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Life Sciences Summit 11/21/13
Research Collaborators
MTAP INHIBITORS AS POTENT, NON-‐TOXIC ANTI-‐CANCER THERAPEUTICS
Technology presented herein is from the laboratory of Vern Schramm, Ph.D. at the Albert Einstein College of Medicine
and globally exclusive to NanomePcs LLC
www.nanomePcslab.com
• National Institute of Health (NIH) funded laboratory specializing in the development of early stage technologies.
• Diverse team of research scientists and clinicians.
• Funded by over $3.1 million in SBIR funding since 2010: • Phase II SBIR, NHLBI – sickle cell disease • Phase I SBIR, NCI – skin cancer prevention • Pending Phase I STTR, NCI – TNBC
Oncology Hematology Personal Care
About NanomePcs
TRACK RECORD: Nanometics sells polymers for skin care globally and has an extensive global network of collaborators and distributors in pharma and personal care. The Einstein team has developed small molecule transition state inhibitors which have recently completed Phase II clinical trials for leukemia and gout.
Diverse team of Academic Collaborators
Inhibitor design is driven by enzymatic transition state theory
Drugs are designed based on the enzymatic transition state
In late stage clinical trials for T-cell and
B-cell leukemia
Completed phase II clinical trials
for gout
In preclinical studies for human cancers:
lung, breast, postate, colon, and head & neck cancers (Option to Nanometics)
N
NH
HN
NH+
HO
HO
O
NH2
DADMe-Immucillin-GIn primate preclinical
trials as an antimalarial
Track Record of Success
TransiPon State Theory and Targeted Drug Design
Triple Negative Breast Cancer
• Value Proposition: There is no effective treatment for Triple Negative Breast Cancer (TNBC).
• Technology from the laboratory of Vern Schramm at Albert Einstein College of Medicine- unique approach and novel target.
• Global market for breast cancer therapeutics is forecasted to reach $13.86 billion by 2017.
• Recently raised $100,000 from the Avon Foundation and have a
pending $225,000 SBIR.
• Goal is to advance the lead therapeutic through an IND and then develop a strategic partnership with a pharmaceutical partner.
Breast Cancer Program – “MTAP Program”
Background
• Breast cancer is the most common cancer among US women.
• TNBC accounts for 15-20% of all breast cancers. • ~170,000 cases per year globally.
• TNBCs are biologically aggressive and carry a particularly poor prognosis: • TNBC lacks estrogen receptor (ER), progesterone receptor
(PR), and human epidermal growth factor receptor- 2 (HER-2). • Shortened disease-free interval. • Greater tendency for visceral metastasis, commonly leading to
brain metastasis.
• New approaches and biomarkers for TNBC are desperately needed.
Soohi Ismali-‐Khan and Marilyn M. Bui. A Review of Triple-‐Nega?ve Breast Cancer, 2010. Cancer Control. 2010;17(3):173-‐176.
Triple NegaPve Breast Cancer
MTA is a central metabolite connecting three biological pathways
The Polyamine-‐AdoMet C1 Pathways
Unique Approach
MTAP InhibiPon for Cancer Treatment
• The enzyme 5´-Methylthioadenosine phosphorylase (MTAP) is responsible for recycling 5´-methylthioadenosine (MTA) in humans.
• MTAP inhibition causes accumulation of the MTA metabolite, a by-product of the polyamine synthetic pathway.
• MTA accumulation alters gene expression and causes anti-cancer effects in both MTAP-positive and MTAP-negative tumors.
• The polyamine synthesis pathway is conserved among all TNBCs and disrupting this pathway has anti-cancer effects, but previous attempts to do so have led to toxicity.
Why not treat cancers with MTA alone? Mul?-‐gram doses of MTA are safe to humans however, MTAP simply recycles
MTA to adenine, methionine and S-‐adenosylmethionine (Ado-‐Met).
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• Nanometics is developing one of the most powerful MTAP transition state inhibitors ever reported as a once daily, oral drug for TNBC.
• Lead candidate: MT-DADMe-Immucillin-A (MTDIA): • MTDIA has 86 picomolar affinity for MTAP. • MTDIA has demonstrated efficacy in six different mouse
xenograft models of human cancer (TNBC, prostate, colon, cervical, head& neck, lung)
• Non-toxic and Orally available.
Ki* = 86 pMMTDIAH
NMeS
HO
N
N
N
NH2H
+POOHOH
O-
TherapeuPc To Be Developed
CMC Developed and kilogram synthesis is underway
MTDIA causes systemic MTAP inhibition and is effective against both MTAP-negative and MTAP-positive tumors"
(A) Highly tumorigenic MDA-‐MB-‐231 xenograRs showed a strong response to oral or i.p. MTDIA treatment. (B) Treatment of MDA-‐MB-‐468 mouse xenograRs with MTDIA caused significant tumor growth suppression. Tumors were grown for 35 days before treatment with MTDIA. At day 71, the untreated (control) group was treated (i.p.) with MTDIA. (C) Selected animals from the ‘Untreated, then treated’ group (1) showed tumor lysis, while cessa?on of treatment allowed slow regrowth in some mice (2). In others, tumor eradica?on was complete (3).
In Vivo Efficacy
Oral or i.p. MTDIA causes tumor suppression and regression in both MTAP (+) and MTAP (-‐) TNBC.
• Cmax ~3 mM; tmax ~2-3 hr; t1/2 ~15 hr
• Lead compound is highly orally available at sufficient concentrations. • MTDIA is > 100,000 pM at 25 hr
• Phosphate and hydrochloride
salts are both orally available.
• Anticancer effects in mouse models at 10 mg/kg.
• MTDIA is > 100,000 pM at 25 hr • This is far in excess of amount
needed for MTAP inhibition.
Lead Compound is Orally Available
MTDIA-‐PO4 auc = 750 µM•m
0
0.5
1
1.5
2
2.5
3
0 50 100 150 200 250 500 1000 1500 2000
Data 1
MP-High(uM)MP-Low(uM)
MP-High(uM)
Time(Min)
25 hr
Mechanism of AcPon
• MTDIA administration causes systemic inhibition of MTAP, and whole-body accumulation of MTA.
• MTA accumulation causes: • Metabolic perturbation of polyamine, folate-C1, AdoMet pathways. • Altered gene expression that slows cancer growth.
• First of Its Kind • Potential for pharmacodynamic (MTA levels) guided dosing and therapy.
• Mice receiving 50, 150, and 400 mg/kg MTDIA for 28 days had no significant adverse effects as determined by:
• Observational, • Histopathologic • Hematologic • Serum chemistry evaluation.
• After 28 days, only mild treatment-related non-adverse hematological changes were evident in the 50 and 150 mg/kg/day groups.
• No evidence of toxicity in all animal efficacy studies.
Toxicology
TASK Status Note
Chemical Properties Completed
MTDIA is well characterized, stable and protected by a family of patents.
Pharmacology Completed
Efficacy trials in mice show MTDIA is effective in multiple cancer indications.
Mechanism of action Completed
Decreased AdoMet and accumulation of the MTA metabolite.
CMC Completed
1-step cGMP synthesis.
PK/PD Completed
Mice
Route of Administration
Completed
MTDIA is orally available.
Non-GLP Mouse Safety and Toxicity
Completed
No adverse effects observed during non-GLP mouse efficacy or toxicity studies up to 400 mg/kg.
Summary
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Steven Isaacman, Ph.D. 111 Great Neck Road, Suite 212
Great Neck, NY 11021 P 646.801.3872
THANK YOU
www.nanomePcslab.com
