Transcript The AL-1 Story

The Stavudine Story
Chemical name:
2'-3'-didehydro-2'-3'-dideoxythymidine (d4T)
Commercial name: Zerit®)
International Non-proprietary name (通用名) : Stavudine
Mechanism of action
Stavudine is an analog of thymidine. It is phosphorylated by
cellular kinases into active triphosphate. Stavudine triphosphate
inhibits the HIV revers transcriptase by competing with natural
substrate, thymidine triphosphate. It also causes termination of
DNA synthesis by incorporating into it.
Simultaneous use of AZT is not recommended, as it can inhibit
the intracellular phosphorylation of stavudine. Other anti-HIV
drugs do not possess this property.
Discovery of d4T. Stavudine (d4T) was initially synthesized by Dr. Jerome
Horowitz of the Michigan Cancer Foundation (Karmanos Cancer Institute) in
1966.
Discovery that d4T would treat HIV/AIDS
Dr. Tai-Shun Lin (Yale) and Dr. William Prusoff (Yale) first discovered d4T's
capability to treat HIV/AIDS. Yale University holds the key use patent. The
patent number in the USA is 4,978,655 (Patent #4,978,655).
The fourth antiretroviral drug on the market, its patent expired in the United
States on 2008-06-25.
Professors. William Prusoff and Tai-Shun Lin
Professors Prusoff and Wang at Yale in August 2009
Stavudine was approved by the U.S. FDA in Jun 24, 1994 for
adults and in Sep 6, 1996 for pediatric use and again as an
extended-release version for once-a-day dosing in 2001.
Stavudine sales from $100-700m /year, and had generated
$276M for Yale University
Yale Univerisity-the hood where D4T was synthesized
Idoxuridine
It was discovered by Prof. William Prussof at Yale
University and was introduced in 1963 for the
treatment of herpes keratitis (角膜炎).
It is the first FDA approved antiviral drug for human
use.
The Onrigin Story
US brand names:
Cloretazine, Onrigin
Code name:
VNP40101M
Chemical structure names:
1,2-bis(methylsulfonyl)-1-(2chloroethyl)-2-(methylaminocarbonyl)hydrazine
Professor Alan Sartorelli and Wang, Summer 2007
Trials
Indication
Dates
Status
Phase III trial with standard remissioninduction therapy
AML and MDS
December 2008
Ongoing
Phase I/II trial in combination with
daunorubicin and Aracytine
Previously untreated adult AML with
unfavorable cytogenetics
March 2009
Ongoing
Phase I/II trial in combination with
cytarabine
Elderly AML and MDS
May 2008
Ongoing
Phase I/II trial in combination with
temozolomide
Brain tumors, adult
September 2007
Ongoing
Phase III trial in combination with AraC
AML, relapsed
March 2005
Closed
Phase II single agent trial
AML, elderly poor-risk
May 2006
Closed
Phase II single agent trial
Small cell lung cancer
September 2005
Closed
Phase I trial in combination with stem
cell transplantation
Hematologic malignancies
November 2007
Closed
Phase II single agent trial
Brain tumors, adult
June 2004
Completed
Phase II single agent trial
AML and high-risk myelodysplastic
syndromes, elderly; AML, relapsed
March 2004
Completed
Phase I/II single agent trial
Chronic lymphocytic leukemia
July 2005
Completed
Phase I trial
Brain tumors, pediatric
April 2005
Completed
Phase I trial in combination with
temozolomide
Hematologic malignancies
October 2004
Completed
Phase I trial in combination with Ara-C
Hematologic malignancies
July 2003
Completed
Phase I single agent trial
Solid tumors
February 2003
Completed
Phase I single agent trial
Hematologic malignancies
August 2002
Completed
Phase I single agent trial
Solid tumors
June 2001
Completed
Sept. 1, 2009 NEW HAVEN, Conn. (TheStreet) -- The FDA's
cancer drug advisory panel voted unanimously against approval
of Vion's leukemia drug Onrigin.
The panel recommended that a new randomized controlled trial
be conducted before the drug is approved. The same panel
rejected Genzyme's leukemia drug during a morning session for
similar reasons.
The Memantine Story
(1-Amino-3,5-dimethyladamantadine Hydrochloride)
(Axura® and Akatinol® by Merz, Namenda® by Forest and Ebixa® by
Lundbeck).
The first in a novel class of Alzheimer's disease medications acting on the NMDA
receptor.
Memantine is a low-affinity voltage-dependent uncompetitive antagonist at
glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher
affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of
Ca2+ ions.
NH 2HCl
H3 C
CH 3
The early development of Memantine as an Alzheimer's disease
treatment was carried by the biotech company Neurobiological
Technologies led by a team including Professors Stuart Lipton,
Jonathan Stamler, Yuqiang Wang and
Dr. James W. Larrick
From year 2007, memantine sales >$1000 M worldwide.
Prof. Stuart Lipton, MD; PhD
Burham Institute
Prof. Jonathan Stamler, MD; PhD,
Duke University
James Larrick,
MD; PhD,
Panorama
Research, Inc
Prof. Yuqiang Wang, PhD,
Jinan University
The AL-1 Story
O
O
O
S
O
S
CH2
HO
CH2OH
AL-1, synthesized by
Professor Yuqiang Wang, is
under development as an
anti-diabetic drug currently.
AL-1 is dual-functional,
i.e., lowering blood glucose
and protecting islet betacells.
Significant Hypoglycemic Effect in STZ-induced Diabetic Rats
Blood glucose level (mmol/L)
Group
day 0
day 7
Change (%)
Normal mice
7.92 ± 2.87
6.45 ± 1.73
-18.5
Diabetic mice
24.93 ± 4.97
23.60 ± 3.06
-5.3
AL-1(80 mg/kg)
19.53 ± 1.90
6.63 ± 2.4
-66.1
Andro (50 mg/kg)
22.15 ± 0.35
18.6 0± 0.28
-16.0
Glibenclamide
(1.2 mg/kg)
26.90 ± 1.56
9.25 ± 0.64
-65.6
*Rats were given ip STZ (60 mg/kg) once. On day 3rd (designated as Day 0), drugs were given po
and continuously daily for 7 days. aP<0.01 compared to solvents, and bP < 0.05 compared to day 0 (by oneway ANOVA analysis and Student’s t-test ).
AL-1 Protects Pancreatic -cells
Normal
Diabetic islet
AL-1(20mg/Kg)
Andro(50mg/Kg)
AL-1(80mg/Kg)
Glib (1.2mg/Kg)
（×400）
AL-1 Protects Functions of -cells
Normal islet
Diabetic islet
AL-1(20mg/Kg)
AL-1(80mg/Kg)
Andro(50mg/Kg)
Glib (1.2mg/Kg)
Development of AL-1:
Needs >10M RMB to get an IND;
5-10M RMB to be a new drug
Commercial potential: 10,00M RMB in China