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At A Glance
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Wisconsin C-corporation
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Equity/debt
funding to date: $8.8m
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WI
State TDF Loan: $0.2m
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Certified
QNBV in Wisconsin for investor tax credits
Unmet Clinical Need
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Numerous
neurodegenerative diseases - symptomatic drugs poorly effective, no
disease-modifying drugs
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26
million Alzheimer’s disease sufferers worldwide, growing fast
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1%
of population with schizophrenia – major opportunity to treat cognitive
impairment
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Several
Orphan Drug opportunities
Clinically Validated Targets
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Validated
in Phase II AD and schizophrenia by Lilly’s xanomeline
Current Markets (2009)
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Alzheimer’s
$7.4bn (+12%)
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Psychosis
$23.1bn (+2%)
Intellectual Property
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Several
families of US and PCT patents or applications
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Worldwide
exclusive license
Management Team
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Trevor
M Twose, CEO
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Wayne
P Hoss, Director, Toledo
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Prof
William S Messer, Jr, CSO
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Patti
A Twose, Operations Director
Board of Directors
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Trevor
M Twose (CEO/Chair)
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Wayne
P Hoss PhD
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John
Neis MBA
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Frederick
A Robertson MD MBA
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Paul
M Weiss PhD MBA
Scientific Advisers
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Prof
Daniel A Rich
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Franklin
P Bymaster
Professional Advisers
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Foley
& Lardner (Legal)
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Perkins
Coie (IP)
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BDO
(Audit/tax)
Investors
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Venture
Investors LLC (Madison, WI)
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State
of Wisconsin Investment Board
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Wisconsin Investment Partners
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Rocket
Venture Fund (Toledo, OH)
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WARF
(Madison, WI)
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Rosetta
Partners (Lake Forest, IL)
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Biopons,
Inc (Fitchburg, WI)
Scientific Rationale
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Activate
muscarinic cholinergic function vital for memory and cognition
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Selectively
activate M1 subtype (MCD-386) or M1 and M4 (MI-10-022), while avoiding
activating M2 and M3
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Activate
multiple modes of disease-modifying actions, including α-secretase to reduce
Aβ production, and inhibit GSKIIIβ to reduce Tau phosphorylation
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Selectively
activate M4 for anti-psychotic actions
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Clinically
validated by Lilly’s xanomeline in AD and schizophrenia,
MCD-386 Pharmacology
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Selective
for M1 receptor in in vitro functional tests (‘functionally selective’ )
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Improves
cognitive function in vivo in animal models of cholinergic deficiency and cognitive
flexibility for PSP, ADAD and other diseases
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Preclinical
proof-of-principle of multiple modes of potential disease-modifying actions
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Engages
key signaling pathways in lab animal models in vivo
MCD-386CR Clinical Development
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Open
US FDA IND
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Controlled
release oral tablet formulation developed
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Completed
Phase I single ascending dose and multiple dose safety, tolerability and PK
studies including food effect, metabolism, elderly subject
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FDA
Orphan Drug status for PSP
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Seeking
partners
MCD-386/Glycopyrrolate Combination
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Preclinical
proof-of-concept
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Hi-dose
to maximize potential disease-modifying actions
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Targeting
ADAD, with potential for prevention in pre-symptomatic ADAD
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Seeking
partners
MI-08-016/035
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Preclinical
proof-of-concept
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Ready
for IND-enabling studies
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NCE
for sporadic AD - same pharmacology as MCD-386
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Fresh
intellectual property
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Seeking
partners
MI-10-022 Series
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>1
potential candidate drug
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MI-10-022
selected as candidate
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Potent,
selective M1/M4 agonist
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Preclinical
proof-of-concept
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Ready
for IND-enabling studies
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Efficacious
in animal models of cognition and psychosis – potential mono-therapy for
schizophrenia with unique first-in-class profile and mechanism of action
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Seeking
partners
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Mission
Mithridion
discovers and develops drugs for serious chronic neurodegenerative diseases,
including orphan diseases, and schizophrenia.
The Opportunity
Mithridion
designs and develops “first-in-class” small molecule drugs to address major
unmet medical needs, such as to improve memory and cognition, stop the
disease processes for which no currently effective drug exists and stop
neuron loss. We are actively targeting certain orphan diseases that offer
unique clinical, technical, personalized medicine, market and regulatory
opportunities, as well as more common diseases. Neurodegenerative
diseases including Alzheimer’s disease (AD) are devastating conditions
affecting >5 million Americans and 26 million people worldwide and are $
multi-billion markets, growing rapidly fuelled by an aging population and the
‘baby boom’ generation.
Product Pipeline
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Strong
and growing pipeline with several partnering opportunities (see page 2).
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MCD-386CR
is potentially a first-in-class drug targeted at Progressive Supranuclear
Palsy (PSP) and several neurodegenerative diseases for treating cognitive
impairments and blocking disease processes.
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MCD-386/glycopyrrolate
is targeted at Autosomal Dominant Alzheimer’s Disease (ADAD), potentially as
a preventative therapy for genetically-defined presymptomatic mutation
carriers at near 100% risk of developing ADAD.
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MI-08-016/035
are new chemical entity drug candidates with pharmacology close to that of MCD-386,
and are targeted for partnering for more common neurodegenerative diseases.
·
A
new drug candidate MI-10-022 is targeted for development with a partner as a
potential first-in-class monotherapy, addressing major unmet needs in schizophrenia.
Through its novel mechanism of action MI-10-022 potentially treats so-called
positive (psychosis), negative (emotional) and cognitive symptoms of
schizophrenia; this differentiates it from current anti-psychotic drugs,
which treat only positive symptoms. MI-10-022 has broad potential in CNS
disorders.
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Oral
controlled release and transdermal delivery options are available for all
three drug candidates, with (preclinical proofs-of-concept established).
Business Model
Mithridion’s
strategy is to develop drug candidates for rare diseases in house, then
project-manage pre-IND studies and Phase I and early Phase II clinical trials,
using contract research companies. Mithridion will seek partners for regulatory-driven
development for rare disease indications, and for all stages of development
for major market opportunities such as sporadic AD and schizophrenia. We seek
to create great value, then to realize it for shareholders as licensing fees
and royalties, and/or a liquidity event. We are currently actively seeking
partners with the resources and expertise to develop and market our drugs in
the major target markets.
Management Team
The
management team is led by an entrepreneur with extensive large and small pharmaceutical
company experience, including start ups and IPOs, Mithridion has a strong
group of scientific, industry and professional advisors.
Scientific Background
and Mithridion’s Product Pipeline
Cholinergic Function and Cognition
Acetylcholine,
(ACh) is a neurotransmitter and neuromodulator vital for arousal, attention, memory
and cognition. Certain of its actions are mediated by activation of muscarinic
receptors. In laboratory animal models, brain-penetrating muscarinic
receptor agonists enhance, and muscarinic antagonists impair, memory and
cognition. In many neurodegenerative diseases, cholinergic neurons are lost,
causing a cholinergic deficiency syndrome.
Five Muscarinic Receptor Subtypes
M1
muscarinic receptors are vital for memory and cognition. M4 is involved in
the control of psychosis. M2 slows down the heart, and M3 causes sweating,
salivation, tear production, and gastrointestinal tract effects, including
diarrhea. Mithridion’s small-molecule drugs selectively activate M1 and M4 muscarinic
receptors, to improve memory and cognition, stop neurodegeneration, and treat
psychosis, while avoiding side effects caused by activation of M2 and M3
receptor subtypes.
Pharmacology of Mithridion’s Drug Candidates
In
preclinical tests of cholinergic function, MCD-386 and MI-10-022 activate M1 receptors,
only weakly activate M3 receptors, and do not activate M2 receptors. MCD-386
had negligible activity on M4 receptors, while MI-10-022 strongly activates
M4 receptors. MCD-386 and MI-10-022 improved memory function in animal
models, including models of ADAD and PSP, at doses that did not cause
untoward effects. MI-10-022 was powerfully antipsychotic by a novel
mechanism different from current anti-psychotic drugs.
Potential Disease-Modifying Action
Mithridion
has demonstrated preclinical proof-of-concept that MCD-386 and MI-10-022 activate
several pathways that potentially will slow or halt the disease process in AD:
activating α-secretase and decreasing apoptosis in cultured cells in
preclinical laboratory models, decreasing Aβ in vivo, thereby
potentially preventing neuron death. M1 agonists are known to inhibit
GSKIIIβ and reduce pathological tau phosphorylation, a feature of many
neurodegenerative diseases. The MCD-386/glycopyrrolate combination enables
higher doses of MCD-386 to be administered to maximize disease-modifying
actions.
Clinical Validation of Target by Xanomeline
In
Phase II clinical trials, Lilly’s xanomeline had beneficial effects on
disease symptoms in both AD and schizophrenia. This first
generation drug validated this therapeutic approach, and defined the key
challenges: to improve agonist activity, but above all, to achieve better
selectivity to avoid side effects.
MCD-386/MCD-386CR Clinical Trials
An
IND for MCD-386 successfully cleared FDA. A controlled release formulation
has been developed and Phase Ib trials were completed successfully. To date
55 human subjects have participated in Phase I trials. MCD-386CR was
well-tolerated and a good understanding was obtained of pharmacokinetics and metabolism.
MI-10-022 in Preclinical Development
This
M1/M4 agonist has demonstrated the potential for cognition enhancing,
anti-psychotic and disease-modifying actions in laboratory animal models and
is being prepared for IND-enabling studies, including CMC work and toxicology
studies.
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