Innovative Therapies for Disorders of the Brain and Nervous System - Discovering and Developing Novel Small-Molecule NMDAr Modulators - Aptinyx
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Nasdaq: APTX
Innovative Therapies for Disorders
of the Brain and Nervous System
Discovering and Developing Novel
Small-Molecule NMDAr Modulators
December 2019
Forward-looking statements
This presentation has been prepared by Aptinyx Inc. (“we,” ”us,” “our,” “Aptinyx,” or the “Company”) and is made
for informational purposes only and does not constitute an offer to sell or a solicitation of an offer to buy
securities, nor shall there be any sale of any securities in any state or jurisdiction in which such offer, solicitation or
sale would be unlawful prior to registration or qualification under the securities laws of any such state or
jurisdiction. The information set forth herein does not purport to be complete or to contain all of the information
you may desire. Statements contained herein are made as of the date of this presentation unless stated otherwise,
and neither this presentation, nor any sale of securities, shall under any circumstances create an implication that
the information contained herein is correct as of any time after such date or that information will be updated or
revised to reflect information that subsequently becomes available or changes occurring after the date hereof.
This presentation contains “forward‐looking statements” within the meaning of the Private Securities Litigation
Reform Act of 1995 relating to business, operations, and financial conditions of Aptinyx including but not limited to
preclinical and clinical development of Aptinyx’s product candidates and the timing and reporting of results from
preclinical and clinical studies evaluating Aptinyx’s product candidates. Words such as, but not limited to, “look
forward to,” “believe,” “expect,” “anticipate,” “estimate,” “intend,” “plan,” “would,” “should” and “could,” and
similar expressions or words, identify forward‐looking statements. Although Aptinyx believes the expectations
reflected in such forward‐looking statements are based upon reasonable assumptions, there can be no assurance
that its expectations will be realized. Actual results could differ materially from those projected in Aptinyx’s
forward‐looking statements due to numerous known and unknown risks and uncertainties. All forward‐looking
statements speak only as of the date of this presentation and are qualified in their entirety by this cautionary
statement. Aptinyx undertakes no obligation to revise or update this presentation to reflect events or
circumstances after the date hereof.
2 12/12/2019
Clinical-stage biopharmaceutical company developing
transformative NMDA receptor-modulating therapies
✓
VALIDATED TARGETING RELEVANT POSITIVE CLINICAL MILESTONES
TECHNOLOGY DISEASE AREAS HUMAN DATA IN NEXT 12-18 MONTHS
with differentiated with significant unmet in Phase 1 & Phase 2 across multiple
science & need & commercial clinical studies compounds &
mechanism opportunity indications
$
ROBUST IP PRODUCTIVE WELL-FUNDED PROVEN TEAM WITH
through internal COLLABORATION & BACKED EXPERTISE & SUCCESS
innovation & with Allergan by highly regarded across pharma
proprietary platform healthcare investors value chain
3 12/12/2019
Development progress to date provides
substantial support for ongoing clinical studies
Preclinical Early Clinical / Mid-to-late Stage
Design & Discovery
Behavioral Studies Safety Evaluations Efficacy Evaluations
De novo, in-house medicinal In-depth screening in Clinical-stage candidates Demonstrated effects on
chemistry platform models of mood, learning, evaluated in > 200 healthy neuroimaging biomarkers
memory, cognition, and volunteers in safety and of pain processing in Phase
Over 1,000 molecules pain pharmacodynamic studies 2 fibromyalgia study
synthesized to date
Rapid, robust, and enduring No SAEs—even at very high Strong evidence of efficacy
Extensive in-vitro and in- activity in preclinical models doses (up to 1.2g) on patient-reported
vivo characterization of of pain, PTSD, and cognitive symptoms across two
novel modulation of NMDA impairment—among others Linear, dose-dependent, Phase 2 studies in chronic
receptors and predictable pain patients
Striking results with NYX- pharmacokinetic profiles
Numerous issued 458 in highly translatable Four ongoing Phase 2
composition of matter non-human primate model Ample CNS exposure studies
patents providing exclusivity of Parkinson’s disease confirmed through Painful DPN
through 2034 and beyond cerebrospinal fluid draws
Fibromyalgia
NMDAr pathway PTSD
engagement confirmed Parkinson’s mild
through two Phase 1 EEG cognitive impairment
studies
4 12/12/2019
Chronic Pain PTSD Parkinson’s Cognitive Impairment
Affects up to 100mm people ~8.5mm people suffering Affects up to 500k people in
in the U.S. from PTSD in the U.S. the U.S.
Current therapies have Caused by numerous 50% of those with
limited efficacy and trauma types and Parkinson’s have cognitive
substantial side effects underdiagnosed impairment
Market leading therapies Elevated suicide risk Significant disease burden
have significant drawbacks, on patients and caregivers
yet have garnered >$5bn in Often with simultaneous
annual revenues each addiction or drug abuse Only 1 approved therapy
with limited efficacy in PD
Significant abuse liability Only 2 approved therapies,
both approved 10+ years ago
Aptinyx is developing innovative therapies in large therapeutic areas
with significant unmet need
5 12/12/2019
Multiple clinical-stage development programs across
various CNS indications
Indication Phase 1 Phase 2 Phase 3 Marketed
Painful Diabetic
Peripheral Neuropathy
Phase 2b Data expected 4Q 2020 / 1Q 2021
NYX-2925
Fibromyalgia Phase 2b Data expected 1H 2021
Post-Traumatic
NYX-783 Phase 2 Data expected 2H 2020
Stress Disorder
Parkinson’s Disease
NYX-458 Cognitive Impairment
Phase 2 Data expected 2H 2021
Four Phase 2 data readouts expected over the next 12 to 24 months
6 12/12/2019
NMDA receptor has been a target of interest to drug
developers for decades
NMDA receptors are vital to normal brain physiology and
abnormal NMDAr function underpins numerous CNS diseases
Dementia
Chronic Pain
Schizophrenia
Alzheimer’s Disease
Huntington’s Disease
Depression
Cerebral Ischemia
PTSD
Cognitive Impairment
Traumatic Brain Injury Anti-NMDAr
Encephalitis
Autism Spectrum
Disorders Parkinson’s Disease
But, NMDAr-targeted drugs discovered to date (largely inhibitors, e.g., PCP, ketamine)
have significant limitations
7 12/12/2019
Modulation: a differentiated approach to targeting
the NMDA receptor
VS.
Aptinyx compounds modulate NMDA receptors, normalizing function and avoiding side
effects of over-activation or inhibition
8 12/12/2019
Modulation: a differentiated approach to targeting
the NMDA receptor
Intracellular Calcium Measured in Rat Cortical Neurons
Modulation – NYX-2925 Antagonism – Ketamine
Max enhancement
~20%
VS.
Max inhibition
~20%
Unlike the full inhibition observed with NMDAr antagonist, ketamine, Aptinyx compounds
demonstrate mild activation and mild inhibition of receptors
9 12/12/2019
Novel modulation of NMDA receptors ultimately
enhances learning and memory processes
NMDAr modulation triggers neurobiological cascade
Changes in Gene and
LTP = long-term potentiation
Protein Expression
LTD = long-term depression
Compounds interact with the NMDA receptor rapidly, triggering a neurobiological cascade, leading to:
Conformational and structural changes of NMDA receptors
Facilitation of calcium flux
Changes in gene and protein expression
Increased expression of NMDA and AMPA receptors at the cell surface,
Enhancement of long-term potentiation and synaptic plasticity, which underpin learning and memory
10 12/12/2019Prolific output from Aptinyx small-molecule NMDAr
modulator discovery platform
Molecules from the Aptinyx chemistry platform…
NMDA Receptor
stem from dozens of novel chemical
scaffolds
bind at a novel, distinct, newly
characterized binding domain
demonstrate high oral bioavailability
and stability
are protected through 2034 and
beyond by Aptinyx composition of
matter patents and patent
applications
have diverse potency, activity,
subtype selectivity, and Over 1,000 unique, small-molecule NMDAr
pharmacology/biology profiles modulators designed and synthesized
11 12/12/2019Chronic pain represents a major healthcare
and societal challenge
Current therapies have limited efficacy and significant drawbacks
Large market: Substantially underserved:
100 million people 40-60% do not achieve
with chronic pain even partial pain relief with
in the U.S. current NP therapies
Cymbalta and Lyrica each have Significant abuse liability
achieved $5B+ in peak annual
sales despite major limitations:
Significant side effects
Variable and marginal efficacy
Compliance challenges due to
burdensome dosing regimens
12 12/12/2019Favorable tolerability and dose-proportional PK
of NYX-2925 observed in 84-subject Phase 1 study
Single Ascending Dose Plasma PK Multiple Ascending Dose Plasma PK
CSF Exposure
With single and repeat dosing…
drug is cleared within 24 hours
no significant accumulation after 7 daily doses
AUC and Cmax are directly proportional to unit dose
no impact on AUC in fed vs. fasted state
brain exposure is ample and predictable
no drug-related SAEs, even at very high doses
✓ no dissociative side effects
✓ no clinically significant changes in safety ECGs
✓ no clinically significant changes in laboratory values
Effective
Doses tested
dose range
in Phase 2
13 preclinically 12/12/2019Mechanism of NYX 2925 targets aberrant, centralized
pain processing in chronic pain conditions
Aberrant Centralized
Normal Pain Processing
Pain Processing
Altered pain
processing in the
brain
Decreased
descending
inhibition
1. Stimulus sensed by peripheral nerve 1. Hyper-sensitivity and overactive nerves in the
2. Impulses depolarize the dorsal horn, increasing Ca2+ in periphery
neurons, causing release of neurotransmitters 2. Functional and processing changes in the brain
3. Signal is sent to the brain via ascending path and 3. Decreased descending inhibition leading to
perceived as pain increased pain perception—even in the absence of
4. The descending pathway carries impulses back to the harmful stimuli
dorsal horn
14 12/12/2019Fibromyalgia is a centralized chronic pain condition
that affects millions and is vastly underserved
A substantial market opportunity with no
What is fibromyalgia?
adequate therapeutic options
2nd most common “rheumatic” disorder behind OA
Aberrant centralized Estimates as high as 15 million1 people in the U.S.
pain processing
Current treatments include antiepileptics,
antidepressants, and opioids
– All have limited efficacy and substantial side effects,
including risk of abuse/addiction
Cymbalta and Lyrica, approved therapies for
fibromyalgia, both achieved in excess of $5bn
annually
Est. U.S. patients by severity
SEVERE
Aberrant processing in fibromyalgia—which MODERATE
can be objectively observed—results in pain MILD 8.2mm
and other symptoms 5.6mm
1.5mm
1 GlobalData Fibromyalgia Global Drug Forecast and Market Analysis to 2023
15 12/12/2019In Phase 2 neuroimaging study, NYX-2925 demonstrated significant
effects on primary endpoint: validated biomarkers of pain processing
Top-line fMRI Findings Top-line Glx/1H-MRS* Findings
Hyper-connectivity between brain regions is Increased Glx levels are observed in fibromyalgia
observed in fibromyalgia patients patients and associated with higher pain
perception
NYX-2925 significantly reduced levels of
connectivity in the dorsal anterior cingulate NYX-2925 reduced Glx levels, leading to pain
cortex (dACC) and the posterior insular cortex alleviation
(pINS)
dACC Glx Levels (Resting State) pINS Glx Levels (Post-Evoked Pain)
Placebo NYX-2925
Effects on objective biomarkers demonstrated clear activity on centralized pain processing
and were strongly correlated with effects on patient-reported measures
* 1H-MRS = Proton magnetic resonance spectroscopy
Notes: p-values calculated using paired-t test based on individual changes from placebo (week 2) to 20mg (week 4) or 200mg (week 6)
Error bars reflect standard error of mean
16 Glx/tCR = glutamate + glutamine normalized over total creatine
12/12/2019NYX-2925 also had significant effects on patient-reported
outcomes across broad spectrum of fibromyalgia symptoms
Average Daily Pain Worst Daily Pain
Pain
Endpoints
Total FIQR Score* PROMISFM Total Fatigue Profile Score**
Key QoL/Function
Endpoints
*Total FIQR reflects composite of Function, Overall Impact, and Symptom domain Scores
**Total Fatigue Profile Score reflects composite of Experience, Social Impact, Motivational Impact, and Cognitive Impact domain Scores
Notes: p-values calculated using paired-t test based on individual changes from baseline to each week or from placebo (week 2) to 200 mg (week 6)
17 Error bars reflect standard error of mean 12/12/2019Chronic painful DPN results in centralization of pain
processing and current therapies are inadequate
Underserved patient population representing a
Centralization in chronic painful DPN substantial market opportunity
Peripheral nerve damage caused by
sustained elevated glucose levels One of the most common complications among
the 26 million patients suffering from diabetes
Estimated to affect up to 30% of diabetes
patients
– ~7.5 million people in the U.S.
Current treatments include antiepileptics,
antidepressants, and opioids
– All have limited efficacy and substantial side
Time
effects, including risk of abuse/addiction
Centralization Cymbalta and Lyrica, approved therapies for
painful DPN, both achieved in excess of $5bn
With continued nerve damage and peripheral pain, annually
pain processing in the brain shifts from sensory regions
to emotional and learning & memory regions.
18 12/12/2019Signal of efficacy observed across total population in Phase 2 DPN
study—with greater separation in group not on concomitant analgesics
Change in average daily pain (primary efficacy endpoint)
Total Efficacy Population (N=300) Efficacy Population – No con. med. (N=148)
50 mg NYX-2925: 50 mg NYX-2925:
24% reduction in pain 25% reduction in pain
0.38-point ∆ vs. placebo 0.58-point ∆ vs. placebo
Clinically meaningful reduction in pain observed in total study population with greater separation seen in
patients not taking a concomitant analgesic medication—approximately half of the study population
19 Note: Pain reduction by DPN duration is Retrospective analysis 12/12/2019In initial Phase 2 DPN study, NYX-2925 demonstrated
robust analgesic activity in more chronic patients
Change in Average Daily Pain (Baseline to Wk 4) by DPN Duration
Duration of DPN Diagnosis
≥ 1 yrs ≥ 2 yrs ≥ 3 yrs ≥ 4 yrs ≥ 5 yrs
(N=275) (N=204) (N=151) (N=127) (N=95)
0
N=68 N=68 N=46 N=54 N=31 N=42 N=26 N=33 N=21 N=22
Change in NRS (0-10) Pain Score from
-0.5
-0.72
-1
Baseline
-0.93
-1.04
-1.26 -1.26
-1.5
-1.51
-1.62
-1.77
-2
-1.93
50mg Placebo **
-2.12
-2.5
*
*PSignificant, and clinically meaningful effects observed in
advanced DPN population—with no plateau in four weeks
Change in average daily pain (primary efficacy endpoint)
Advanced DPN population (N=127)* Advanced DPN population – No con. med. (N=64)*
50 mg NYX-2925: 50 mg NYX-2925:
31% reduction in pain 35% reduction in pain
1.2-point ∆ vs. placebo 1.8-point ∆ vs. placebo
NYX-2925 exhibited robust effects in patients with advanced DPN—and the separation from
placebo was even more pronounced in the population not on concomitant analgesic medications
21 *Retrospective analysis of advanced DPN population includes patients who had DPN for ≥ 4 years 12/12/2019Effect of NYX-2925 in advanced DPN was consistent across
endpoints in the study
Advanced DPN population (N=127)*
Worst Daily Pain: Pain on Walking:
26% Improvement 32% Improvement
0.93-point ∆ vs. placebo 1.1-point ∆ vs. placebo
DSIS:
38% Improvement
1.4-point ∆ vs. placebo
22 *Retrospective analysis of advanced DPN population includes patients who had DPN for ≥ 4 years 12/12/2019Key study findings provide foundation for further
development of NYX-2925 for painful DPN
NYX-2925 was safe and well tolerated in the study no SAEs and an overall AE profile
comparable to placebo
Patients with advanced DPN showed the greatest treatment benefit
– Mechanism of NYX-2925 addresses the increasing central manifestation of pain perception and processing
associated with the prolonged chronic pain these patients experience
– Patients with advanced DPN represented nearly half of the entire study population (N = 127)
50 mg identified as the most active dose level among the three doses tested
– Evidence of inverted-U-shaped dose response, consistent with previous preclinical and clinical data with
this mechanism
In patients with advanced DPN, effect of 50 mg dose was robust and clinically meaningful
– Week 4 change vs. baseline in average daily pain (on 10-point NRS) = 1.93 points (pRecently initiated two follow-up Phase 2 studies of
NYX-2925 in centralized chronic pain conditions
Painful DPN Fibromyalgia
~200-patient, placebo-controlled, ~300-patient, placebo-controlled,
double-blind double-blind
Advanced DPN population 12-week endpoint
12-week endpoint 50 mg or 100 mg daily vs placebo
50 mg daily vs placebo No concomitant analgesics
No concomitant analgesics Primary endpoint: Change in average
daily pain (NRS)
Primary endpoint: Change in average
daily pain (NRS) Other endpoints: daily sleep
interference, FIQR, PROMIS
Other endpoints: Worst daily pain,
daily sleep interference, pain on
walking
Data expected 4Q 2020/1Q 2021 Data expected 1H 2021
24 12/12/2019PTSD affects millions, is likely underdiagnosed, and has
common and debilitating comorbidities
Large market Detrimental comorbidities
~8.5 million people suffering compound the medical
from PTSD in the U.S. and societal costs
with an estimated lifetime
prevalence of 4.7%
PTSD Elevated suicide rates
among PTSD suffers
~20 veterans or
servicemembers die from
suicide daily
Limited effective therapy options Numerous causes of PTSD
Only 2 currently Car accidents
approved therapies
both SSRI antidepressants
Criminal assault 50-66 % also battle
with limited utility that were War combat simultaneous addiction
approved 10+ years ago Natural disaster to alcohol and other drugs
Sexual trauma
25 12/12/2019NYX-783 in Phase 2 clinical development for the
treatment of PTSD
Clear Mechanistic Rationale Significant Unmet Need
Learning and memory dysfunction is at Currently, only 2 FDA-approved therapies for PTSD:
the root of PTSD symptomatology both SSRI antidepressants with limited efficacy
D-cycloserine (DCS), an NMDAr Current therapies only target symptoms of PTSD
modulator, has demonstrated effect in
Side effects limit utilization of some effective therapies
PTSD
Strong Preclinical Evidence
NYX-783 resulted in more robust, accelerated,
and enduring fear extinction in conditioned
fear model
Preclinical evidence indicates the potential for NYX-783 to
address the learning and memory dysfunction underpinning PTSD
26 12/12/2019Favorable safety and tolerability and dose-proportional
PK of NYX-783 observed in 62-subject Phase 1 study
Single Ascending Dose Plasma PK Multiple Ascending Dose Plasma PK
CSF Concentration NYX-783 exhibits favorable tolerability
NYX-783 50 mg PO and PK properties:
Predictable and dose-proportional PK
Cleared from plasma in 24 hrs.
No accumulation with repeat dosing
No apparent impact on AUC in “fed” state
Ample, predictable brain exposure
No SAEs at any dose tested
27 12/12/2019Ongoing first-in-patient Phase 2 study of NYX-783 in
patients with post-traumatic stress disorder
Screening Stage 1 (4 weeks) Stage 2 (4 weeks)
Placebo non-responders
N ≈ 150 Placebo
Placebo NYX-783 10 mg
NYX-783 50 mg
Placebo non-responder criteria:
Diagnosis of • CAPS-5 reduction from baseline ≤35% Placebo responders
PTSD (DSM-5) • CAPS-5 score @ re-randomization ≥26 Placebo
CAPS-5 ≥30 NYX-783 10 mg
PCL-5 ≥38
NYX-783 50 mg
NYX-783 10 mg
Placebo
NYX-783 50 mg
Primary analysis for efficacy
Evaluating effects of NYX-783 on PTSD symptoms using multiple endpoints
Outcome of study to inform dose selection, most appropriate enrollment criteria, and endpoints
for future studies
Data from this first-in-patient Phase 2 study expected 2H 2020
CAPS-5 (Clinician Administered PTSD Scale – DSM 5th Edition)
PCL-5 (PTSD Checklist – DSM 5th Edition)
28 12/12/2019Vast unmet need in Parkinson’s disease cognitive
impairment despite significant disease burden
~1 million ~500k
people suffering from Parkinson’s ~250k with MCI
disease in the U.S. ~250k with dementia
50%+ 1
of those with Parkinson’s Disease therapy approved to date, Exelon®,
have some form of cognitive which is minimally efficacious in PD
impairment patients
29 12/12/2019NYX-458 in clinical development for the treatment of
cognitive impairment associated with Parkinson’s disease
Clear Mechanistic Rationale Substantial Opportunity
Synaptic plasticity and LTP – both enhanced by Significant unmet need
NYX-458 – play key roles in learning and memory Concentrated patient and prescriber base
NMDAr dysregulation and dysfunction caused by Attractive potential follow-on indications in a
neuronal loss (dopamine neurons in Parkinson’s) number of cognitive disorders
Strong Preclinical Evidence
In light of striking effects in rodent models… …NYX-458 was evaluated in a highly translatable model
of Parkinson’s in non-human primates
Robust effects on cognition in preclinical models support development
in Parkinson’s disease cognitive impairment
30 12/12/2019NYX-458 exhibits robust, long-lasting effects on cognitive
deficits in non-human primate model of Parkinson’s disease
After healthy baseline cognitive performance was impaired with MPTP,
NYX-458 resulted in reversal of cognitive impairment
Recovered effects after re-induced impairment Effects lasted ~3 months after final dose
Sustained effects with repeat dosing Did not worsen motor symptoms or interfere with L-Dopa
31 *MPTP is a neurotoxin employed to deplete dopamine-related neural cells -- similar to the way Parkinson’s disease does in humans 12/12/2019Favorable safety and tolerability and dose-proportional
PK of NYX-458 observed in 62-subject Phase 1 study
Single Ascending Dose Plasma PK Multiple Ascending Dose Plasma PK
CSF Concentration NYX-458 exhibits favorable tolerability
NYX-458 10 mg PO
and PK properties:
Predictable and dose-proportional PK
Cleared from plasma in 24 hrs.
No meaningful accumulation with repeat dosing
Ample, predictable brain exposure
No SAEs at any dose tested
32 12/12/2019Ongoing first-in-patient Phase 2 study of
NYX-458 in PD-MCI
Placebo-controlled period
Screening Follow Up
(12 Weeks)
N ≈ 135
Placebo
PD (>1 year)
Cognitive impairment NYX-458 10 mg
- and - Follow up Visit
MoCA ≥ 17 NYX-458 30 mg
(not severely impaired)
NYX-458 100 mg
Evaluating safety and tolerability of NYX-458 in Parkinson’s population
Evaluating effects of NYX-458 on cognitive impairment using multiple endpoints
Outcome of study to inform most appropriate dose, enrollment criteria, and endpoints for future
studies
Data from this first-in-patient Phase 2 study expected 2H 2021
PD = Parkinson’s disease
33 MoCA = Montreal Cognitive Assessment 12/12/2019Aptinyx is well-funded into 2021, enabling multiple
clinical milestones
2020 2021
1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q
Painful
Phase 2 data
NYX- DPN
2925
Fibromyalgia Phase 2 data
NYX-
PTSD First-in-patient Ph2 data
783
Parkinson’s
NYX- Cognitive First-in-patient Ph2 data
458 Impairment
Cash and Cash Equivalents $114mm
as of September 30, 2019
34 12/12/2019Experienced management team and a board of
highly regarded healthcare investors and leaders
Executive Management Team
Norbert Riedel, PhD Ashish Khanna Andy Kidd Kathryn King, PhD
President & CEO CFO & Chief Business Officer Chief Operating Officer SVP of Clinical Development
Board of Directors
Wilbur Gantz (Chairman) Henry Gosebruch
President EVP, Chief Strategy Officer, AbbVie
Patrick Enright Robert Hombach
Founder & Managing Director Retired CFO, Baxter and Baxalta
Terry Gould Adam Koppel, MD, PhD
Partner & Head of Venture/ Growth Equity Managing Director
Rachel Sherman, MD, MPH James Topper, MD, PhD
Former FDA Principal Deputy Commissioner Managing General Partner
Norbert Riedel, PhD
President & CEO
35 12/12/2019You can also read
