REPRINT FROM JULY 18, 2011

BioCentury
T H E BERNSTEIN REPORT O N BI OB USINESS™

Article Reprint • Page 1 of 2

Product Discovery & Development

Rigosertib’s arresting story
vinca alkaloids, which kill any rapidly dividing cells, rigosertib
By Aaron Bouchie
maintains healthy cells in the G1 phase, which does not trigger
Senior Writer
Onconova Therapeutics Inc. believes the dual mecha- apoptosis.
As a result, “rigosertib kills cancer cells but doesn’t cause
nism of its rigosertib against PLK1 and PI3K will give it anadvantage over compounds that inhibit either mitosis or PI3K things like cytopenia, leukopenia, neutropenia and anemia thatalone. The company also believes rigosertib will be safer than other mitotic inhibitors cause,” Kumar said.
First-generation PLK1 inhibitors, like BI 2536 from Boehringer
other mitotic inhibitors, including other PLK1 inhibitors inIngelheim GmbH, caused side effects similar to those seen withdevelopment.
Japanese in-licenser SymBio Pharmaceuticals Ltd. thinks other mitotic inhibitors, like neutropenia, leukopenia and gasthe concept fits into its fast-moving specialty pharma model, and trointestinal events. The pharma company attributes these side
this month obtained rights to late-stage compound for Japan and effects to the compound arresting both cancer and rapidly dividing
healthy cells in the M phase and triggering
Korea in exchange for undisclosed upfront
apoptosis.
payments, milestones and royalties.
There are at least two other PLK1
Rigosertib is in the U.S. and European“We can have theinhibitors in clinical trials. BI’s volasertib
Phase III ONTIME trial for myelodysplastic
synergism of inhibiting two(BI 6727) is in Phase II testing for nonsyndrome (MDS), the Phase II/III ONTRAC
small cell lung cancer (NSCLC), ovariantrial in combination with gemcitabine toessential pathways without
cancer and urothelial cancer and in Phase
treat pancreatic cancer, and Phase I/II andthe cumulative toxicity
I/II testing for acute myelogenous leukePhase II trials in various hematologic canmia (AML).
cers and solid tumors.
from two drugs.”
TKM-PLK1 from Tekmira PharmaThe compound inhibits tumor growthceuticals Corp. is in a Phase I trial inby blocking phosphoinositide 3-kinase
Ramesh Kumar,
patients with solid tumors or lymphomas(PI3K), whose signaling promotes a range
Onconova Therapeutics
with interim data expected by year end.
of cellular functions, including cell growth,
Boehringer spokesperson Julia Meyerproliferation, survival and metabolism.
It also blocks polo-like kinase 1 (PLK1; STPK13), thus Kleinmann said both volasertib and BI 2536 showed reversible,
arresting cancer cells in the M phase and triggering apoptosis. dose-dependent hematotoxicity. The company decided to priOnconova CEO Ramesh Kumar noted that all cancer cells oritize volasertib for clinical development “based on pharmacohave defects in the G1 regulatory mechanisms. These defects kinetic characteristics indicative of high and sustained exposure
make them go past this checkpoint and become arrested in the in tumor tissue,” she said.
There are at least 13 PI3K inhibitors in clinical development.
M phase, which triggers apoptosis.
However, unlike other mitotic inhibitors such as taxanes andSee next page

BioCentury®

DAVID FLORES
President & CEO

KAREN BERNSTEIN, Ph.D.
Chairman & Editor-in-Chief

T H E B ERNSTEIN R EPORT O N B I OB USINESSPO Box 1246
San Carlos CA 94070-1246
Voice: 650-595-5333
Fax: 650-595-5589
www.biocentury.com

BioCentury®, The BioCentury 100, and The Clear Route are trademarks of BIOCENTURY PUBLICATIONS INC.
All contents © Copyright 2011, BIOCENTURY PUBLICATIONS INC. ALL RIGHTS RESERVED. No part of thispublication may be reproduced, photocopied or reproduced in any form, retransmitted, or stored in a
retrieval system without prior written consent of the publisher.
The contents of this publication are gathered from sources believed to be reliable, but in any case are
not warranted by the publisher for a particular use or purpose. Also, the content and opinions herein
may change without notice and do not constitute investment advice.

BioCentury, THE BERNSTEIN REPORT ON BIOBUSINESS
Product Discovery & Development,from previous page

Kumar said rigosertib’s dual mechanism enables development for cancers
such as relapsed/refractory MDS that
could not be treated with a PI3K inhibitoror mitotic inhibitor alone.
“By using a single drug that targets two
non-overlapping pathways we can havethe synergism of inhibiting two essential
pathways without the cumulative toxicity
from two drugs,” he said.
The company is leading with secondline MDS, where existing treatments leaveroom for improvement and there are noapproved drugs for patients with relapsed/refractory disease.
There are three drugs approved for
MDS in the U.S. Two are the hypomethylating agents Vidaza azacitidine from Celgene Corp. and Nippon Shinyaku Co.
Ltd. and Dacogen decitabine from SuperGen Inc., Johnson & Johnson andEisai Co. Ltd. The third, Celgene’s thalidomide analog, Revlimid lenalidomide, isapproved for a subgroup of patients whoare missing part of chromosome 5 (del5q).
Vidaza is approved in Europe, andVidaza and Revlimid are approved in Japan.
“The main MDS drugs are the two
hypomethylating agents, and neither has areally high rate of success. And even thosepatients who do respond have a high rateof resistance,” Kumar said. “The Phase Iand II data we have suggest we have very
good activity in these relapsed/refractorypatients, and we are helping these patientslive longer.”A meta-analysis of 48 MDS or AML
patients refractory to hypomethylating
agents enrolled in four Phase I, I/II or II
trials showed 19 (40%) had an initial bone

REPRINT FROM JULY 18, 2010

marrow response by weeks 4 to 8 or acomplete bone marrow response.
These responses were significantly associated with an increase in overall survival compared with patients who did nothave a bone marrow response (p=0.0001),
including in MDS patients alone (p=0.008).
The underlying OS data were not reported.
Data were presented at the American Society of Hematology (ASH)
meeting last year in Orlando.
SymBio CFO Hiroki Maekawa said thecompany had been looking for anotherhematological cancer product to go withbendamustine, which it in-licensed from
Astellas Pharma Inc. in December
2005.
SymBio has since received approval ofbendamustine for non-Hodgkin’s lymphoma (NHL) and mantle cell lymphoma(MCL) in Japan; NHL and chronic lymphocytic leukemia (CLL) in China and Singapore;
and CLL and multiple myeloma (MM) inKorea.
Cephalon Inc. markets bendamustineas Treanda in the U.S., while Mundipharma
International Ltd., which has European
rights, markets it in Germany as Ribomustin.
“We were very impressed that in lessthan five years they in-licensed a product,
conducted clinical trials and launched inJapan, Singapore and Hong Kong,” Kumar
said.
SymBio has not disclosed details of its
rigosertib program, but Maekawa said thecompany plans to start clinical trials in Japan“soon.”
While SymBio partnered out the marketing of bendamustine because it could notafford a sales force at that time, Maekawa
said the company plans to market rigosertib
itself with a sales force of 30-40 reps atlaunch.
Onconova also is looking to partner out

P AGE 2 OF 2

the commercialization of rigosertib in most,
if not all, other parts of the world.
“We are a discovery and development
company right now. Realistically, there is noway we can commercialize rigosertib inmany territories,” Kumar said.
Onconova hopes to receive approval of
the compound for MDS in the U.S. in 2013.
Rigosertib has Orphan Drug designation
for MDS in the U.S., where it is called
Estybon.
Onconova has completed Phase I tolerability trials with an oral formulation ofrigosertib in MDS and solid tumor patients,
but has not yet decided how to pursue it.
The company could submit an sNDA for
second-line MDS after the injectable formulation is approved or conduct additional
trials as a first-line therapy.
COMPANIES AND INSTITUTIONS MENTIONED
American Society of Hematology (ASH),
Washington, D.C.
Astellas Pharma Inc. (Tokyo:4503), Tokyo, Japan
Boehringer Ingelheim GmbH, Ingelheim,
Germany
Celgene Corp. (NASDAQ:CELG), Summit,N.J.
Cephalon Inc. (NASDAQ:CEPH), Frazer, Pa.
Eisai Co. Ltd. (Tokyo:4523; Osaka:4523),
Tokyo, Japan
Johnson & Johnson (NYSE:JNJ), New
Brunswick, N.J.
Mundipharma International Ltd., Cambridge, U.K.
Nippon Shinyaku Co. Ltd. (Tokyo:4516;Osaka:4516), Kyoto, Japan
Onconova Therapeutics Inc., Newton, Pa.
SuperGen Inc. (NASDAQ:SUPG), Dublin,Calif.
SymBio Pharmaceuticals Ltd., Tokyo,Japan
TekmiraPharmaceuticals
Corp.
(TSX:TKM; NASDAQ:TKMR), Burnaby, B.C.