The Emergence of Synaptic Plasticity in the CNS Therapeutics Landscape - Will Resilience Pay Off?
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The Emergence of Synaptic Plasticity in
the CNS Therapeutics Landscape –
Will Resilience Pay Off?
Takeaways • A variety of candidate-stage therapeutic modalities are emerging
to modulate synaptic plasticity with putative applications across a
range of CNS disorders.
• Development of novel diagnostic tools, namely imaging and FDG-
PET, will greatly abet the ability to optimize such therapeutic
candidates, and select and monitor patients in real-time.
• Over the next several years, a number of companies discussed
herein will have clinical read-outs; successful data could have
significant implications for the CNS therapeutics field at large.
A growing cadre of biotech companies and their investors believe
that synapses are key to understanding and addressing a wide
range of CNS disorders. Synaptic plasticity and resilience refers to the
ability of synaptic connections, which can number on the order of 104 per
neuron, to strengthen, weaken, or change over time, often in correlation
with memory formation and other neuronal processes.
For the past several decades, investigators have been unraveling their role
not only in healthy development but also various neurodegenerative and
mood disorders. With the development of novel diagnostic tools and a
variety of therapeutic modalities positioned to monitor and correct such
insults, respectively, synaptic resilience appears at long last to be gaining
traction among investors. The next several years will be telling as these
technologies advance through preclinical and early-stage clinical testing.
AUTHOR:
Joel Sandler, PhD,
Associate Principal Developing novel therapeutics and diagnostic tools based upon an
understanding of neuroplasticity is critical in order to improve the treatment
and ultimately the prevention of a broad range of nervous system disorders.
– Fass et al., Neuroscience. 2014
© Defined Health, June 2018
The Emergence of Synaptic Plasticity in the CNS Therapeutics Landscape – Will Resilience Pay Off?
Cognition Therapeutics has developed a high-content screening platform to
identify small molecules capable of displacing and preventing the binding of
amyloid beta (Aβ) oligomers to neurons, thereby decreasing the synaptotoxic
effects of Aβ oligomers, reversing neuronal spine loss and potentially slowing
or reversing cognitive decline in Alzheimer’s disease (AD). This effort led to
the identification of the σ2R complex, a regulator of the saturable binding site
for soluble Aβ, as the relevant target of its lead program ElaytaTM (CT1812),
potentially casting new light on the importance of soluble oligomers, rather
than the plaque itself, in disease etiology.
According to CSO and company founder Susan Catalano, “these polymer-like
fibrils that form the majority of plaque material are tombstones…the disease is
elsewhere, that’s where you have to look.” And whereas neuronal death is
irreversible, it is likely occurring far later in the disease trajectory relative to
synaptic damage, which should both be reversible and, potentially, more closely
associated with pathology. To date, Elayta has demonstrated good tolerability,
as well as significant reduction of synaptic damage proteins in the cerebrospinal
fluid (CSF) as exploratory objectives in a Ph1b/2a AD trial. The company is
now collaborating with investigators at Yale to measure the impact of 6 months
of Elayta treatment on synaptic density in mild to moderate AD patients via in
situ monitoring with a synaptic vesicle glycoprotein-2A positron emission
tomography (SV2A PET) ligand in the Phase 2 SPARC trial.
Atlas-incubated Rodin Therapeutics is pursuing approaches to modulate
epigenetic regulation via targeted histone deacetylase (HDAC) inhibition, which
the company believes can restore synaptic function, health and survival across
an array of CNS diseases. Far from being in the business of advancing
oncology’s blunt HDAC inhibitors of yore, the company is developing brain-
penetrant target-selective HDAC complex modulators. For its lead program,
CEO Adam Rosenberg believes that Rodin has “identified the key class 1
HDAC complex that we need to inhibit, which then effectively disinhibits the
repression of pro-synaptic genes.”
As with Cognition, Rodin is investing heavily in biomarker development
necessary to track impact on synaptogenesis in baseline and treated patients.
According to Rodin’s Head of Discovery Magnus Ivarsson, “there’s the SV2A
PET ligand which we are evaluating to measure synaptic density. We are also
developing assays to measure synaptic proteins in both CSF and in neuronally-
derived exosomes from plasma samples.” While their first clinical trial is a
biomarker study in AD, Rosenberg notes that Rodin is taking “a disease-
agnostic approach, both in our preclinical and in our translational work”.
Beyond AD, the company website notes potential applications in
neurodegenerative disorders such as Parkinson’s, Huntington’s, and
frontotemporal degeneration (FTD), along with post-traumatic stress disorder
(PTSD), traumatic brain injury (TBI), and Rett Syndrome.
© Defined Health, June 2018
The Emergence of Synaptic Plasticity in the CNS Therapeutics Landscape – Will Resilience Pay Off?
Spun out from UCB Pharma in February 2018, Syndesi Therapeutics is
building upon findings that the marketed anti-epileptic drugs levetiracetam
(Keppra®) and brivaracetam (Briviact®) exert their effects via SV2A modulation.
Syndesi has an exclusive license to a novel series of compounds from UCB
which regulate the function of SV2A in a distinct manner, showing pro-cognitive
but not anti-epileptic properties in preclinical models. Unlike the companies
that are attempting to modulate synaptic wiring and hence modify underlying
pathology, Syndesi is targeting synaptic function as a means to address cognitive
symptoms in AD and other dementia disorders, albeit in a far more robust way
than has been achieved to date.
According to CEO Jonathan Savidge, the most commonly used AD treatments
“are very different from our approach of trying to mitigate symptomatic
dysfunction more generally, rather than targeting a particular neurotransmitter
in the case of Aricept or a particular glutamate receptor subtype in the case of
Namenda.” Syndesi’s lead program is anticipated to enter the clinic in early
2019, and in addition to safety and cognitive function, the company intends to
measure and optimize receptor occupancy and dosing using the
aforementioned SV2A PET ligand, which was in fact invented at UCB for such a
purpose.
Several additional companies are advancing orthogonal approaches to address
deficits in synaptic plasticity associated with different CNS disorders.
Probiodrug AG, for example, has demonstrated that its lead program PQ912,
which inhibits glutaminyl cyclase, an enzyme capable of catalyzing the formation
of the synaptotoxic Aβ species pGlu-Aβ, can achieve clinical impact on synaptic
CSF markers and electroencephalogram-theta (EEG-θ) rhythm, both of which
are reflective of synaptic plasticity.
EIP Pharma just raised $20.5 million to continue developing neflamapimod,
which has been shown to inhibit neuronal p38α, a MAP kinase known to
mediate synaptic dysfunction in AD, and was licensed from Vertex. Recruitment
is underway for a proof-of-concept study to measure episodic memory, a
surrogate for synaptic function, in a placebo-controlled mild AD trial.
Aptinyx, which was spun out of Naurex after the latter was acquired by
Allergan in August 2015, is advancing a series of NMDA receptor modulators
to enhance synaptic plasticity in patients suffering from disorders ranging from
chronic pain to PTSD and cognitive impairment associated with Parkinson's.
Lastly, Annexon is developing therapeutic antibodies against C1q, the initiating
molecule of the classical complement cascade, to protect against synapse loss
and inflammatory nerve damage as a means to address neurodegenerative
disorders and eye disease.
© Defined Health, June 2018The Emergence of Synaptic Plasticity in the CNS Therapeutics Landscape – Will Resilience Pay Off?
So What? Immense amounts of public and private funds have been exhausted on
discrete therapeutic modalities such as anti-amyloid drugs, which have to
date demonstrated modest clinical benefit at best. While combination
approaches may ultimately provide some salvage to these programs,
investigators such as Amsterdam Neuroscience’s Arjen Brussaard,
who collaborates with a number of synaptic plasticity-focused companies,
believe that “there must be common-denominator mechanisms that are
more seminal than just protein misfolding.” Magic bullets
notwithstanding, CNS pathologies and their corresponding burdens
march on relatively unabated in the face of clinical defeat, and new
investors, industry players, and therapeutic approaches continue to
emerge even as others fall by the wayside.
For decades, the concepts and tools converging under the common
theme of synaptic resilience have been percolating. The implications of
their ultimate success in the clinic would be far-reaching, both in terms of
our understanding of the underlying disease biology and development of
means to monitor and modulate it. Should reversibly modulating
synaptic connections have robust effects on cognition in
neurodegenerative disease, the trend towards increasingly early
positioning of disease modifying therapies with other
modalities may not be necessary. The modulation of synaptic
connections associated with affective disorders such as major depressive
disorder (MDD) or PTSD, on the other hand, may require concomitant
psychotherapy (as appears to be the case with MDMA in PTSD, for
example).
Regardless, preclinical and clinical readouts slated for the next 1-2 years
will doubtless contribute to our growing understanding of disease
pathology and development of means to correct it. And with the latest
FDA and EMA draft guidance documents released in February positing a
more pronounced role for surrogate endpoints in neurodegenerative
disorder trials such as AD, the field is well-positioned to achieve near-
term clinical and even commercial success if synaptic biomarkers can be
sufficiently validated as means to demonstrate clinically meaningful
benefit of corresponding therapeutic candidates. The upside case would
be huge, since success of one such program would have potential
readthrough to numbers of others. On a road littered with failure,
success stories benefit everyone. Or, as Rodin’s Rosenberg puts it,
“there are no competitors in neuroscience.”
© Defined Health, June 2018The Emergence of Synaptic Plasticity in the CNS Therapeutics Landscape – Will Resilience Pay Off?
About the Joel S. Sandler, PhD
Author Associate Principal
jsandler@definedhealth.com
Office: +1 973 292 5001 x 5260
Direct: +1 973 805 2087
As an Associate Principal and practice lead at Defined Health, Joel
provides insight to various CNS and oncology therapeutics-focused
clientele (biotechnology/pharmaceutical) on fundamental issues in drug
development and partnering based on a comprehensive analysis of the
key scientific, clinical, regulatory, and commercial questions relevant to
the client’s particular situation.
In previous industry roles, Joel was instrumental in the scouting and
evaluation of licensing and partnering opportunities for various oncology
assets. Prior to his BD&L activities, Joel spent ten years focused on the
discovery and characterization of bioactive compounds for cancer and
infectious disease research at several leading academic institutions. His
work has resulted in numerous grants, fellowships, patent filings, and
peer-reviewed publications.
He received his BA with honors from Cornell University, a PhD in
Organic Chemistry from UCSD/Scripps, and was a NIH Postdoctoral
Fellow at The Rockefeller University.
He is a member of numerous professional societies, including the
American Academy of Neurology (AAN), American Neurological
Association (ANA), the American Society of Clinical Oncology (ASCO),
the American Society of Hematology (ASH), and the American
Association for Cancer Research (AACR).
© Defined Health, June 2018The Emergence of Synaptic Plasticity in the CNS Therapeutics Landscape – Will Resilience Pay Off?
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