Ultimate fate of cellular immune responses is determined by the balance between positive & negative signals delivered by T-cells..Melanoma ..Jim Breit

ICOS Expression,To secrete and what to secrete is the question.







My research has taken me to the costimulators and coinhibitors of the T-cell activation. The Delicate balance between the costimulators and coinhibitors render the right immune response at the right time. One of these costimulators is the ICOS. But if there is to much ICOS, then there is a down regulation of the the immune response by the secetion of IL-10 into the tumor's microenviroment.

The level of ICOS surface expression regulates the magnitude of the in vivo Th1/Th2 ratio, perhaps by influencing Th2 differentiation. This regulation plays a major role in the differentiation of the T-cells.


The linkage between low ICOS expression and “early” cytokines, and between intermediate/high ICOS expression and “late” cytokines is intriguing and could mean that ICOS is gradually up-regulated in the course of progressing T cell differentiation.

ICOS-low-cells were found to be loosely associated with the early cytokines interleukin (IL)-2, IL-3, IL-6, and interferon (IFN)-gamma.

ICOS-medium cells, the large majority of ICOS_ T cells in vivo, were very tightly associated with the synthesis of the T-helper type 2 (Th2) cytokines IL-4, IL-5, and IL-13, and these cells exhibited potent inflammatoryeffects in vivo.

In contrast, ICOS-highT cells were highly and selectively linked to the antiinflammatory cytokine IL-10.

The strength of the effector response of Th cells is regulated by the control of ICOS expression.

Overall, this data seem to indicate that ICOS cell surface density serves as a regulatory mechanism for the release of cytokines with different immunological properties.

We want the low expression of ICOS which seems to differeniate the niave T-cells towards the TH1 T-cell phenotype. We can accomplish that with Yervoy (Anti-CTLA-4). STAT5 signaling is found in both the Th2 and Treg pathway.It just so happens Yervoy causes the phosphorylation of STAT5 to decreased significantly with increasing concentrations . Yervoy skews the T-cell differentiation towards the Th1/Th17 phenotype which we want.

Another coinhibitor which surpresses the immune resonse is (PD-1) Program Death 1.

Blockade of PD-1 by monoclonal antibodies specific to its ligands (PD-L1 and PD-L2) results in significant enhancement of proliferation and cytokine (gamma interferon [IFN-gamma] and interleukin-2 [IL-2]) secretion by tumor-specific CTLs. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Tregs.

So by do a combinatorial therapy with Yervoy and PD-1 antibodies, It would most likely have a synergistic immune response.



This why on 9-20-2011, Bristol Myer Squibb expanded it's deal with Japan's Ono Pharmaceutical Co. Ltd. BMS now knows that they have an monopoly on T-cell activation and can be applied to many other cancers besides Melanoma. They are collecting the "String of Pearls". It would not surprise me they will go after the rest of the costimulators and coinhibitors on the T-cells. Only time will tell.

My hope is that Bristol Meyer Squibb uses it for the cure of cancer one day and not just monetary gains.

“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~
Take Care,
Jimmy B

It takes two (IL-2) to Tango! Melanoma..Jim Breitfeller

Immune responses involve multiple cell-cell interactions within lymphoid tissues, the
trafficking of activated cells to sites of effector function, and the migration of such effector cells within peripheral tissues. To gain a more detailed appreciation of the dynamics of such cell behavior and the relationship between cell dynamics and function, I have put together a series of events that take place during the activation phase of the immune response.


We know based on research that once the CD4+ T cell is activated, within two hours the IL-2 expression and IL-2 receptor are unregulated. IL-2 is secreted 45 minutes into this activation phase.



Experimental work has shown that IL-2 signaling in the first 10 hours is critical for the proliferation decision of T cells in culture. The spacial resolution of the Tregs and the T helper cells during this phase plays a major part in the immune response.
Secreted IL-2 is competed for by the Tregs and the activated CD4+ and CD8+ T-cells. If the Tregs are in close proximity of the T effector cells that are secreting the IL-2, the Tregs will create an IL-2 sink in the microenvironment. This will cause the proliferation and survival of the Tregs which suppresses the effector cell function. The IL-2 sink is where all the IL-2 that is secreted by the T helper cells is adsorbed by the IL-2 receptors on the Treg cells. Tregs don’t have the capability to produce IL-2 so they must scavenge the IL-2 out of the microenvironment of the CD4+ T helper cells. In Treg cells, the IL-2 gene is silenced and IL-2Rα is constitutively expressed through the action of the Treg-lineage-specifying transcription factor FoxP3.

The model proposed by Dr. Dorothea Busse and colleages predicts that the IL-2 secretion rate must exceed a threshold value Theta (θ) to switch IL-2Rα expression to the activated state and permit extensive autocrine IL-2 signaling.

This is just like the three little bears. You need the microenviroment conditions just right to activate T Helper cells.




As you can see in the above diagram, you don’t need high concentration of IL-2, you need spacial distance from one cell to the other. That can be achieved by Anti-CTLA-4 Blockage. By blocking the CTLA-4 receptors, the spacial distance between the T helper cell and the Treg cells increases and it also helps to differentiate the niave CD4+ T cells into Th17 cells.

IL-2 is mainly captured by the Treg cell, whereas autocrine reuptake by the T helper cells predominates when the cells are further apart. So we want to introduce IL-2 before the tumor recruites the Tregs to the Tumor Microenviroment and or when the Treg population is in the contration phase of the CD4+ T-cell cycle.




Cellular signal response is potentially controlled by ratio between ligand (IL-2)
number and surface receptor (IL-2R) number per cell.

Ligand n. An ion, a molecule, or a molecular group that binds to another chemical entity to form a larger complex.
.

Suboptimal amounts of IL-2 during priming promoted apoptosis, little proliferation and cell cycling, yet the CD8+ effectors generated produced high levels of cytokines and proliferated autonomously. Although IL-2 deprivation caused apoptosis and little proliferation initially, the effectors generated under these conditions possessed optimal effector functions. This low IL-2 concentration, allows the T help cell to activate and proliferate.
This is the reason why it takes a while for the tumors to begin to shrink because of little proliferation at first. It takes time for the immune system to assemble an army of Cytotoxic T Lymphocytes.


So how can we minimize the proliferation of the Tregs which are a subset of CD4+ T-cell subset without doing a full blown depletion of the CD4+ T-cells?

1. Anti-CTLA-4 Blockage
2. Local IL-21 Promotes the Therapeutic Activity of Effector T cells by
Decreasing Regulatory T Cells Within the Tumor Microenvironment
3. Anti-PD-1 Blockage
4. A combination of the above three.



This is the future of Melanoma Therapy, Combinatorial Therapy.




“It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change.”
~Charles Darwin~

Take Care,
Jimmy B

For the Record, Ipilimumab, Melanoma..Jim Breitfeller

For the Record, Ipilimumab, Melanoma

During Bristol-Myers Squibb's investor day March 4, 2010, management's enthusiasm for an important late-stage drug in development for metastatic melanoma, ipilimumab, was palpable. CEO designate Lamberto Andreotti told the room full of analysts and investors that ipilimumab "has the potential to become a paradigm changer in the emerging field of immuno-oncology."

Ipilimumab, the immunotherapy in development by Bristol-Myers Squibb and Princeton, N.J.-based Medarex to treat melanoma, may be more effective at higher, and more toxic, doses, but the side effects are a small price for survival, according to one of the lead investigators studying the drug. June 1, 2008

Two-year melanoma survival data from three Phase II studies of Medarex/Bristol-Myers Squibbs' immunotherapeutic ipilimumab presented at the American Society of Clinical Oncology meeting May 31 bode well for an ongoing pivotal Phase III study and an eventual first approval for the oncologic. June 1, 2009

Medarex/Bristol Myers Squibb took pains to differentiate its CTLA-4 immunotherapy ipilimumab from Pfizer's failed tremelimumab during a July 10 2008 R&D update.

The BLA delay for ipilimumab for melanoma, disclosed April 24 2008 by Medarex and Bristol-Myers Squibb, surprised few in the wake of Pfizer's Phase III fizzle earlier this month with a similar drug, tremelimumab.

Pfizer is discontinuing a Phase III clinical trial evaluating the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) inhibitor tremelimumab as a single agent in patients with advanced melanoma after an interim review showed it performed no better than standard chemotherapy, the firm said April 1, 2008.


Dosage_____________Patient Response Rate
0.3 mg/kg__________ 0
3.0 mg/kg__________ 4.2 %
10 mg/kg___________ 11.1 %

February 2010 Dr. Jedd Wolchok


For the record, I see a combinatorial therapy in Ipilimumab’s near future



The Making of an Immune Response by Combinatorial Therapy Using Anti-CTLA-4 Blockade and Interleukin-2



Take Care,
Jimmy B

Why Should We Believe That There Was Even a Shortage of Ipilimumab?Melanoma ..Jim Breitfeller

On June 11, 2007, BMS agreed to plead guilty and pay a $1 million criminal fine for misleading the government about the Plavix patent deal. BMS paid the maximum fine permitted by statute for committing two violations under the federal False Statements Act."

They mislead Government officials so why would they tell us the Patients, the truth about the shortage?

April 25 2008

Medarex and Bristol-Myers Squibb Joint Statement on Submission Status of Ipilimumab

PRINCETON, N.J., April 25 2008 /PRNewswire-FirstCall/ -- Medarex, Inc.
(Nasdaq: MEDX) and Bristol-Myers Squibb Company (NYSE: BMY) today announced that, after meeting with the U.S. Food and Drug Administration (FDA), the companies will delay the Biologics License Application (BLA) submission for ipilimumab, an investigational immunotherapy for patients with advanced metastatic melanoma. The FDA has requested additional overall survival (OS)data to further demonstrate the benefit of ipilimumab. Revised timelines are under development, but a BLA for ipilimumab will not be submitted to the FDA in 2008.

As far as my research to date(10-22-2009), BMS/Medarex has not file a BLA with the FDA.


On September 12 2008 they closed the compassionate use for Ipilimumab

Your email was forwarded to us by CBER (this IND resides in the Center for Drugs Evaluation and Research). We have contacted BMS to check into the availability of ipilimumab and here is the information that BMS provided to us.

"To ensure treatment is not interrupted for patients currently receiving ipilimumab and to provide ongoing supply to the registrational program, Bristol-Myers Squibb and Medarex have suspended enrollment of new patients into the compassionate use program, single patient exemptions and initiation of some non-registrational trials effective September 12, 2008.

Bristol-Myers Squibb and Medarex are working to manage the supply issue and may be able to re-open compassionate use in the future.

The companies are committed to providing uninterrupted treatment to patients who initiate therapy with ipilimumab. Therefore, if and when the compassionate use program reopens, it will be at such time when continuous and unconstrained supply is available."

Please let us know if you have any questions.

Sincerely,
CDER Drug Shortage Team


It Takes about a month to make a batch of monoclonal antibodies. By the time the batch is tested and packaged and approved, let us allow another two months. So in a year you should be able to make 3 to 4 batches.


Melanoma Treatment Information - Updated 09.10.09

"Ipilimumab which ASCO reported some promising results had been widely available in compassionate use trials across the county until a shortage halted the studies. Bristol Myers Squibb, is now manufacturing the drug again and there are a few small “pharmacokinetic” trials to prove the agent is the same as the previous one used in trials. Most of these trials already have waiting lists, but it may be worth checking out. Screening started August 4th and you can find the locations on www.clinicaltrials.gov."

Source:https://www.z2systems.com/np/clients/mif/news.jsp?news=381

Melanoma International Foundation


Well come to find out that BMS/Medarex is opening up new clinical trials with Ipilimumab and continue to keep the compassionate use trial closed. How ethical is that?

When big pharma is involved in clinical development, it usually means large-scale clinical trials with patients and multiple sites.

Here are the trials:

Study of Ipilimumab and Dasatinib Combination Therapy in Patients With Chronic or Accelerated Chronic Myeloid Leukemia
Start Date: August 2009
Estimated Study Completion Date: Feb 2011
Estimated Enrollment: 30
ClinicalTrials.gov Identifier: NCT00732186

Ipilimumab +/- Vaccine Therapy in Treating Patients With Locally Advanced, Unresectable or Metastatic Pancreatic Cancer
Start Date: February 2009
Estimated Study Completion Date: Feb 2013
Estimated Enrollment: 30
ClinicalTrials.gov Identifier: NCT00836407

Bevacizumab Plus Ipilimumab in Patients With Unresectable Stage III or IV Melanoma
Start Date: February 2009
Estimated Study Completion Date: Feb 2011
Estimated Enrollment: 33
ClinicalTrials.gov Identifier: NCT00790010

Laboratory-Treated T Cells With or Without Ipilimumab in Treating Patients With Metastatic Melanoma
Start Date: February 2009
Estimated Study Completion Date: Feb 2011
Estimated Enrollment: 30
ClinicalTrials.gov Identifier: NCT00871481

Study of Immunotherapy to Treat Advanced Prostate Cancer
Start Date: May 2009
Estimated Study Completion Date: December 2012
Estimated Enrollment: 800
ClinicalTrials.gov Identifier: NCT00861614

Further study details as provided by Bristol-Myers Squibb:


These are all trials that were started after the halting of the compassionate Use. Bristol-Meyer Squibb thinks we the Melanoma Patients are expendable so they continued there quest to seek out new uses for the Drug.

Get a bigger bang for the buck.

They already know it works well with Melanoma, so why not find other uses.

Base on my calculation, 923 late stage Melanoma Patients were denied the drug while Bristol–Meyer Squibb continued to apply and start up new trials.



Bristol-Meyer Squibb Quote:

“What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life.”

All Lip Service!!!!!!

“Jim, thank you so much for your efforts. My father passed away this past March. He was also scheduled to start the ipi trial last year and found out the Saturday before he was to go in that the compassionate use trial was suspended. He developed 3 mets in his brain by Thanksgiving. The ipi trials with brain mets were closed to new patients by then. I've spent countless hours and days frustrated and angry, unable to express or figure out what you have with BMS and wanting to take some sort of action. I also sent letters, made phone calls, etc. One day, someone will be able to stop these drug companies from playing with our lives. Please keep me posted in your findings.”



Update on Ipilimumab

Ipilimumab is not back yet. Patients are not being encouraged to wait for Ipilimumab to become available for now. The only Ipilimumab melanoma trials currently enrolling new patients in the US are the brain metastases trial (CA-184042) and the phase 3 adjuvant trial (CA-184029) because the supply for those trials was protected in advance. Bristol Myers Squibb is working diligently to overcome the drug shortage, but can’t guarantee a time that it will return to the compassionate use setting.

Source: Melanoma International Foundation:
https://www.zsystems.com/np/clients/mif/news.jsp?news=376


Melanoma International Foundation



Response from BMS as of 10-21-2009

“Regarding compassionate use, as you are aware, the rate of enrollment in the compassionate use program for ipilimumab was greater than anticipated with 30 to 40 percent of patients continuing on therapy beyond the initial induction schedule. This demand depleted drug supply at a faster rate than anticipated. Bristol-Myers Squibb had to suspend enrollment of new patients into the compassionate use program and single patient exemptions to ensure treatment is not interrupted for patients currently receiving ipilimumab and to provide supply for ongoing clinical studies.

We are working through the manufacturing and testing process, and continue to carefully manage the supply to enable the potential re-opening of compassionate use at the earliest possible time and when continuous supply is available.

Bristol-Myers Squibb remains committed to the development of ipilimumab and to addressing the great unmet medical need for patients with metastatic melanoma.”

As you can read, BMS is not even acknowledging that they even produced other batches.They are hiding the fact that they are back online. Their communication skills with the public/patients are NIL. Instead they are starting new protocols with Ipilimumab. Where is the FDA in al of this? Who is watching the hen house?

When I searched for drug shortages on the FDA website, Ipilimumab did not show up.

What is going on?

We the Patients deserve better, We are the ones who are taking all the risk. We should have some control in this process.

We the Patients have had to hear it from second-hand sources like the Melanoma International Foundation and Melanoma Research Foundation. I don’t believe that their ad advertisers (The Ogilvy Group Inc) can repair the public’s trust in this company. They have major issues.

This Month will be the anniversary of the discovery of Anti-CTLA-4 antibodies, celebrating ten years in the making of the drug. This is way to long for a drug to come to market. It usually takes 8.7 years for monoclonal antibodies. So what gives?

I hope see some dialog started between the patients and BMS. BMS needs somehow to regain the public's trust.

I am under the impression that greed and power-play is mixed in all of this. It all has to do with the STRING OF PEARLS intiative.



How Drugs are Developed and Approved by the FDA?

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/default.htm#


How Drugs are Developed and Approved by the FDA



Take Care,

Jimmy B

Bristol-Meyer Squibb has a lot to Explain!!Melanoma..Jim Breitfeller

Bristol-Meyer Squibb has a lot to Explain!!!!!!

Guess what, Bristol-Meyer Squibb is not as ethical as they would like you to think. Bristol-Meyer Squibb and Medarex which is now a subsidiary of Bristol after the takeover, stopped the compassionate Use for Ipilimumab Anti-CTLA-4 Blockage. This happen in September of 2008 it has been a year without this compassionate use. I know that is does not take a year to manufacture Monoclonal antibodies. It takes about three months to produce a batch of them. So why is there still no compassionate use?

Well, I got to thinking that they (Bristol Meyer Squibb) must be producing it and if so it would show up as Clinical Trials. So I crossed referenced Clinical trials starting after September 2008. Low and behold, I found NEW CLINICAL TRIALS. This means Bristol-Meyer Squibb have been scamming the Melanoma patients that need it the most. The ones that have run out of options and Ipilimumab was their last hope for survival.


Here are the trials:

Study of Ipilimumab and Dasatinib Combination Therapy in Patients With Chronic or Accelerated Chronic Myeloid Leukemia

Start Date: August 2009
Estimated Study Completion Date: Feb 2011
Estimated Enrollment: 30
ClinicalTrials.gov Identifier: NCT00732186


Ipilimumab +/- Vaccine Therapy in Treating Patients With Locally Advanced, Unresectable or Metastatic Pancreatic Cancer

Start Date: February 2009
Estimated Study Completion Date: Feb 2013
Estimated Enrollment: 30
ClinicalTrials.gov Identifier: NCT00836407

Bevacizumab Plus Ipilimumab in Patients With Unresectable Stage III or IV Melanoma

Start Date: February 2009
Estimated Study Completion Date: Feb 2011
Estimated Enrollment: 33
ClinicalTrials.gov Identifier: NCT00790010

Laboratory-Treated T Cells With or Without Ipilimumab in Treating Patients With Metastatic Melanoma

Start Date: February 2009
Estimated Study Completion Date: Feb 2011
Estimated Enrollment: 30
ClinicalTrials.gov Identifier: NCT00871481

Study of Immunotherapy to Treat Advanced Prostate Cancer

Start Date: May 2009
Estimated Study Completion Date: December 2012
Estimated Enrollment: 800
ClinicalTrials.gov Identifier: NCT00861614


Further study details as provided by Bristol-Myers Squibb:

These are all trials that were started after the halting of the compassionate Use. Bristol-Meyer Squibb thinks we the Melanoma Patients are expendable so they continued there quest to seek out new uses for the Drug.

Get a bigger bang for the buck.

They already know it will work well with Melanoma so why not find other uses.

Base on my calculation, 923 late stage Melanoma Patients were denied the drug while Bristol–Meyer Squibb continued to apply and start up new trials.

Bristol-Meyer Squibb Quote:

“What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life.”

All Lip Service!!!!!!

Where are the Ethical Standards??

BMS did not make the 2009 World’s Most Ethical Companies

“The World’s Most Ethical Companies are the ones that go above and beyond legal minimums, bring about innovative new ideas to expand the public well being, work on reducing their carbon footprint rather than contributing to green washing and won’t be found next to the words “Billion Dollar Fine” in newspaper headlines any time in the near future. These are the companies that stand out among the competition in their industry.”

Source: Ethishere.com

Jimmy B



Take Care,

Jimmy B

Bristol's String of Pearls are Shining!!

FDA NEWS RELEASE
For Immediate Release: Sept. 25, 2009

Media Inquiries: Karen Riley, 301-796-4674, karen.riley@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

FDA Approves New Drug to Treat Psoriasis

The U.S. Food and Drug Administration today approved Stelara (ustekinumab), a biologic product for adults who have a moderate to severe form of psoriasis.

Plaque psoriasis is an immune system disorder that results in the rapid overproduction of skin cells. About 6 million people in the United States have plaque psoriasis which is characterized by thickened patches of inflamed, red skin, often covered with silvery scales.

“This approval provides an alternative treatment for people with plaque psoriasis, which can cause significant physical discomfort from pain and itching and result in poor self-image for people who are self-conscious about their appearance,” said Julie Beitz, M.D., director, Office of Drug Evaluation III, in the FDA’s Center for Drug Evaluation and Research.

Stelara is a monoclonal antibody, a laboratory-produced molecule that mimics the body’s own antibodies that are produced as part of the immune system. The biologic treats psoriasis by blocking the action of two proteins which contribute to the overproduction of skin cells and inflammation.

Three studies of 2,266 patients evaluated the biologic’s safety and effectiveness.

Since Stelara reduces the immune system’s ability to fight infections, the product poses a risk of infection. Serious infections have been reported in patients receiving the product and some of them have lead to hospitalization. These infections were caused by viruses, fungi, or bacteria that have spread throughout the body. There may also be an increased risk of developing cancer.

The FDA is requiring a risk evaluation and mitigation strategy or REMS for Stelara that includes a communication plan targeted to healthcare providers and a medication guide for patients.

Stelara is manufactured by Centocor Ortho Biotech Inc. of Horsham, Pa., a wholly-owned subsidiary of Johnson & Johnson of New Brunswick, N.J.

Well Medarex is the partner who developed the antibody, (ustekinumab).

We shall soon hear about Ipilimumab, I hope

Bristol-Meyer Squibb just bought out Medarex in what I would call a give away by the Board of Directors and the Top Management of Medarex.

My guess, Bristol had information on Stelara proir to buying out Medarex.

The Pearl Neckace Lives On!!!!!!!!

I believe each pearl represents an antibody or Drug that is commercialized and FDA approved.

commercialized.. Definition --To apply methods of business to for profit.

BMY will get some royalites that can fund their war chest.

Check Mate!!!!!!!

Take Care,

Jimmy B

Bristol-Myers Squibb at Morgan Stanley Global Healthcare Conference 9/14/2009..Melanoma .Jim Breitfeller

Bristol-Myers Squibb at Morgan Stanley Global Healthcare Conference 9/14/2009

If you go to Bristol-Myers Squibb's website and click on investor, you will see:

Events and PresentationsBristol-Myers Squibb at Morgan Stanley Global Healthcare Conference
Monday, September 14, 2009
Webcast replay

If you sign up and play the webcast, you get the feeling that it all comes down to greed and money in my opinion. Market share, Patients, Doctors all in one breath.

Have patient become a comodity? We will vote with our feet and voices.

When they say, “What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life.”

All smoke and mirrors!!!!!!!

But if you listen and reach 25.55 minutes into the webcast, there is a question on Medarex and Ipilimumab. Fully human anti CTLA-4 monoclonal antibody in advanced clinical trials, Metastatic Melanoma. Phase III Data Overall Suvival data will be out shortly. With these results (I believe will be positive) in hand, I believe that Bristol-Myers Squibb (BMY) will apply for a biological licence from the FDA.

Biological products often represent the cutting edge of medical science and research. Also known as biologics, these products replicate natural substances such as enzymes, antibodies, or hormones in our bodies.

What is FDA's role regarding biological products?

FDA's regulatory authority for the approval of biologics resides in the Public Health Service Act (PHS). However, biologics are also subject to regulation under the Federal Food, Drug, and Cosmetic Act (FD&C Act) because most biological products also meet the definition of "drugs" cited within this Act.



BMY Webcast




Take Care,

Jimmy B

I am Not going to tender my Shares of Medarex to Bristol Meyer Squibb. Melanoma..Jim Breitfeller

I am Not going to Tender my Shares of Medarex to Bristol-Meyer Squibb. BMY low balled the tender and Medarex would be better off as a separate company. Here why.

Therapeutic Monoclonal Antibody Production Is More Profitable Than Small Molecule Drugs

New study has suggested that therapeutics based on monoclonal antibodies (mAbs) are fare more likely to be commercially successful than their small molecule predecessors. According to a study completed by // consultancy Propagate Pharma, about half the mAbs launched so fare appear to be profitable. That means mAbs are recouping more in revenues than their estimated $1 billion to $1.8 billion cost of development and marketing. By comparison, the study estimates that only 30% of conventional small molecule drug launches ever recover their costs. Drug is likely to be profitable if peak revenues pass the $300 million mark. So far, of the 17 mAbs launched in the US, eight have achieved this benchmark. And of these, four have become blockbusters earning over a billion dollars a year.

Of 57 mAbs launched so far, 16 have become blockbusters, 14 have at least recouped their costs, and the other 27 are either question marks or failures. The high success rate of biotherapeutics is due to low levels of competition in the markets they address, says Jo Collett, author of the Propagate study. There are signs that the tail end of a biotherapeutics products life cycle might be more profitable than that of a small molecule drug. However, this high level of success may be difficult to sustain as competition increases, especially in the cancer market, says Propagate’s Collett. “It’s not going to be quite as easy as it was for the pioneers,” she prophesies.

There are more than 150 mAbs in development worldwide, over 100 of which are in phase 2 or phase 3 trials. Nearly 40% of these are in the oncology field; 18 are in development for breast cancer alone. Collett predicts that companies launching the next generation of mAb therapeutics will have to be more commercially acute with a better understanding of their products positioning that the pioneers of the field were. Although there is respectable data showing that obtaining regulatory approval tends to be easier for antibodies than for other drug classes, he warns it is too early to make firm predictions. “The mid and longer term future may look quite different in terms of competitive threats, so past performance is not necessarily a guide”.

Source: Nature Biotechnlogy.




Date:10/8/2005


http://www.bio-medicine.org/medicine-news/Therapeutic-Monoclonal-Antibody-Production-Is-More-Profitable-Than-Small-Molecule-Drugs-5161-2/



Take Care,

Jimmy B

15. Standards of Integrity Removed from Medarex website..Melanoma..Jim Breitfeller

15. Standards of IntegrityMedarex maintains Standards of Integrity that apply to Directors, Senior Management and all other employees of Medarex. Medarex’s Standards ofIntegrity may be found on Medarex’s website

at:www.medarex.com/Investor/Corporate.htm.The page you are looking does not exist. It may have been removed, its name may have been changed, it may be under construction, or it may be temporarily unavailable. Try using the menus on the left side of the page to find what you are looking for. If you entered in a URL, please check to make sure you typed the address correctly.


What are they Hiding!!!!!!!!!!


Take Care,

Jimmy B

Bristol-Meyer Squibb is Stealing the Pearl Necklace!!!Monoclonal Antibodies FDA approval over the last 10 years..Melanoma..Jim Breitfeller

Monoclonal antibodies used to treat cancer MAb Name
Trade Name
Used to Treat:
Approved in:

Rituximab
Rituxan
Non-Hodgkin lymphoma
1997

Trastuzumab
Herceptin
Breast cancer
1998

Gemtuzumab ozogamicin*
Mylotarg
Acute myelogenous leukemia (AML)
2000

Alemtuzumab
Campath
Chronic lymphocytic leukemia (CLL)
2001

Ibritumomab tiuxetan*
Zevalin
Non-Hodgkin lymphoma
2002

Tositumomab*
Bexxar
Non-Hodgkin lymphoma
2003

Cetuximab
Erbitux
Colorectal cancer
Head & neck cancers
2004
2006

Bevacizumab
Avastin
Colorectal cancer
Non-small cell lung cancer
Advanced breast cancer
2004
2006
2008

Panitumumab
Vectibix
Colorectal cancer
2006



*conjugated monoclonal antibodies

Two types of monoclonal antibodies are used in cancer treatments:

Naked monoclonal antibodies are those without any drug or radioactive material attached to them.
Conjugated monoclonal antibodies are those joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells).

http://www.cancer.org/docroot/ETO/conten...

Think what Our 40+ Antibodies in the pipeline of the Medarex Company are worth.

We have been sold out by Pien and Company!!!!

Bristol-Meyer Squibb is stealing the Pear Necklace from the Medarex Shareholders.

The Boards of Both Companies should be Investigated along with the CEO's

Take Care,

Jimmy B

Is Medarex and Bristol-Meyer Squibb in Collusion With this Tender Offer??..Melanoma..Jim Breitfeller

"Our opinion does not address the underlying business decision of the Company to engage in the Transactions, or the
relative merits of the Transactions as compared to any strategic alternatives that may be available to the Company. We
were not requested to solicit, and did not solicit, interest from other parties with respect to an acquisition of or other
business combination with the Company. This opinion addresses only the fairness froma financial point of view, as of the
date hereof, of the $16.00 per Share in cash to be paid to the holders (other than Bristol and its affiliates) of Shares
pursuant to the Agreement.We do not express any view on, and our opinion does not address, any other term or aspect of
the Agreement or Transactions, including, without limitation, the fairness of the Transactions to, or any consideration
received in connection therewith by, the holders of any other class of securities, creditors, or other constituencies of the
Company; nor as to the fairness of the amount or nature of any compensation to be paid or payable to any of the officers,
directors or employees of the Company, or class of such persons in connection with the Transactions, whether relative to
the $16.00 per Share in cash to be paid to the holders (other than Bristol and its affiliates) of Shares pursuant to the
Agreement or otherwise. Our opinion is necessarily based on economic, monetary, market and other conditions as in
effect on, and the information made available to us as of, the date hereof and we assume no responsibility for updating,
revising or reaffirming this opinion based on circumstances, developments or events occurring after the date hereof. Our
advisory services and the opinion expressed herein are provided for the information and assistance of the Board of
Directors of the Company in connection with its consideration of the Transactions and such opinion does not constitute a
II-2
recommendation as towhether or not any holder of Shares should tender such Shares in connectionwith the Tender Offer
or how any holder of Shares should vote with respect to the Merger or any other matter. This opinion has been approved
by a fairness committee of Goldman, Sachs & Co.
Based upon and subject to the foregoing, it is our opinion that, as of the date hereof, the $16.00 per Share in
cash to be paid to the holders (other than Bristol and its affiliates) of Shares pursuant to the Agreement is fair from a
financial point of view to such holders."


Very truly yours,
/s/ Goldman, Sachs & Co.
(GOLDMAN, SACHS & CO.)













BMY is just pay the same price as before the Financial downturn. Shareholders are getting ripped off!!!!

What about Fiduciary Duty on the part of Medarex?

http://www.medarex.com/Investor/documents/Medarex_14D-9.pdf
Goldman Sachs' Letter to MEDX Board of Directors (BOD) OPENLY Acknowledges that MEDX BOD Failed to Perform Its Fiduciary Responsibilities....


> STRATEGIC ALTERNATIVES NOT CONSIDERED......
--->> "Our opinion does not address the underlying business decision of the Company to engage in the Transactions, or the relative merits of the Transactions as compared to any strategic alternatives that may be available to the Company. "

> MEDX Board DID NOT REQUEST Solicitation of Other Companies......
--->> "We [Goldman Sachs] were not requested to solicit, and did not solicit, interest from other parties with respect to an acquisition of or other business combination with the Company."


Here, as I see it, Goldman Sachs openly acknowledges that the MEDX BOD did not perform its fiduciary responsibility, because:

1). It did NOT ASK GS to consider... "any strategic alternatives that may be available to the Company."

2). The MEDX BOD did NOT ASK GS... "to solicit, and did not solicit, interest from other parties with respect to an acquisition of or other business combination with the Company."

I think that GS stated these two points in their letter to the MEDX BOD, because they knew that the MEDX BOD did perform their Fiduciary Responsibilities to the shareholders, and did NOT want to be sued.

I think the MEDX BOD has utterly and completely FAILED to perform its FIDUCIARY RESPONSIBILITY to the shareholders of MEDX, and that Goldman Sachs' letter CLEARLY DEMONSTRATES THIS AS A FACT.




Take Care,

Jimmy B

Bristol-Myers Squibb to Acquire Medarex

I believe, BMS now has the the Monopoly on Anti-CTLA-4 monoclonal antibodies. BMS wants it all. Greed at its finest.

"What sets us(BMS) apart?" Greed!!!!!!!!

And what does Bristol-Myers Squibb say:

"What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life.”

This is nice PR, but if you don’t walk the walk and it is all talk, then it means NOTHING!!!!!!!

Source:http://www.medarex.com/cgi-local/item.pl/20090722-1310338

Positions Bristol-Myers Squibb for Long-Term Leadership in Biologics Acquires Proven Antibody Discovery Technology Gains Full Rights to Promising Phase III Compound, Ipilimumab Significantly Expands Oncology and Immunology Pipeline



NEW YORK & PRINCETON, N.J.--(BUSINESS WIRE)--Jul. 22, 2009--
Bristol-Myers Squibb Company (NYSE:BMY) and Medarex, Inc. (NASDAQ: MEDX) announced
today that the companies have signed a definitive merger agreement
providing for the acquisition of Medarex by Bristol-Myers Squibb, for
$16.00 per share in cash. The transaction, with an aggregate purchase
price of approximately $2.4 billion, has been unanimously approved by
the boards of directors of both companies. Medarex's projected $300
million in net cash and marketable securities at closing would be an
asset acquired by Bristol-Myers Squibb resulting in an implied purchase
price of approximately $2.1 billion.


The Board must have deep pockets!!!!!!!!!!!!!!!! What is their cut??

"Medarex's technology platform, people and pipeline provide a strong
complement to our company's biologics strategy, specifically in
immuno-oncology," said James
M. Cornelius, chairman and chief executive officer, Bristol-Myers
Squibb. "With its productive and proven antibody discovery capabilities,
ability to generate interesting therapeutic programs and unique set of
pre-clinical and clinical assets in development, Medarex represents what
we're looking for in terms of our String
of Pearls strategy. This acquisition is another important step in
our BioPharma transformation."


"We believe that this combination with Bristol-Myers Squibb, a global
leader in oncology, provides an excellent opportunity to realize the
full potential of Medarex's development portfolio and our UltiMAb(R)
technology platform through a transaction which also provides an
attractive valuation for our shareholders," said Howard H. Pien,
chairman and chief executive officer, Medarex. "Medarex has evolved
significantly over the past two decades from a research platform to a
development company. We believe that this transaction represents a great
opportunity to place our clinical programs and technology assets in the
hands of one of the world's premier biopharmaceutical companies with the
expertise, resources, motivation and dedication to bring innovative
cancer treatment options to patients in need."


Bristol-Myers Squibb gains the following as a result of the acquisition:


Medarex's UltiMAb Human Antibody Development System(R), which produces
high affinity, fully human antibodies for use in a broad range of
therapeutic areas, including immunology and oncology. This validated
technology platform has produced compounds which are now currently
marketed therapies (SIMPONI(TM), STELARA(TM) and ILARIS(R)).



Medarex's next-generation Antibody-Drug Conjugate (ADC) technology,
which is a novel and proprietary platform that could open new fields
in oncology drug development.


Rights to seven antibodies in clinical trials under Medarex's sole
sponsorship and three other antibodies being co-developed with other
partners. Rights to pre-clinical assets in various stages of
development by Medarex -- in particular, monoclonal antibodies focused
in oncology and immunology.


Full ownership and rights to ipilimumab, which, if approved, could be
an important contributor to Bristol-Myers Squibb's future growth. The
companies have collaborated on the development of ipilimumab, a novel
immunotherapy currently in Phase III development for the treatment of
metastatic melanoma. The companies also have an ongoing Phase II study
in lung cancer as well as Phase III studies in adjuvant melanoma and
hormone-refractory prostate cancer.


Royalties based on percentage of sales for SIMPONI(TM), STELARA(TM) and
ILARIS(R).



"We welcome the opportunity to further collaborate with the Medarex
scientific leadership," said Elliott Sigal, M.D., Ph.D., executive vice
president and president, research and development at Bristol-Myers
Squibb. "In addition to our Adnexus team, which has been expanded since
it was acquired in 2007, Medarex scientists will help us create an
industry-leading biologics capability. We believe Medarex's antibody
generation expertise, located in California and New Jersey, will
complement our existing biologics efforts with a dedicated discovery and
development capability in immuno-oncology."


Under the terms of the definitive merger agreement, Bristol-Myers Squibb
will commence a cash tender offer on or about July 27, 2009 to purchase
all of the outstanding shares of Medarex common stock for $16.00 per
share in cash. The closing of the tender offer is subject to customary
terms and conditions, including the tender of a number of shares that,
together with the number of shares already owned by Bristol-Myers
Squibb, constitutes at least a majority of Medarex's outstanding shares
of common stock (on a fully diluted basis) and expiration or termination
of the waiting period under the Hart Scott Rodino Antitrust Improvement
Act. The agreement also provides for the parties to effect, subject to
customary conditions, a merger to be completed following the completion
of the tender offer which would result in all shares not tendered in the
tender offer being converted into the right to received $16.00 per share
in cash. The merger agreement contains a provision under which Medarex
has agreed not to solicit any competing offers for the company.
Bristol-Myers Squibb will finance the acquisition from its existing cash
resources. The companies expect the tender offer to close in
approximately thirty (30) days after commencement of the tender offer.


JPMorgan Securities, Inc. is serving as financial advisor to
Bristol-Myers Squibb in connection with the acquisition, and
Bristol-Myers Squibb is represented by Cravath, Swaine & Moore LLP, New
York, New York. Goldman, Sachs & Co. is serving as financial advisor to
Medarex in connection with the acquisition, and Medarex is represented
by Covington & Burling LLP, New York, New York.


About Bristol-Myers Squibb



Bristol-Myers Squibb is a global biopharmaceutical company whose mission
is to extend and enhance human life. For more information visit www.bms.com.




Take Care,

Jimmy B

Medarex and Lonza Sign Collaboration Agreement for the Supply of Antibody-Based Products.Melanoma..Jim Breitfeller

Medarex and Lonza Sign Collaboration Agreement for the Supply of Antibody-Based Products.

I believe that they are gearing up for a full marketing Blitz.

Lonza:
"As one of the frontrunners in the contract manufacture of monoclonal antibodies and recombinant proteins from mammalian cell culture, Lonza produces the essential ingredients for tomorrow’s life-saving medicines with four state-of-the-art cGMP multi-product facilities. One of these facilities is in the UK in the Thames Valley technology corridor, which focuses on process development and clinical trial supply (including small-scale manufacture of licensed products). The second is in the USA, just outside Boston, Massachusetts, focusing on large-scale manufacture for late-stage clinical trials and in-market supply. The third is in Northern Spain, and the fourth is currently under construction in Singapore. We are hard at work developing the world’s most advanced biotechnology manufacturing processes."

"Lonza is the world's leading contract manufacturer of monoclonal antibodies and recombinant proteins. Lonza undertakes highly specialized development and manufacturing services for the pharmaceutical and biotechnology industries based on more than 25 years of experience in mammalian cell culture and proprietary technology for large-scale manufacture of innovative biopharmaceutical products"

Source:http://www.lonza.com/group/en/products_services/custommanufactoring/mammalian.html

Now all we have to wait for is the FDA Approval. As far as I know,Ipilimumab has not been submitted to the FDA for approval at this time.



Take Care,

Jimmy B

Followup of the Anti-CTLA-4 Shortage Story..Melanoma..Jim Breitfeller

Base on this Clinical trial which is not active yet, It looks like Bristol Meyer Squibb/Medarex is trying different processes.

Comparison of Ipilimumab Manufactured by Two Different Processes in Patients With Advanced Melanoma

This study is not yet open for participant recruitment.

Verified by Bristol-Myers Squibb, June 2009
First Received: June 9, 2009 Last Updated: June 12, 2009 History of Changes
Sponsors and Collaborators: Bristol-Myers Squibb
Medarex

Information provided by: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00920907

Purpose
The purpose of this clinical research study is to compare pharmacokinetics of ipilimumab manufactured by two different processes.


Condition Intervention Phase
Advanced Melanoma
Biological: Ipilimumab
Phase I

I wish they would just come out and tell the world so we would stop the speculations.

This was posted on MPIP:

"Jim! I don't believe that Medarex involve anthing to the shortage of drug in its compassionate trial.

Medarex is just a research company... not a drug manufacturing... it does not have any capacity to scale up the drug. That's a reason why they partner up with Bristol Myers for MDX-010. Because BMS is the big drug company, which already has production plans/manufacture facilities.

I do believe BMS actually ran into a shortage of production due to unexpected demands. Right now they are working on the other process production plan, which called plan B vs plan C. But the FDA still requires them to run a trial for it. See my link..

http://www.clinicaltrial.gov/ct2/show/NCT00920907?term=ipilimumab&rank=13
Comparison of Ipilimumab Manufactured by Two Different Processes


If anyone to blame for.. it's the FDA.. From the recent ASCO data, MDX-010 proves that it doubles 1 year overall survival rate, it doubles 2 years survival rate.. when compares to the history data of DTIC. But that is still not good enough to let the company market the drug? Why the FDA want to sacrifice more human lives in order to prove the drug is efficacy? The history data of DTIC, which has been studied for 30 years.. which including very recent studies ... but still not convince them. What they want.. is another trial.. 300 human lives or more in DTIC arm, and another 300 human lives in MDX-010 arm.. then to seen if 300 human lives or more in DTIC arm die sooner?

30 years since DTIC approved, NO single drug has improve overall survive.. and now the only MDX-010 has proved it.."

Thanks John for your perspective on the situation


Take Care,

Jimmy B

Remember the Letter that I sent to CBER about the Anti-CTLA-4 Shortage? Melanoma..Jim Breitfeller

Remember the Letter that I sent to CBER about the Anti-CTLA-4 Shortage??

Dear Mr. Breitfeller,

Your email was forwarded to us by CBER (this IND resides in the Center for Drugs Evaluation and Research). We have contacted BMS to check into the availability of ipilimumab and here is the information that BMS provided to us.

"To ensure treatment is not interrupted for patients currently receiving ipilimumab and to provide ongoing supply to the registrational program, Bristol-Myers Squibb and Medarex have suspended enrollment of new patients into the compassionate use program, single patient exemptions and initiation of some non-registrational trials effective September 12, 2008.
Bristol-Myers Squibb and Medarex are working to manage the supply issue and may be able to re-open compassionate use in the future.

The companies are committed to providing uninterrupted treatment to patients who initiate therapy with ipilimumab. Therefore, if and when the compassionate use program reopens, it will be at such time when continuous and unconstrained supply is available."

Please let us know if you have any questions.
Sincerely,

CDER Drug Shortage Team

Well, I did a little research!!!!! See I came from a background of using bioreactors for growing things like detergent enzymes, bacteria ..etc.

1990’s “Degradation of the Ferric Chelate of EDTA by a Pure Culture of an Agrobacterium sp”

John J. Lauff,1* D. Bernie Steele,2 Louise A. Coogan,1 and James M. Breitfeller1†
1Genencor International, 1870 Winton Road, South, Rochester, New York 14618, and Department of Botany and Microbiology, Auburn University, Auburn, Alabama 36899, 2
* Corresponding author.
† Present address: Analytical Technology Division, Eastman Kodak Co., Rochester, NY 14650.

So when Bristol Meyer Squibb contacted me this week and said that they are going to continue the ban on the compassionate use for Critically Ill Melanoma Patients, I was furious. They told me that they serviced 1400 compassionate patients before stopping the program.

So Lets do the Math!!!!!!!

1400 times 10 doses times 10mg/dose equals 140,000 mg or

Answer: 140000 mg = 140 grams of anti-CTLA-4 antibodies

0ne pound = 454 grams

That doesn’t seem like a lot. Are they using a small reactor vessel? I bet they are not.


Well I forgot to take into account the Patients bodyweight.

800 mg per dose, So about 8000 mg for 10 doses for a person weighing 175 lbs.

Thank for checking my math Jerry!!!!!!



So what does it entail to make these antibodies?


Source:http://www.sumanasinc.com/webcontent/animations/content/monoclonalantibodies.html

The making of Monoclonal Antibodies


Once you have them separated and frozen, and stored in cryogenic storage, all you have to do is to take some vials and inoculate your bioreactor with them. With the correct medium, temperature, pH and oxygen and nutrients, they begin to grow.





Figure 4. Comparison of first and second generation MTCM basal media for a HuMAb production using Expression System I.

“HuMAb batch processes with MTCM A and B were developed that can yield up to 1 g/L without feed addition. In general, MTCM B supports better cell growth and longevity of the culture, and as a result, leads to better productivity in batch and fed-batch processes. For example, Figure 4 shows that, cell culture processes in MTCM B not only reached higher peak cell density, but also expressed higher antibody levels for both batch and fed-batch compared to those in MTCM A.”

As you can see it does not take a year to produce these antibodies. Most likely they have quite a number of bioreactors. So when one reactor is down due to sterilization, they can start another run in the other one.

Source:http://biopharminternational.findpharma.com/biopharm/article/articleDetail.jsp?id=601146&sk=&date=&pageID=2

The Impact of Cell Culture Medium on Cell Line and Process Development Timelines and Strategies


So the Million dollar question is, Why did they stop the compassionate use program??
So I wrote back to them and said:

I find it hard to believe that your “process” is taking a year to get under control and be efficient. If it was FDA approved, and you were loosing capital, it would be under control by now. See, I am not your typical Patient. I worked in the Biosciences Industry for a number of years. You can’t sweep this under the table. There are Melanoma Patients dying. I am seeing it first hand. The blood is on your hands!!!!!!!

Your Company states: ” What sets us apart? We believe it's our commitment to patients with serious diseases, our focus on finding innovative medicines that combat those diseases, and our dedication to extending and enhancing human life.”

This is nice PR, but if you don’t walk the walk and it is all talk, then it means NOTHING!!!!!!! And the most ill Melanoma patients don’t have time on their side.


Take care

Jimmy B

Melanoma_Missionary

Two-Year Survival Rate Ranging from 30 to 42 Percent in Metastatic Melanoma Patients Treated with Ipilimumab Melanoma..Jim Breitfeller

Results from Three Phase 2 Studies Reported a Two-Year Survival Rate Ranging from 30 to 42 Percent in Metastatic Melanoma Patients Treated with Ipilimumab (10 mg/kg)

PRINCETON, N.J.--(BUSINESS WIRE)--May. 31, 2009--Bristol-Myers
Squibb Company (NYSE: BMY) and Medarex,
Inc. (NASDAQ: MEDX) today announced updated survival results from
follow-up extensions of three Phase 2 ipilimumab studies of patients
with advanced metastatic melanoma (Stage III or IV). The two-year
survival rate ranged from 29.8 to 41.8 percent in patients who received
ipilimumab (10 mg/kg). Results of the survival data were presented at
the 45th Annual Meeting of the American Society of Clinical
Oncology in Orlando, FL., May 29 -- June 2, 2009.


The results are based on follow-up of up to 37.5 months (median
follow-up ranging from 10.1 to 16.3 months) of the patient population
from studies 008, 022 and 007 treated with 10 mg/kg of ipilimumab
(induction and maintenance) and, specifically, showed:


Two-year survival rate of 32.8 percent (95% CI: 25.37%- 40.49%) in
patients who had progressed while on or after receiving standard
treatment (Study 008, Abstract #9033);


Two-year survival rate of 29.8 percent (95% CI: 19.13%- 41.14%) in
patients who were previously treated, relapsed or failed to respond to
experimental treatment or were unable to tolerate currently approved
therapies (Study 022, Abstract #9033);


Two-year survival rate of 40.6 percent (95% CI: 27.12%- 54.37%) and
41.8 percent (95% CI: 28.30%- 55.46%) in patients receiving ipilimumab
plus budesonide or ipilimumab plus placebo, respectively, which
included treatment-naïve patients and patients previously treated with
therapy other than ipilimumab (Study 007, Abstract #9033).



Historical melanoma survival rates from previous clinical trials have
been estimated by a recent meta-analysis of 42 Phase 2 trials of over
2,100 patients with Stage III or IV metastatic melanoma indicating that,
at one year, approximately 25 percent of patients were alive. Results
from three separately published randomized Phase 3 studies using
dacarbazine as the control arm reported that, at two years,
approximately 8 to 12 percent of metastatic melanoma patients were alive.


The updated survival analyses did not include additional safety data. As
previously reported, safety results include follow-up of up to 16.3
months with a median follow-up ranging from 4.7 to 5.65 months. The most
common immune-related adverse events were rash, diarrhea and hepatitis.
Grade 3 and 4 immune-related adverse event rates were approximately 20
to 29 percent and zero to 12 percent, respectively, in patients who
received 10 mg/kg of ipilimumab. Adverse events were managed with the
use of supportive care and systemic steroids using established treatment
guidelines in the majority of patients. Additionally, the use of
systemic steroids to manage adverse events does not appear to diminish
or impact the clinical effect of ipilimumab (Abstract #9037).


"The ongoing survival data observed with ipilimumab are encouraging,
particularly because the advanced melanoma patient population currently
has limited treatment options," said Steven J. O'Day, M.D., Chief of
Research and Director of the Melanoma Program at The Angeles Clinic and
Research Institute, California. "The potential of ipilimumab is also
underscored by the fact that we can report two-year survival results
from these studies involving a significant number of metastatic melanoma
patients."


Candidate Biomarkers of Ipilimumab

Researchers also presented an exploratory analysis from four Phase 2
ipilimumab studies (008, 022, 007 and 004) that looked at the
association between clinical activity and multiple potential biomarkers,
including the change in absolute lymphocyte count (ALC) in melanoma
patients after they received ipilimumab (Abstracts #9008 and #3020). ALC
is a measure of the number of immune cells in circulation.


In a combined analysis of studies 007, 008 and 022, clinical activity
was associated with an increase in the rate of change in ALC. Patients
with clinical activity had a higher average increase in ALC over time
than did patients without clinical activity (P=0.0013) and no patient
with a decrease in ALC over time had clinical activity. This association
was separately confirmed in Study 004. Increases in ALC following
administration of ipilimumab were also significantly associated with
dose (studies 007, 008, 022: P<0.0001; study 004: P=0.0015), favoring
the 10 mg/kg regimen. Based on these early biomarker findings, further
research to explore the implication of ALC and other potential
biomarkers of clinical activity of ipilimumab continues.


About Studies 008, 022 and 007

The three studies enrolled a total of 487

patients across North
America, Europe, South America, Africa and Australia with Stage III or
Stage IV metastatic melanoma treated with ipilimumab therapy (0.3 mg/kg,
3.0 mg/kg or 10 mg/kg every three weeks for up to four doses, followed
by maintenance dosing every 12 weeks). Specifically, the three Phase 2
monotherapy trials include:


A Phase 2 open-label, single-arm trial (008) evaluating overall
response rate in 155 patients who progressed while on or after
receiving standard treatment;


A Phase 2 randomized, double-blind trial (022) evaluating the efficacy
of three dose levels of ipilimumab in 217 patients who were previously
treated, relapsed or failed to respond to experimental treatment or
were unable to tolerate currently approved therapies; and


A Phase 2 randomized, double-blind trial (007) evaluating the rate of
Grade 2+ diarrhea in 115 patients receiving ipilimumab with or without
prophylactic oral budesonide.



The primary endpoint of studies 008 and 022 was best overall response
rate and the primary endpoint of study 007 was to compare the rate of
Grade 2+ diarrhea in patients receiving ipilimumab with or without
prophylactic oral budesonide. Overall survival, one-year survival rates,
disease control rate, stable disease, and other measurements of
anti-tumor activity and patterns of responses were secondary endpoints
in studies 008, 022 and 007. The two-year survival data reported are
current (through March, 2009) for all subjects followed: 93.6% from
study 008, 91.7% from study 022 and 84.2% and 82.8% from the two
subgroups of study 007 (placebo and budesonide, respectively).


About Study 004

Study 004 is a Phase 2 randomized, double-blind biomarker trial. The
study enrolled 82 patients with advanced melanoma who were previously
treated with therapy other than ipilimumab or who received no prior
therapy. All patients received ipilimumab therapy (3.0 mg/kg or 10
mg/kg). Pre- and post-treatment (week four) tumor biopsies were
performed to assess associations between tumor biomarkers and clinical
activity of ipilimumab. Clinical activity was defined as complete or
partial response or stable disease at ≥24 weeks using modified World
Health Organization criteria.

Subject: Anti-CTLA-4 blockage shortage.... Medarex and BMS..Melanoma..Jim Breitfeller

Sent: Friday, April 10, 2009 8:59 AM
To: CBER Product Shortages
Subject: Anti-CTLA-4 blockage shortage.... Medarex and BMS
Importance: High

As a patient Melanoma stage IV. I have heard that there is a shortage on this monoclonal antibody for companionate use. I have watched people die because it is not available.

Please could you investigate and get back to me.

Best Regards,

Jim Breitfeller

Reply:
Dear Mr. Breitfeller:

I am forwarding your inquiry to the Center for Drug Evaluation and Research (CDER). They will respond to you as soon as possible.




CBER/OCBQ

Letter to Medarex 3-24-2009 Melanoma Jim Breitfeller

Ms wolfe,
This not about who has what product? This about a theory and therapy that will make your product the greatest invention since sliced bread. Your product has the potential of help cure Melanoma. The dose has to be 15mg/Kg to invoke an innate immune response. Once that has happen, the Interluekin -2 (growth factor) promotes propagation and is need to activate the CD8+ Tcell. IL-2 Regulates Perforin and Granzyme Gene Expression in CD8+ T Cells Independently of Its Effects on Survival and Proliferation. With all this said and done, IL-2 needs the get Immune response started. That is done by your Monoclonal Antibody. “The Magic Bullet”.

Well now I have a request for you. Please pass this on to your Clinical Team. I have been data mining on the internet and have been able to piece together why my combination therapy worked. etc...........

The rest is the same as Dr. Rosenburg Letter.

I am still trying to make contact with Novartis the, Manufacturer of Interluekin-2. I don't have a contact name or email yet. I hope to get one soon. If any one has a contact please get intouch with me.

Thanks

Jimmy B

Time to do a Road Show!! Melanoma..Jim Breitfeller

I am in the process of writng to Medarex and Dr. Roesnberg at NCI. I 've been data mining on the internet and I have been able to piece a sound theory together. It has taken me over a year to put all the pieces together. I started at the edges and worked my way across the board. I am putting the final pieces in and it is my belief that I found a needle in the hay stack. It may not be the only way to get to a stabilization, but I think I am on the "Yellow brick road". Now it is time to see the great Wizard of OZ, Dr. Rosenberg. I hope He will give a thumbs up (Brain).

So I am off to see the Wizard.


And in the previous post this graph shows when the innate immune response should take place by a natural antibody. Check out the timeline. The maximum response is at about two weeks. My Inflamoratory response happen in 15 days.

This is not a coincidence!!!!!!!


Wish me luck

Jimmy B

I Took My Dream to the Drug Manufacturer ..Melanoma..Jim Breitfeller

I am more convinced than ever that we are on the right track.

HOMEWORK,HOMEWORK,HOMEWORK

This was posted this morning:

Posted 27 minutes ago 3/12/2009 9:00 am

by Teri

I was told yesterday that the "Til Harvest" that MDA,(MD Anderson) is doing is seeing more response (positive) to patients that have had IL-2 prior to using their T-cell harvested cells. They told me currently there is a 36 year old female patient being treated and she is almost NED....she had lung lesions, did IL-2, and now is doing T-cell.

You're much more technical than I am, but I think that goes along w/ your hypothesis....the cells were pre-activated and then more responsive when the T-cells were used.

Well done my faithful servant!

Teri2007
=================================================================
Medarex, Inc. Manufacturer of the monoclonal antibodies

Dear Mr. Breitfeller:

Thank you for your email. It has been forwarded to our clinical development team.

We are continuing to develop Ipilimumab with Bristol-Myers Squibb and studies are ongoing.

Your interest is appreciated.

Best Regards,
Alicia Allen
Assistant to Christian Schade
Senior Vice President &
Chief Financial Officer
Medarex, Inc.