Untangling the Nimotuzumab Conundrum
An easy google or reading posts on Yahoo about
Nimotuzumab can get confusing .....
* Nimotuzumab had NO RESPONSE in Colon Cancer
** True
** That means Nimotuzumab is Junk
** No. Thats what clinical trials decide.
* Nimotuzumab comes from Cuba.
** Cuba can't afford good science:
** Not True
cim.sld.cu
cancerres.aacrjournals.org
cancerres.aacrjournals.org
* The Nimotuzumab trials are being done by no name companies
** Not True
** For example -
Daiichi is the 20th largest pharm in the world
en.wikipedia.org
* Erbitux is a (MAb)
** True
* Nimotuzumab ain't a (MAb)
** Not True
en.wikipedia.org
en.wikipedia.org
And so on ....
OK - Lets summarize some issues about
Nimotuzumab and Erbitux
====================
Nimotuzumab Issues
====================
1 - Invented in CUBA
2 - No Response Rate in Colon Cancer (about 4%)
3 - Nimotuzumab _NOT_ an Anti-EGFR MAb
4 - Who OWNS Nimotuzumab?
5 - Trials - Erb/Rad HN Trials - Skin Toxicity problems?
6 - Nimotuzumab can't work in Cancer
7 - Erb/Rad Skin toxicity. No serious follow up
8 - Nimotuzumab ain't real
9 - $64 question - Why Erb/Rad toxicity - was trial better than actual experience?
10 - Erb/Rad Toxicity - A Big Deal?
11 - Strange Companies doing Nimotuzumab Trials
====================
Erbitux Issues
====================
1 - The Erbitux (MAb) binds to healthy and Cancerous cells
True or False
2 - The Erbitux+Radiation may lead to Grade IV radiation dermatitis
True or False
3 - What do the Erbitux+Radiation Trials say?
====================
Erbitux - Some Answers
====================
1 - The Erbitux (MAb) binds to healthy and Cancerous cells
In this study we examined EGFR expression of
human renal cortical epithelial cells,
human epidermal cells and
A431 cancer cell line,
and compared binding of nimotuzumab and cetuximab to these cells by Flowcytometric analysis (FACS).
Human renal cortical epithelial and epidermal cells were found to express low levels of EGFR compared to A431 cancer cells.
Nimotuzumab’s binding to the epidermal and renal cells was several fold lower than that of cetuximab.
Concurrently, binding of nimotuzumab and cetuximab to
A431 EGFR overexpressing cancer cells was equivalent.
Source:
Abstract # 2763
AACR
Erbitux = Cetuximab Toxicity
100th Annual Meeting in Denver, Colorado
April 20th, 2009
ymbiosciences.com
2 - The Erbitux+Radiation may lead to Grade IV radiation dermatitis
May 2009
Page 9
A recent survey by the EORTC of 125 patients
with head and neck cancer from 15 institutions
found that grade 3 to 4 dermatitis occurs in approximately
49% of patients treated with cetuximab and
concurrent RT.57
In another group of 14 patients with head and neck cancer treated with cetuximab
and concurrent RT, 5 developed grade 3 to 4 dermatitis,
and 10 (71%) also developed superinfection
with S aureus.53
Grade 4 dermatitis has also been
described when cetuximab is administered in the
setting of reirradiation, when using radiation to a
recurrence or second primary within a previously
radiated field.63,64
In 5 patients who were reirradiated,
2 experienced complete necrosis of the skin
in the area of radiation. In the histologic specimen,
complete apoptosis of the keratinocytes throughout
the epidermis and evidence of superinfection were
seen.63,65
In patients who must undergo reirradiation
in the same field, whether they can also receive
concurrent EGFR inhibitors is not currently clear.
A phase I study of reirradiation and erlotinib has
been completed recently.
nccn.org
May 2009
Pictures
See pages 9/26
See pages 10/26
See pages 11/26
See pages 15/26
nccn.org
3 - What do the Erbitux+Radiation Trials say
This Trial EXCLUDES radiation - just Erbitux+Chemo
IT SAYS IN PART -
The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence =>50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss
(84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events (=> 10%) included:
radiation dermatitis (23%), acneform rash (17%), and weight loss (11%).
redorbit.com
This Trial INCLUDES radiation - just Erbitux+Chemo
IT SAYS IN PART -
With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxicity, including mucositis, which often precludes combining chemotherapies with
radiation, did not differ significantly between the treatment arms.
redorbit.com
I don't see "radiation dermatitis" mentioned.
More Info ERBITUX + Radiation dermatitis
??? 2009
Severe radiation dermatitis with concurrent cetuximab and radiation — There is accumulating evidence that the administration of cetuximab and other EGFR inhibitors concurrent with radiation therapy increases the risk of potentially severe radiation dermatitis, rash, and
mucositis [24,25]. (See "Concurrent chemoradiation for locoregionally advanced head and neck cancer", section on Complications and supportive care).
uptodate.com
Feb 2009
High rate of severe radiation dermatitis during radiation therapy with concurrent cetuximab in head and neck cancer: results of a survey in EORTC institutes.
Radiother Oncol. 2009 Feb;90(2):
Giro C, Berger B, Bölke E, Ciernik IF, Duprez F, Locati L, Maillard S, Ozsahin M, Pfeffer R,
Robertson AG, Langendijk JA, Budach W.
Department of Radiation Oncology, University Hospital Düsseldorf, Germany.
ncbi.nlm.nih.gov
March 2009
in-field dermatitis and mucositis represent new safety concerns. Improved reporting and management strategies are critical for quality of life and the optimization of radiation plus EGFR inhibitor protocols.
uptodate.com
May 2009
American Journal of Clinical Oncology:
Results:
Serious radiation dermatitis was noted in 26 (23%) patients, with 22 patients developing grade 3 dermatitis and 4 patients developing grade 4 dermatitis.
All 4 patients who developed grade 4 dermatitis did so within the radiation field.
The dermatitis was manifested by spontaneous bleeding from the involved skin, and in 1 case, skin necrosis. These toxicities developed during the fifth week of treatment.
Conclusions:
Treatment with concurrent radiation and cetuximab for locally advanced HNC is a relatively new treatment modality, and the toxicities of this regimen are becoming better understood.
We believe that the serious skin toxicities that these patients develop when treated with concomitant cetuximab occur more frequently than when patients are treated with concurrent
cisplatin, although further study is needed to confirm this.
journals.lww.com
Annals of Oncology - 2008
Results: Both general and grade-specific approaches for the management of dermatitis in this patient group are presented. It was concluded that where EGFR inhibitor-related acne-like rash and dermatitis coexist within irradiated fields, management should be based on the grade of dermatitis: for grade 1 (or no dermatitis), treatment recommendations for EGFR-related acne-like rash outside irradiated fields should be followed; for grades 2 and above, treatment
recommendations for dermatitis were proposed.
annonc.oxfordjournals.org
NEJM SEPT 2009
Severe Cutaneous Reaction during Radiation Therapy
with Concurrent Cetuximab
nejm.highwire.org
JAN 2009
Severe cutaneous toxicity following treatment with radiotherapy and cetuximab: a case report
Interestingly, there was no significant increase in grade 3 radiation dermatitis for the cetuximab group (23% versus 18%) in this study. However, multiple reports have subsequently
emerged of severe radiation dermatitis complicating treatment with concurrent cetuximab and radiotherapy for HNSCCs [3-5]. Radiation dermatitis must be distinguished from the acneiform
rash of the face, neck and upper torso that affects up to 2/3 of patients receiving anti-EGFR agents[6,7].
pubmedcentral.nih.gov
====================
A google Test
====================
(1) Link to Google - google.com
Count the Images:
(2) Search Vagina Images - a private part of the body
(3) Search Penis Images - a private part of the body
(4) Search Mein Kampf Images - helped kill/murder > 60 million people
Now Search
(5) Search Grade IV radiation dermatitis Erbitux - How did you do?
Remember - this is the world wide web you are searching
====================
Nimotuzumab - Some Answers
====================
1 - True
2 - True
3 - False
4 - Univ of Havana + YM BioSciences + Licencees
5 - Mentioned
6 - gekkowire.com P2 HN
7 - Growing # of Links
8 - See Table 1 Trials and - Upcoming Events 2010
9 - ???
10 - Choose:1/5 or 1/4 or 1/3 chance Skin Toxicity -vs- 0% chance
11 - Are Daiichi Sankyo - Oncoscience - Innogene Kalbiotech
Kuhnil all DUMMIES spending $$$$
11 (continued)
====================
The 4 Companies
====================
Who are they?
--------------------
Daiichi Sankyo
--------------------
US $13 billion Market Cap
per R&R Presentation
--------------------
dsi.com
dsi.com
dsi.com
2009
YM BIOSCIENCES REPORTS DAIICHI-SANKYO ENROLLS FIRST PATIENTS IN PHASE II,
FIRST-LINE LUNG CANCER TRIAL WITH NIMOTUZUMAB
reuters.com
--------------------
Oncoscience
--------------------
Private Compamy
--------------------
oncoscience-ag.de
oncoscience-ag.de
oncoscience-ag.de
2008
Oncoscience - PUNTS ON Nimotuzumab
Oncoscience has withdrawn its MAA for cancer drug candidate
nimotuzumab because it would not be able to meet requirements
for approval from the EMEA’s advisory committee in time.
The Committee for Medicinal Products for Human Use (CHMP)
expressed concerns regarding the quality and efficacy of nimotuzumab.
genengnews.com
2009
Oncoscience - BACK IN THE GAME ON Nimotuzumab
MISSISSAUGA, ON, June 29 /CNW/ - YM BioSciences Inc. (NYSE Amex:YMI, TSX:YM, AIM:YMBA), a life
sciences product development company that identifies and advances a diverse portfolio of promising cancer-related products at various stages of development, today reported that YM's subsidiary, CIMYM BioSciences Inc. and Oncoscience AG have resolved the issues between the companies in a cooperative effort. CIMYM BioSciences has formally notified Oncoscience that it no longer intends to submit its application to the London Court of International Arbitration
for
... CEO of Oncoscience. "I am delighted that we may now focus our combined resources exclusively on the contribution to the clinical program being undertaken globally for this
promising drug. Recruitment of our Phase III trial in newly diagnosed pediatric pontine glioma has been concluded and we anticipate that recruitment in our randomised Phase III trial in adult glioblastoma grade IV will be completed in 2009. We are confident that data from these trials, along with data that will come from our placebo controlled randomised pancreatic cancer trial currently underway, in addition to data from a well diversified clinical development
program being advanced internationally, will further strengthen and confirm the clinical value of nimotuzumab."
istockanalyst.com
--------------------
Innogene Kalbiotech
--------------------
Innogene Kalbiotech, subsidiary Kalbe Farma
Indonesia, US$850mm market cap -
largest publicly-listed pharmaceutical company in SE Asia)
--------------------
innogene-kalbiotech.com
innogene-kalbiotech.com
innogene-kalbiotech.com
TheraCIM (Nimotuzumab)
innogene-kalbiotech.com
Innogene's Nimotuzumab Selected For Multinational
Phase III Trial by National Cancer Centre of Singapore
theracim.com
singapore-nccs-takes-lead-in-clinical-trial-for-new-drug-to-treat-head-and-neck-cancer&catid=5:
general&Itemid=7
--------------------
Kuhnil
--------------------
Private Compamy
--------------------
kuhnil.en.ec21.com
cim.sld.cu
From the R&R Presentation
-----------------------------------------
Together with its four licensees YM is,
through its 80% owned subsidiary, CIMYM
BioSciences Inc., conducting (as at calendar Q1, 2009)
eleven Phase II and Phase III clinical trials worldwide (Table 1).
As a result of the subsidiary structure and its
leadership of a consortium of nimotuzumab licensees,
a number of the trials are being
conducted under common protocols sharing the costs and
improving the speed of recruitment. This volume of clinical activity
is believed to be unique for any sub $500
million North American development company
==============================
Terms you need to know
==============================
Nimotuzumab - Anti-EGFR MAb
Cetuximab - Anti-EGFR MAb
Erbitux - Anti-EGFR MAb
Erbitux = Cetuximab
Erbitux
-------------------------
Erbitux is a chimaeric monoclonal antibody (MAb)
that is specific for the epidermal growth factor receptor (EGFR).
drugdevelopment-technology.com
Nimotuzumab
-------------------------
Nimotuzumab is a humanized monoclonal antibody (mAb) that targets the epidermal growth factor receptor (EGFR), a key target in the development of cancer therapeutics. EGFR-targeting drugs have been shown to improve response when used with conventional treatments such as radiation therapy and chemotherapy.
nimotuzumab.com
EGFR
-------------------------
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family (EGF-family) of extracellular protein ligands.
en.wikipedia.org
Radiation dermatitis
Grade IV radiation dermatitis
-------------------------
Google
==============================
YM BioSciences
==============================
ymbiosciences.com
Nimotuzumab
----------------
nimotuzumab.com
President
----------------
David Allen
==============================
Presentations
==============================
Sept-2009 R&R Presentation
--------------------------
wsw.com
--------------------------
* Nimotuzumab Revised Targets
--------------------------
* Head and Neck Cancer
* Brain Cancer
* Lung Cancer
* Gastric
--------------------------
* Nimotuzumab Past Failures
--------------------------
Colon - No Response Rate
This failure is explained in the R&R presentation
and why Nimotuzumab cannot be used for certain kinds
of cancers
Cash
--------------
As at March 31, 2009 the Company had cash and cash equivalents and short-term deposits approximating $45.0 million. Management believes that these resources are
adequate to achieve several key clinical milestones with nimotuzumab. YM’s business model is to license, develop and partner - the Company will always consider new
licensing opportunities.
ymbiosciences.com
Said they were burning $4.0 a quarter.
License Rights WW except -
-----------------
China and India
==============================
Other Presentations
==============================
Similar Presentation
-------------------
ymbiosciences.com
March 2009 Presentation
-------------------
ymbiosciences.com
CURRENT CLINICAL TRIALS
-------------------------
Resorted By ME
--------------
Table 1
Current Trials
Page 3 of 11
Not all Trials listed
Source:
ymbiosciences.com
--------------------------------------
P3 - HN - Innogene Kalbiotech - 710 Patients - CT + RT ± N <-> OG
P2 - HN - YM BioSciences - ?? Patients - RT ± N <-> CP
P2 - HN - Innogene Kalbiotech - 37 Patients - CT + RT ± N <-> OG
P3 - Kid Glioma - Oncoscience - 42 Patients - RT ± N <-> RC
P3 - Adult Glioma - Oncoscience - 148 Patients - RT ± N <-> OG
P2 - Kid Glioma - Oncoscience - ?? Patients - N only <-> CP
P2 - Kid Glioma - YM BioSciences - 44 Patients - N only <-> OG
P2 - LUNG - YM BioSciences - 128 Patients - RT ± N/P <-> OG
P2 - LUNG - YM BioSciences - 88 Patients - WBRT ± N/P <-> OG
P2 - LUNG - Daiichi Sankyo/Kuhnil - 39 Patients - CRT + N <-> OG
P1 - LUNG - YM BioSciences/Kuhnil - 34 Patients - RT ± N <-> CP
P2/3 - Pancreatic - Oncoscience - 188 Patients - G ± N <-> OG
P2 - Pancreatic - Oncoscience - 188 Patients - N <-> cp
P2 - Gastric - Daiichi Sankyo/Kuhnil - 80 Patients - CT ± N <-> OG
P2 - Cervical - Innogene Kalbiotech - 71 Patients - RT ± N <-> OG
<-> cP = Completed
<-> OG = Onging
<-> RC = Recruitment Completed
<-> Read Table 1 from LINK for complete information
.
.
.
2010 Events
Clinical Data Summary - Upcoming Events
-------------------------------------------
• Nimotuzumab European final Phase III pediatric glioma data in 2010
• Nimotuzumab European Phase III adult glioma data in 2010
• Nimotuzumab North American Phase II pediatric glioma data in 2010
• Esophageal Phase II data (Brazil) in 2010
• Nimotuzumab Phase II (Japan) gastric cancer data in 2010?
ymbiosciences.com
Out-licensing strategy
-------------------------------
Specifically, as at June 1, 2009:
• Daiichi Sankyo (#4568, Tokyo SE, ~US$13bn market cap) is conducting, a randomized
Phase II trial in 2nd line gastric cancer, a Phase II trial in first-line NSCLC, and
anticipates launching trials in additional indications.
• Innogene Kalbiotech, a wholly-owned subsidiary of Kalbe Farma (KLBF.JK, Jakarta
Indonesia, US$850mm market cap - largest publicly-listed pharmaceutical company in SE
Asia) has enlisted the highly regarded National Cancer Center of Singapore to conduct,
at its expense,
both a Phase III trial in adjuvant SCCHN and continues with a Phase II trial in
locally-advanced SCCHN.
• Innogene Kalbiotech has also received marketing authorization for nimotuzumab in
Indonesia, Cambodia and the Philippines.
• Kuhnil Pharma (Korea - private) is participating in the gastric trial, has participated with
YM in the NSCLC trial published at ASCO 2008 and is expected to participate in YM’s two
randomized, double-blinded NSCLC-related trials that are currently being initiated.
• Oncoscience AG (Germany - private) is conducting a Phase III trial in adult glioma, a
Phase III in 1st line pediatric DIPG, and a Phase II/III trial in pancreatic cancer.
-------------------------------
Who originated Nimotuzumab?
-------------------------------
Center for Molecular Immunology
affiliated with the University of Havana.
redorbit.com
SIDEBAR:
Breast Cancer Trial
----------------------
Skin RASHES _DID_ occur with Nimotuzumab when
used with:
nimotuzumab in combination with doxorubicin and cyclophosphamide
ymbiosciences.com
SIDEBAR:
--------------------------------------------
USA has OK'd Nimotuzumab Brain Trial in USA
--------------------------------------------
Cuban cancer drug undergoes rare U.S. trial
For the first time since Fidel Castro took power in Cuba
over a half-century ago, a drug developed by the Communist
regime is going through clinical trials in the United States.
The drug nimotuzumab is designed to target cancer cells including
those in rare and deadly types like
glioma, the brain cancer that killed Sen. Ted Kennedy.
A researcher at the University of Florida, where one
trial is already in progress, calls the drug "exciting, interesting."
www.physorg.com/pdf171277649.pdf
What YM wrote March 2009 concerning
======================================
Erbitux = Cetuximab Toxicity
======================================
The authors conclude that toxicities of Erbitux(R) should
not be viewed as markers for clinical benefit of EGFR-targeting antibodies in general, but only as markers of
indiscriminate targeting of that particular antibody,
with the EGFR blockade of normal cells by the marketed antibodies disrupting the cell's function.
This finding is especially important in view of the recent papers describing the underreporting of the toxicities of Erbitux(R), particularly Grade IV radiation dermatitis in head and neck cancer, reportedly not previously observed with radiation alone.
These presentations by YM help to demonstrate the nature of
differentiation of nimotuzumab from the other
anti-EGFR antibodies and show that its intrinsic properties confer a wide therapeutic window compared to Erbitux(R) and thus, in contrast to it, nimotuzumab is a more precisely targeted therapy.
reuters.com
======================================
AACR
Erbitux = Cetuximab Toxicity
100th Annual Meeting in Denver, Colorado
April 20th, 2009
Abstract # 2763;
======================================
The objectives of the study to be presented at AACR were to examine whether the cause of the toxicities seen with currently marketed anti-EGFR antibodies, particularly severe skin rash and hypomagnesemia, were the result
of properties intrinsic to the individual antibodies or to the class.
The results show that Erbitux(R)
binds to normal cells because it is capable of monovalent binding to very low expressions of
EGFR
whereas nimotuzumab's monovalent binding is transient.
It is this transient monovalent binding that
results in its benign safety profile.
Both antibodies bind definitively when binding bivalently.
prnewswire.co.uk
======================================
THE ACTUAL POSTER
======================================
AACR
100th Annual Meeting in Denver, Colorado
April 20th, 2009
ymbiosciences.com
Abstract # 2763;
----------------
Greta Garrido1,
Ailem Rabasa1,
Elias Gracia2,
Ilia Tikhomirov3,
Tania Crombet-Ramos1,
Alicia Viloria-Petit4,
Robert S. Kerbel5,6,
Eric Yang5,
Rolando Perez1
----------------
Binding properties of the anti-EGFR monoclonal antibody, nimotuzumab, limit its interaction
----------------
ymbiosciences.com
Severe skin rash and hypomagnesemia are hallmark toxicities of anti-EGFR antibodies cetuximab and panitumumab.
Nimotuzumab is an EGFR-targeting Affinity-Optimized Antibody™
currently under investigation in advanced clinical trials.
The antibody has demonstrated antitumor activity in the absence of severe skin, renal, GI mucosa and other toxicities commonly associated with other EGFR-targeting agents.
As a result of optimal affinity, attachment of nimotuzumab to the cellular surface has previously been reported to rely on bivalent binding, which is facilitated by EGFR overexpression.[1]
This intrinsic property was postulated to result in selective targeting of EGFR-overexpressing cancer cells and sparing of healthy tissues.
In this study we examined EGFR expression of human renal cortical epithelial cells, human epidermal cells and A431 cancer cell line, and compared binding of nimotuzumab and cetuximab to these cells by Flowcytometric analysis (FACS).
Human renal cortical epithelial and epidermal cells were found to express low levels of EGFR compared to A431 cancer cells.
Nimotuzumab’s binding to the epidermal and renal cells was several fold lower than that of cetuximab.
Concurrently, binding of nimotuzumab and cetuximab to A431 EGFR overexpressing cancer cells was equivalent.
Surface Plasmon Resonance results were consistent with the FACS binding data.
Whether the equivalent binding of nimotuzumab and cetuximab to A431 cancer cells translates into similar levels of anti-tumor activity was examined by subcutaneously injecting SCID mice
with A431 cells.
As shown in Figure 3, nimotuzumab and cetuximab had identical anti-tumor activity in the xenograft study.
This translational research demonstrates that in clinical settings where cancer cells overexpress EGFR, equivalent anti-tumor activity is expected between nimotuzumab and
cetuximab.
However, the sparing of healthy tissues expressing low levels of EGFR will only result from the administration of nimotuzumab.
The current clinical development program for nimotuzumab is focused on EGFR-overexpressing malignancies and/or settings where nimotuzumab is combined with radiotherapy, which has been established to increase EGFR expression.[2,3]
ymbiosciences.com
Publisher: Informa Healthcare
-------------------------------
Nimotuzumab: a novel anti-EGFR monoclonal
antibody that retains anti-EGFR
activity while minimizing skin toxicity
Abstract:
Due to the broad importance of EGFR to tumorogenesis, targeted therapy against it has rapidly developed into a novel paradigm for cancer treatment. Two promising classes of drugs are now in use and undergoing development that target this receptor: tyrosine kinase inhibitors (TKIs) and mAbs that inhibit EGFR's extracellular domain.
Nimotuzumab, a humanized murine mAb created in Cuba, has demonstrated antitumor activity similar to that of other anti-EGFR mAbs and shows promise as a single agent and as an adjunct to radiation in Phase I and II clinical trials. Surprisingly, the typical severe dermatological
toxicities thus far associated with anti-EGFR therapy have not been described with nimotuzumab.
Here we summarize the background, development and characteristics of this new drug while reviewing the latest preclinical and clinical trial data that underpin its gradual adoption into clinical practice.
ingentaconnect.com
2008
-------------------------------
Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell
lines of differing epidermal growth factor receptor status
pubmedcentral.nih.gov |
