
• Managed in highly-specialized expert centers • 6-mins walking test with 2-mins distance captured
• Affects men to women at a ratio of 3:1 • Modified time up and go
• Primary treaters: Neurology and Rheumatology • Manual Muscle Testing
• Isometric contraction testing of bilateral quadriceps muscle
• Grip strength
22Arimoclomol Preclinical and Phase 2 studies support MoA and
potential for disease modification
83% of arimoclomol patients
Preclinical Arimoclomol Phase 2 stabilized versus 25% on placebo
Double-blinded, randomized pilot trial (n=24: 16 arimoclomol;
Arimoclomol effects on sIBM-like pathology*1 8 placebo) 4 months of treatment, 12-month observation period
4M (n=16 vs 8) 8M (n=14 vs 8) 12M (n=15 vs 8)
0.0
▪ Cross-section of muscle cells from
WT-VCP
-0.5 Δ60%
healthy mouse
Change in IBMFRS sum score
-1.0
▪ No inclusion bodies (aggregates) -1.5 Δ75%
present (ubiquitin, red) -2.0
-2.5
-3.0
Δ40%
▪ Inclusion bodies (red aggregates) are
mVCP
-3.5
evident throughout the muscle cells -4.0
Arimoclomol 100 mg TID
▪ Shows degeneration of muscle tissue and -4.5 Placebo
decrease in muscle force -5.0
• 4 months of continuous Month
treatment resulted in a 60%
mVCP + Ari
▪ HSP70 upregulated reduction in progression with arimoclomol vs placebo
▪ Inclusion bodies (aggregates) are cleared • At 8 months (4 months after treatment discontinuation)
▪ Prevents degeneration of muscle tissue 75% reduction in progression
and preserves muscle force • 83% of arimoclomol treated patients were stabilized vs
25% on placebo
*Mutated mice with IBM hallmarks are treated with arimoclomol from disease onset
23
(4 months) + 10 months 1.Ahmed M et al., Sci Translat Med 2016; 8:331The Inclusion Body Myositis Functional Rating Scale (1/2)
Score
Domain 0 1 2 3 4
Early eating
Dietary consistency
Swallowing Needs tube feeding Frequent choking
changes
problems— occasional Normal
choking
Able to grip pen but Not all words are Slow or sloppy; all
Handwriting Unable to grip pen
unable to write legible words are legible
Normal
Can cut most foods,
Food must be cut by Somewhat slow and
Needs to be fed although clumsy and
Cutting food someone, but can still
slow; some help
clumsy, but no help Normal
feed slowly needed
needed
Independent but
Frequently requires
Fine motor requires modified Slow or clumsy in
Unable assistance from Independent
tasks caregiver
techniques or completing task
assistive devices
Requires assistance Independent but
Independent but with
from caregiver for requires assistive
Dressing Total dependence
some clothing items devices or modified
increased effort or Normal
decreased efficiency
techniques
24The Inclusion Body Myositis Functional Rating Scale (2/2)
Score
Domain 0 1 2 3 4
Requires occasional Independent but Independent but with
Completely
Hygiene dependent
assistance from requires use of assistive increased effort or Normal
caregiver devices decreased activity
Turning in bed Unable or requires Can initiate, but not Can turn alone or adjust Somewhat slow and
and adjusting total assistance turn or adjust sheets sheets, but with great clumsy but no help Normal
covers alone difficulty needed
Unable to stand Requires assistance Performs with substitute Independent
Requires use of arms
Sit to stand from a device or motions but without use (without use of
person of arms arms)
Wheelchair Dependent on Intermittent use of an Slow or mild
Walking dependent assistive device assistive device unsteadiness
Normal
Dependent on hand Slow with hesitation or
Dependent on hand rail
Climbing stairs Cannot climb stairs rail and additional increased effort; uses Normal
support hand rail intermittently
25Arimoclomol: a novel approach for the treatment of ALS, a
fatal progressive neurodegenerative disease
ALS is a rare fatal progressive neurodegenerative disease Phase 3 Trial
• US & EU: up to 50,000 patients • 18-months randomized, 2:1 randomization placebo-
• Two approved treatments: riluzole and edaravone controlled trial in early-stage ALS
(ca.150’000 USD/ year) • 245 patients (includes 7 patients on stable edaravone); fully
• Riluzole is shown to prolong survival by 2-3 months enrolled in July 2019
• Edaravone slows functional decline, but has burdensome IV • Randomization:
regimen (IV infusion over 60 mins for a 14 days period; • Arimoclomol 400mg (TID): n=141
subsequent cycles are infused over 60 mins for 10 days) • Placebo TID: n= 71
• Average age of patients: 50 years
• Affects men to women at a ratio of 3:2 Phase 3 Trial Endpoints
• Life expectancy 3-5 years
• Leading cause of death is respiratory failure and aspiration • Primary endpoint: Combined function and survival (CAFS)
pneumonia
• Secondary endpoints:
• Survival
Learnings from PRO-ACT database applied
• Function (ALSFRS-R)
• ≤ 18 months since onset of weakness ALSFRS-R ≥ 35 • Pulmonary function (SVC)
• Slow vital capacity (SVC) ≥ 70-80% (90% of patients have
SVC ≥ 80%)
*PRO-ACT database (>10’000 patients) applying machine
• Mortality rate at 12 months (10%) and 18 months (35%) learning and conventional statistics to select a
26
homoegeneous patient populationArimoclomol preclinical studies support MoA and potential
for disease modification
Preclinical 25% increase in lifespan of treated mice
Untreated
Arimoclomol demonstrated a strong effect in two
SOD-1 MOdel
ALS mouse models even after administration Untreated mice (SOD1G93A)
following disease onset:
% survival
Treated mice (SOD1G93A)
Arimoclomol treated
@ day 35 (pre-symptoms)
1) SOD1-model:
Treated mice (SOD1G93A)
• Arimoclomol extends lifespan in SOD1-ALS @ day 70 (symptoms seen)
mice by 25%
• Motoneuron death is prevented
2) VCP-model:
• Mislocalization of TDP-43 is reverted
TDP-43 pathology in mVCP mice spinal-chord is improved with
• Amplifies HSP70 in the spinal cord and arimoclomol and associated with increased HSP70
ameliorates the phenotypes of the VCP mouse Healthy mice VCP mouse model
VCP Model
model (TDP-43 in green) VCP mouse model + arimoclomol
• Prevents formation of ubiquitin-rich inclusion
bodies
• Findings were confirmed in both patient skin
cells and patient stem cell derived
motor neurons
27 *VCP: valosin containing proteinArimoclomol Phase 2 trials indicate slowing of disease
progression and prolonged survival
Arimoclomol slowed disease progression in Arimoclomol slowed disease progression and improved
sporadic ALS by 30% survival in SOD1-ALS
0 Sporadic ALS trial • Arimoclomol was well tolerated
ALSFRS-R total change from
• Efficacy (secondary endpoint) most pronounced in subpopulation with
-2
A4V mutation (13 patients in each treatment arm)
ALSFRS-R: Difference of 0.98 pts/month (A4V) and 0.50 (all)
baseline
-4 Survival: HR unadjusted: 0.59 (A4V) and 0.67 (all) in favor of
arimoclomol
-6 Combined assessment of function & survival: CAFS output in favor
Arimoclomol open label
Celecoxib placebo of arimoclomol. Treatment difference 5.92 (A4V) and 4.57 (all),
-8 corresponding to +41% (A4V) and +28% (all)
0 1 2 3 4 5 6
Month FEV6: A reduction in pulmonary function decline of 33%
The ALSFRS-R total; change from baseline by visit (in months) in the
• Clinical Proof of Concept based on consistent and clinically meaningful
open label arimoclomol study (100 mg TID; n = 69) vs the historical
trends across all efficacy measures with very aggressive disease course
control group is displayed
Dose ranging followed by 6-month open 12-month trial, double blinded placebo-
Study label extension (not head-to-head) Study controlled, two-arm design. 1:1 randomization,
indicative of slowing disease progression design 36 patients, arimoclomol 200 mg TID
design
28 ALSFRS, Amyotrophic Lateral Sclerosis Functional Rating Scale
Cudkowicz ME et al. Muscle Nerve 2008;38:837–44; Benatar M et al. Neurology 2018;90:e565-7412-domain ALSFRS-R: Amyotrophic Lateral Sclerosis
Functional Rating Score (1/2)
Score
Domain
0 1 2 3 4
Speech combined with Detectable speech
Intelligible with
Speech Loss of useful speech non-verbal
repeating
disturbance Normal
communication
Marked drooling, Slight but definitive
Marked excess of Moderately excessive
requires constant excess of saliva; may
Salivation tissue
saliva with some saliva, may have
have night-time
Normal
drooling minimal drooling
drooling
Exclusively parenteral Needs supplemental Dietary consistency Early eating problems –
Swallowing or enteral feeding tube feeding changes occasional choking
Normal
Able to grip pen but Not all words are Slow or sloppy; all
Handwriting Unable to grip pen
unable to write legible words are legible
Normal
Independent and
Dressing & Needs attendant for Intermittent assitance complete self-care with
Total dependence Normal
Hygiene self-care or substitute methods effort or decreased
efficiency
2912-domain ALSFRS-R: Amyotrophic Lateral Sclerosis
Functional Rating Score (2/2)
Score
0 1 2 3 4
Domain
Can cut most foods,
Food must be cut by Somewhat slow and
Cutting food and although clumsy and
Needs to be fed someone, but can still clumsy, but no help Normal
handling utensils feed slowly
slow; some help needed
needed
Turning in bed Can initiate, but not Can turn alone or adjust Somewhat slow and
and adjusting Helpless turn or adjust sheets sheets, but with great clumsy but no help Normal
covers alone difficulty needed
No purposeful leg Non-ambulatory Early ambulation
Walking Walks with assistance Normal
movement functional movement difficulties
Mild unsteadiness or
Climbing stairs Cannot do Needs assistance Slow Normal
fatigue
Significant difficulty, Occurs with one or more
Dyspnea considering using Occurs at rest of the following: eating, Occurs when walking None
mechanical support bathing, dressing
Some difficulty sleeping at
Needs extra pillows in
Orthopnea Unable to sleep Can only sleep sitting up night due to shortness of None
order to sleep
breath
Invasive mechanical
Respiratory Continuous use of BiPAP Continuous use of BiPAP
ventilation by intubation Intermittent use of BiPAP None
insufficiency or tracheostomy
during night and day during night
30Neurological Gaucher disease: high unmet need with no
approved treatment
Gaucher Disease Phase 2 Trial
• US & EU: up to 15,000 patients • 6-months placebo-controlled randomized double blind
• No approved treatment for neurological symptoms trial, followed by extension phase, stratified for GD type
1 (n=23) and type 3 (n=16)
• Managed in highly-specialized expert centers
• 39 patients; fully enrolled in August 2019
• Gaucher Type I
• Patients are treatment naïve to ERT and SRT
• Most prevalent in Western countries (95% of cases)
• 3 active dose arms: 100mg, 200mg, 400mg (all TID)
• Up to 50% develop neurological symptoms
including 5-7% with Parkinsonism symptoms • Randomization:
• Gaucher Type III • Arimoclomol: n=30
• Most prevalent across rest of world (China: 95%, • Placebo: n= 10
Japan: 60%, India: 30%)
Phase 2 Trial biomarkers, CSF and blood
• Chronic neuronopathic GD with 100% CNS
involvement
• Mutations in the GBA gene cause misfolding and loss of • Chitotriosidase (traditionally used in ERT trials)
activity of the glucocerebrosidase (GCase) enzyme • HSP70
• GCase activity
• Glucosylsphingosine / Lyso-Gb1 (subtrate broken down
by Gcase)
31Thank you
For further information:
contact@orphazyme.com
32Reference slides 33
Our story so far: building a biopharmaceutical company
from pioneering scientific discovery to positive clinical
outcomes
Phase II/III study
Nature publication: sIBM initiated
HSP70 augments
lysosomal function,
stabilizes lysosomal Positive NPC
membranes, Acquisition of Orphazyme listed
Phase II/III
Kirkegaard et al. arimoclomol on NASDAQ
full results
2009 2010 2011 2016 2017 2018 2019
Orphazyme founded • Science Translational Medicine Neurology publication: Randomized,
publication: Heat shock protein- double-blind, placebo-controlled trial of
based therapies as a platform for arimoclomol in rapidly progressive
Discovery of the treating multiple lysosomal storage SOD1-ALS, Benatar et al. (Phase II
function of heat shock diseases, Kirkegaard et al.
study in SOD1-ALS)
proteins and their • Science Translational Medicine
role in stabilizing publication: Targeting protein
lysosomes, by homeostasis in sporadic inclusion Phase III trial in ALS initiated
Dr Thomas Kirkegaard body myositis: Preclinical and phase
II clinical study of arimoclomol in Phase II trial in Gaucher
Jensen and Professor Type III initiated
sIBM, Ahmed et al.
Marja Jäättelä
• Phase II/III trial initiated NPC Positive NPC Phase II/III top line
results
34The heat shock protein response is the body’s normal
defense mechanism to restore cells under stress
Heat shock response Heat shock proteins: 3 key effects
Protein
• Cell stress leads to cell aggregates Prevent and correct
DNA
dysfunction and death 1 protein misfolding:
• Stress conditions induce the HSPs ensure correct folding
2
heat shock response (HSR), Protein and function of proteins
a normal defense degradation
mechanism to cell stress 1
• The HSR is triggered in all Prevent and degrades
cells of the body
3
2 protein aggregates:
(e.g. brain, muscle, neuron) Nucleus HSPs can degrade protein
Nascent
under stress protein aggregates by facilitating
• Triggering the HSR causes removal through degradation
increased levels of heat 1
shock proteins, e.g. HSP70,
HSP90, HSP40 Promote lysosomal function:
Folded &
functional 3
3 HSPs are biological chaperones
protein
promoting lysosomal function by
increasing lipid and protein
metabolism and removal,
Lysosome thereby stabilizing lysosomal
1
membranes and preventing cell
death
Misfolding
35Our executive team has breadth of experience in
discovery, clinical development and commercialization
Kim Stratton Chief Executive Officer
Anders Vadsholt Chief Financial Officer
Thomas Kirkegaard
Chief Scientific Officer Orphan Disease Council
Jensen Danish Cancer Society
Thomas Blaettler Chief Medical Officer
Molly Painter US President
Head of Global Product
Angus Hogg
Strategy
Head of Global Strategy &
Julia Barr
Operations
36Working in partnership with leading institutions and
patient groups
Patient
Scientific and community
collaboration partnerships
NPC
ALS
Financial
partnerships IBM
Danish Cancer Society
Gaucher
37Arimoclomol improves refolding, maturation and
lysosomal activity of glucocerebrosidase (GCase)
Efficacy of arimoclomol in common genotypes
• Arimoclomol amplifies HSP70
leading to an increase in refolding,
maturation and correct intracellular Effective in all Visualization of active GCase in GD cells
localization of GCase in patient well-known mutations
skin cells arimoclomol
• Arimoclomol significantly increases
GCase activity
• Increase in GCase activity is
confirmed in a complimentary
neurological Gaucher disease
stem cell model
Untreated Gaucher Arimoclomol
• Marked effects of arimoclomol seen patient skin cells treated Gaucher
patient skin cells
across common genotypes,
including L444P
38Arimoclomol has a sustained effect on slowing disease
progression in NPC
CHANGE FROM BASELINE TO 24 MONTHS
5-domain NPC-CSS Change from baseline
4.50 Annual Disease Progression: FAS and excl. null mutations (n = 38) • Reduction in progression with arimoclomol during
core study was sustained during open-label extension
4.25
Arimoclomol Placebo: Constant progression [*]
4.00
Estimated change from baseline 5-domain NPC-CSS
Placebo–arimoclomol Arimoclomol: Constant progression [*]
3.75
• Early treatment initiation had a greater benefit at
3.50
3.25 month 24 than delayed start, indicating that the
3.00
64%
disease course was modified by arimoclomol
2.75
2.50 • 64% reduction
*DOUBLEvs extrapolated
NULL MUTATIONnatural history
progression
2.25
2.00
33%
1.75
• 33% vs delayed start
1.50
1.25
• Switching to arimoclomol from placebo reduced
1.00
0.75
progression
0.50
0.25 DOUBLE FUNCTIONAL NULL MUTATIONS
0.00
0 3 6 9 12 15 18 21 24 • This analysis excludes individuals with double
Time since baseline (month)
functional null mutations (n = 3) in arimoclomol
Placebo-controlled phase Open-label extension treatment group who had rapid disease
progression during the study
Solid lines: Observed simple means +/- SE based on data obtained while patients were exposed to IMP
39
[*] Dashed lines: Model estimates from random intercept and slope model based on blinded 12 months dataEarly and sustained treatment with arimoclomol is superior to
delayed start of treatment on miglustat alone
CHANGE FROM BASELINE OVER 24 MONTHS
5-domain NPC-CSS Change from baseline
4.50 Annual Disease Progression: FAS and on miglustat • Early and sustained arimoclomol plus miglustat
4.25
4.00
Arimoclomol Placebo: Constant progression [*]
results in 72% progression reduction vs
Placebo–arimoclomol
3.75 extrapolated natural progression at 24 months
3.50
• 39% difference vs delayed start at 24 months
Estimated change from baseline 5-domain NPC-CSS
3.25
3.00
54%
2.75
• Delayed arimoclomol initiation still results in a 54%
72%
2.50 reduction in progression vs extrapolated
2.25
progression
2.00
1.75
1.50 39%
1.25
1.00
0.75
0.50
0.25
0.00
-0.25
-0.50
0 3 6 9 12 15 18 21 24
Time since baseline (month)
Solid lines: Observed simple means +/- SE based on data obtained while patients were exposed to IMP
40
[*] Dashed lines: Model estimates from random intercept and slope model based on blinded 12 months dataYou can also read
