Download Squalamine oncology - Genaera Corporation

PRODUCT FACT SHEET
Spring 2007
MISSION STATEMENT
Genaera Corporation is a biopharmaceutical company with a focus on
metabolic and respiratory diseases.
The compounds in the Genaera
pipeline address signal transduction
pathways at the cellular level to
treat a number of challenging diseases. These compounds hold
promise as potential medical breakthroughs in asthma, obesity and diabetes.
Genaera has made a strategic decision to out-license its
non-core assets, including
Squalamine.
CONTACT
Genaera Corporation
5110 Campus Drive
Plymouth Meeting, PA 19462
Ph: 610-941-4020
Fax: 610-941-5399
Investor Relations: 610-941-5675
Wed: www.genaera.com
Email: [email protected]
Henry Wolfe, Ph.D.
Executive Vice President
and Chief Scientific Officer
Squalamine Lactate:
Anti-angiogenic agent for Oncology
Squalamine lactate is an intravenously administered anti-angiogenic agent developed for
the treatment of solid tumors. A Phase 2 clinical trial is ongoing in prostate cancer.
Several Phase 2 trials have been conducted in advanced NSCLC and ovarian cancer
patients. The active ingredient (squalamine) is a small molecule produced synthetically
with an excellent cost of goods.
CLINICAL STUDIES
Multiple Phase 1 dose ranging studies have been conducted in advanced cancer patients at multiple
sites. The drug was generally welltolerated, with reversible hepatic
transaminases elevation at higher
dose levels and frequency. Several
small phase 2 clinical studies have
been conducted in advanced (stage
III or IV) ovarian cancer and nonsmall cell lung cancer (NSCLC) patients, a Phase 2 prostate cancer
clinical trial is ongoing.
Table 1: Oncology Study results
Ovarian1
NSCLC2
NSCLC3
Complete
Partial
19%
15%
0%
28%
2%
22%
Stable
38%
19%
49%
Progression
27%
53%
27%
Response
1
Continuous 5-day squalamine (200 mg/m2/day) infusion with carboplatin (AUC = 6), every 3 weeks, x6
2
Continuous 5-day squalamine infusion (300 mg/m2/day) following
carboplatin (AUC = 6) and paclitaxel (225 mg/m2/day), every 3 wks, x6
3
Weekly squalamine (100 or 200 mg/m2) infusion with carboplatin
(AUC = 2) and paclitaxel (75 mg/m2), x12
SQUALAMINE vs. STANDARD-OF-CARE LITERATURE
Clinical results obtained with squalamine in non-small cell lung cancer patients are
promising (Table 1). The definitive study in this field is a study by Schiller, et al(1) which
compared four different treatment regimens in a randomized study of 1155 stage IIIb
and IV NSCLC patients. As seen in Table 2, the results for Squalamine (Herbst, et al(2))
showed slightly more promising response rates, but were comparable to those reported by Schiller(1).
(610) 941-5268
Table 2: Squalamine vs Standard-of-care literature
This Product Fact Sheet contains
forward-looking statements within the
meaning of the Private Securities
Litigation Reform Act of 1995 that are
subject to risks and uncertainties, known
and unknown. Forward-looking statements
reflect management's current views and are
based on certain expectations and
assumptions. You may identify some of
these forward-looking statements by the use
of words in the statements such as
“anticipate,” “believe,” “continue,”
“develop,” “expect,” “plan” and “potential”
or other words of similar meaning.
Genaera’s actual results and
performance could differ materially
from those currently anticipated and expressed in these and other forward-looking
statements as a result of a
number of risk factors, described more fully
in Genaera’s filings with the U.S. Securities
and Exchange Commission,
all of which are available from the
Commission in its EDGAR database at
www.sec.gov or on the Company’s website
Herbst
Schiller
35 evaluable
290 evaluable
Day 1 = 225 mg/m2
Day 2 = AUC = 6
Day 2-6 at 100-400 mg/
m2/day
21 days
1-6
Day 1 = 225 mg/m2
Day 2 = AUC = 6
Response Rates
Complete Response
Partial response
Stable
Disease Progression
Could not be determined
34 % overall
0%
28 %
19 %
53 %
0%
17 % overall
<1%
16 %
23 %
49 %
11 %
Median Survival
1 year survival
8.5 months
33 %
8.1 months
34 %
Patients (similar eligibility
criteria )*
Paclitaxel
Carboplatin
Squalamine
Rest between cycles
Cycles
21 days
1-6
* For both studies, similar eligibility criteria were used for stage IIIB and IV NSCLC patients.
Squalamine Lactate:
Anti-angiogenic agent for Oncology
PRECLINICAL ACTIVITY
Anti-angiogenic activity has been demonstrated in several solid tumor xenograft models, which lead to the clinical
development of squalamine in oncology.
LUNG CANCER XENOGRAFT
Effect of combination chemotherapy
Nude mice bearing the MV-522 human lung tumor were treated for days 1–5 with vehicle (5% dextrose in water; t) or
with paclitaxel (10 mg/kg/day, q.d. for 5 days) and carboplatin (20 mg/kg/day, q.d. for 5 days; r, X). Some treatment
groups (…, X) received squalamine (20 mg/kg/day) on days 1–5 and 8–9. Error bars, SE; hatched box, squalamine dosing
period.(2)
Vehicle
Squalamine
Paclitaxel and Carboplatin
Paclitaxel, carboplatin and squalamine
Ovarian Cancer Xenograft
CAOV3 ovarian cancer cells were inoculated subcutaneously in nude mice. After 7 days, animals with tumors of comparable size were randomized to treatment with control solution, squalamine (2 mg/kg on days 1 ± 10), cisplatin (4 mg/
kg on day 1), or cisplatin administered in combination with squalamine. Tumor volumes (mm3) are expressed as
mean+s.e.m. for measurements to assess tumor growth delay due to the several treatments.(3)
3
Tumor Volume (mm )
600
400
Squalamine/Cis-Plat
200
Cis-Platin
Control
Squalamine
0
0
1
2
3
Time, Months
Page 2 of 5
4
5
Squalamine Lactate:
Anti-angiogenic agent for Oncology
MECHANISM OF ACTION: ANTI-ANGIOGENIC
Unlike other treatments for anti-angiogenic therapies, squalamine does not interfere with the binding of VEGF to its
receptor on proliferating endothelial cells. Squalamine is a potent small molecule that works INSIDE these actively
growing cells to specifically block the multiple intracellular pathways generated by the binding of VEGF and PDGFβ to
their respective receptors. Squalamine is rapidly eliminated from the systemic circulation (t1/2 = 7.5 hours in humans),
but retained in its intracellular site of action for more than 5 days. We believe this may be a key to the excellent safety
observed with squalamine in clinical studies to date. Once inside the cell, Squalamine exerts a number of effects which
prevent activation of the p38 inflammatory pathway as well as VE-cadherin and αvβ3 and their downstream signaling
pathways. This multi-faceted inhibition of intracellular pathways converts the actively proliferating endothelial cells into
a dormant, normal vasculature, slowing tumor growth.
Squalamine lis a systemically administered anti-angiogenic drug being tested for the treatment of wet AMD.
Unlike other treatments for wet AMD, squalamine does not interfere with the binding of VEGF to its receptor
on proliferating endothelial cells. squalamine works INSIDE these actively growing cells to block the intracellular
signals generated by the binding of VEGF and PDGFβ to their respective receptors. squalamine is rapidly eliminated from the systemic circulation (half-life = 7.5 hours in humans), but retained in its intracellular site of action
for more than 5 days. Once inside the cell, squalamine exerts a number of effects which prevent activation of
the p38 inflammatory pathway as well as VE-cadherin and ανβ3 and their downstream signaling pathways. This
multi-faceted inhibition of intracellular pathways converts the actively proliferating endothelial cells into a more
normal vasculature (Figure 1)
Figure 1: EVIZON Mechanism of Action
Squalamine inhibits angiogenesis and
inflammatory pathways
(inhibits activities of MAPK, p38, avβ3, and VE cadherin)
Squalamine (blue dots)
enters endothelial cells
No eNOS inhibition
Page 3 of 5
Squalamine Lactate:
Anti-angiogenic agent for Oncology
SQUALAMINE AND HYPERTENSION
The Competition:
Anti-VEGF therapies, such as Avastin®, block all intracellular downstream VEGF pathways, including eNOS, an enzyme
which helps maintain normal blood pressure (Figure 2). As a result, administration of Avastin has been associated with
clinically significant increases in blood pressure in patients.
Squalamine:
Squalamine, however does not block all intracellular VEGF pathways in proliferating endothelial cells, but rather only
blocks specific pathways, such as the MAP kinase proliferative pathway, the p38 inflammatory pathway, as well as VEcadherin and αvβ3 and their downstream signaling pathways. A key difference in the mechanism of Squalamine is that it
does not block eNOS activity (Figure 2).
Figure 2: Squalamine does not inhibit eNOS activity
No inhibition by EVIZON
% Maximum Response
100%
75%
50%
Avastin inhibits eNOS
25%
(p<0.001)
0%
Control
VEGF
Squalamine
EVIZON
+VEGF
Page 4 of 5
Avastin
+VEGF
Squalamine Lactate:
Anti-angiogenic agent for Oncology
We believe this mechanistic difference with Squalamine will have a profound impact on patient safety. A Preliminary
analysis of patients treated with squalamine in our Phase 2 wet AMD studies provides a first look at this effect. As
seen in Figure 3, treatment of wet AMD patients with up to 40 mg of squalamine is not associated with clinically significant increases in systolic and diastolic blood pressure.
Figure 3: Preliminary Analysis of Blood Pressure in wet AMD Patients treated with squalamine
10
Mean Change from
5
0
Systolic
Diastolic
-5
-10
-15
N = 17
N = 26
N = 81
* 4 to 29 weeks of intravenous Squalamine therapy
REFERENCES
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH 2002 Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98
Herbst RS, Hammond LA, Carbone DP, Tran HT, Holroyd KJ, Desai A, Williams JI, Bekele BN, Hait H, Allgood V,
Solomon S, Schiller JH 2003 A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clin Cancer Res 9:4108-4115
Li D, Williams JI, Pietras RJ 2002 Squalamine and cisplatin block angiogenesis and growth of human ovarian cancer cells with or
without HER-2 gene overexpression. Oncogene 21:2805-2814
McLane, et al, Angiogenesis Foundation 4th Annual International Conference – Antiangiogenesis, New Frontiers in Therapeutic
Development. Boston, MA. October 2006
Page 5 of 5