MedImmune Inks Deal for Pfizer's Anticancer mAb Therapeutic..Melanoma .Jim Breitfeller

MedImmune inked an in-license agreement with Pfizer for tremelimumab, a mAb therapeutic for various types of cancer. Pfizer presented final toxicity results of a Phase I dose-escalation trial of tremelimumab in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer.

Under terms of the deal MedImmune will assume global development rights to tremelimumab. Pfizer retains rights to use the drug compound with specified types of combination therapies.

Pfizer previously signed over developments rights covering tremelimumab in melanoma to Debiopharm after the mAb failed in a Phase III melanoma trial. The interim analysis found that it would not offer any benefit over standard chemotherapy. Thus in April 2008, Pfizer was forced to halt the trial.

A full evaluation of the data revealed a biomarker that predicted patients who were more likely to respond, according to Pfizer. Debiopharm will be responsible for conducting a new Phase III study that leverages this marker to select patients with unresectable, stage IV melanoma. At the time of inking the deal with Debiopharm, Pfizer said it would retain all commercial rights.

Tremelimumab is a fully human mAb that binds to the protein CTLA-4, expressed on the surface of activated T lymphocytes. "Adding another immunotherapeutic approach to our oncology pipeline, one which may employ the immune system itself to fight cancer, exemplifies our continued commitment to embracing this new era of cancer care," says Bahija Jallal, Ph.D., MedImmune's evp, R&D.

MedImmune has seven clinical-stage mAb programs for cancer treatment. Phase I candidates bind to CEA and CD3, CD22, IGF, CD19, and Ang2. The Phase II candidate targets PDGFRα and is being tested in lung cancer and glioblastoma. The company believes that the platelet-derived growth factor receptor alpha (PDGFRα) pathway, with its potential role in regulating transformation as well as tumor microenvironment, progression, and metastasis, may be an important cancer target.

MEDI-575 is a fully human mAb to PDGFRα being tested in lung cancer. It has been shown to inhibit signaling from PDGFRα on cancer cells and supportive stroma. However, MEDI-575 reportedly does not inhibit PDGFRβ, the inhibition of which has been associated with significant clinical toxicities including extravascular fluid accumulation.

MEDI-575 is a fully human mAb to PDGFRα being evaluated as a treatment for glioblastoma multiforme. MEDI-575 has been shown to inhibit signaling from PDGFRα on cancer cells and supportive stroma but not PDGFRβ, MedImmune says


Bristol Myer Squibb will now be looking in the rearview mirror and seeing MedImmune in it. Down the road we may see the price of these anti-CTLA-4 antibodies go down.


Also MedImmune has an US Patent Application 20100028330 - METHODS OF UPMODULATING ADAPTIVE IMMUNE RESPONSE USING ANTI-PD1 ANTIBODIES.

This is becomming Very Intersesting!!!

A race for the CURE!!!!!




It is good to see some Competition.



“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

How does Ipilimumab (Yervoy) work? Melanoma..Jim Breitfeller

Ipilimumab is anti-CTLA-4 monoclonal antibody.

Ipilimumab C6742H9972N1732O2004S40
immunoglobul has a calculated molecular formula of C6472H9972N1732O2004S40 and a molecular weight of 145.4 kDa.in G1, anti-(human CTLA-4 (antigen)) (human gamma1-chain), disulfide with human kappa-chain, dimer [CAS] immunoglobulin G1, anti-(human CTLA-4 (antigen)) (human g1-chain), disulfide with human k-chain, dimer [CAS]

Half Life = 15 days

Tremelimumab (from Pfizer) is an IgG2
Tremelimumab is a fully human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) IgG2 monoclonal antibody, presumably manufactured using transformed mammalian cells. Tremelimumab is a dimer (composed of two chains) linked by a disulfide/sulfhydryl bond. Tremelimumab has a calculated molecular formula of C6500H9974N1726O2026S52 and a molecular weight of ~150 kDa

Half life= 21 days




In T-cell activation, the receptor, CTLA-4 is upregulated on about day 3.

The CTLA-4 complex can suppress the immune response.

CTLA-4 that interferes with Dendritic cell (DC) costimulation via reduced CD80/CD86, (B7-1-2) expression and CD25 (IL-2 receptor) to allow for Treg survival, activation, and effective competition for limited IL-2 during infection.

Ipilimumab (Yervoy) works by blocking the CTLA-4/ B7-1/2 complex, which allows the costimulation of the CD28// B7-1/2 complex to take place. This takes the brakes off the immune response allow the response to go unchecked.

Another thing Yervoy does is that it decreases the signaling of STAT5 with increasing concentrations. That is why the best overall concentration is 10mg/Kg.

Phosphorylation of STAT5 decreased significantly with increasing concentrations of tremelimumab/Ipilimumab in monocytes from five healthy donors and from three patients with melanoma. Overall, these data demonstrate that monocytes express mostly intracellular CTLA4 and that CTLA4 is biologically active in this cell subset since exposure to tremelimumab/ipilimumab induces changes in intracellular signaling molecules.
By decreasing the signaling of STAT5 during Cell differentiation, TH17 and TH1 cells are mostly produced.






“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

Faltering Cancer Trials Melanoma.. Jim Breitfeller

Faltering Cancer Trials
Editorial
Published: April 24, 2010


The government’s system for judging the clinical effectiveness of cancer treatments, recently found to be in “a state of crisis,” must be repaired.

Here is a recent article from the New York Times. Thanks to Ed a carepage friend and colleage for bringing this to my attention.


Source:http://www.nytimes.com/2010/04/25/opinion/25sun1.html

Faltering Cancer Trials



We need the Patients to unite and get the best therapy for their condition. This is not rocket science, it is biochemistry at it's best. We need Big Pharma(Bristol Myer Sqiubb, Novartis,Pfizer, Plexikkon, Hoffman La Roche and others) to step up to the plate and do what is ethical. Not just looking at their bottom line. Without patients/consumers, these drug companies would not exist.

Our future survival is in our hands. The cure is out there. We need the medical community to take notice.




Take Care,
Jimmy B

Tregs Rule without Anti-CTLA-4 Blockade Melanoma..Jim Breitfeller

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


Take Care,

Jimmy B

Future Directions in Targeted Therapy for Melanoma..Jim Breitfeller

Future Directions in Targeted Therapy for Melanoma

“Our improved understanding of the molecular pathways that underlie the progression of melanoma has revealed numerous potential therapeutic approaches. We now face the challenge of developing targeted therapies directed at signaling pathways that are activated through mutations. Single-agent therapy is unlikely to be markedly successful,so there is also a pressing need to evaluate combination therapies, both with multiple targeted therapies and with targeted therapies plus conventional chemotherapeutic agents. It is hoped that these approaches will result in effective treatment options for patients with metastatic melanoma.”

~Dr. Keith T. Flaherty~


The Complexity of the T cell

In the midst of many promising discoveries, it became apparent to Dr. Allison and other researchers working in the field that stimulation of T cell response was more complicated than originally thought. As Dr. Allison and others discovered, first the T cell uses a structure called the antigen receptor to recognize a foreign antigen in the system (created by infecting viruses or bacteria, or new antigens found in tumor cells). Using an automobile as an analogy, Dr. Allison likens this step to turning the key in the car's ignition. "The car is running, but it's not going anywhere."

Recognition is not enough. Dr. Allison explains: "A second signal is also required, which, in the car analogy, would be the foot on the gas pedal." This second signal occurs when a particular family of molecules called the B7 molecule engages a molecule known as CD28 found on the surface of the T cell. Only these molecules are capable of initiating T cell response.

The final part of the car analogy is the immune system's brake -- an immune-regulating molecule, whose function was discovered by Dr. Allison's lab, known as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 inhibits activated T cells in the immune system, preventing them from attacking the body's own tissues

It is now well accepted that recognition of specific antigen by the TCR is not sufficient for activation but that a second antigen nonspecific "co-stimulatory" signal is required. We have demonstrated that this second signal is provided the co-stimulatory receptor CD28 upon recognition of its counter-receptors, members of the B7 family, on the antigen-presenting cell. CD28 engagement is required under most situations for IL-2 production and proliferation. The lack of a CD28-mediated co-stimulatory signal upon TCR engagement can result in the induction of a long-lived state of nonresponsiveness.

We have recently found that co-stimulation is more complex than previously thought. CTLA-4, a homolog of CD28, also binds members of the B7 family, and binds them with affinities much higher than CD28. A wealth of data accumulated in the past few years show that CTLA-4 is an important downregulator of T cell responses. We have proposed that CTLA-4 plays a critical role in both the initiation and termination of T cell responses. According to this view, T cell activation is a dynamic process that is determined by the strength of the TCR signal; the strength of co-stimulation provided by CD28; and the magnitude of inhibitory signals generated by CTLA-4.

We have also demonstrated that CTLA-4 blockade can be used in combination with other methods of immunopotentiation or even conventional chemotherapy to obtain rejection of resistant tumors. We are currently examining the cellular and molecular mechanisms of the anti-tumor effect. The strategies we have developed in the mouse are currently in clinical trials for evaluation of effectiveness in treatment of prostate cancer and melanoma

Source: Sloan-Kettering Institute

"I believe that we are on the verge of bringing the manipulation of immune responses into the mainstream of cancer therapy," Dr. Allison said. "Recent work in cancer biology has shown that the genetic instability that is inherent in cancer results in a large number of mutations in proteins that create new antigens that the body has never seen before and ought to be readily recognized as foreign by the immune system. If we can kill some tumor cells, either as a result of a vaccine or treatment with more-conventional therapies, using agents such as anti-CTLA-4 ought to result in induction of potent immunity to these new targets. Thus, I believe that it is not unreasonable to think of many of the new targeted therapies as immunosupportive, and to use them in conjunction with the new approaches to enhancing immune responses."

~Dr. James Allison~

We are on the Verge of Harnessing the Immune System to recognize Melanoma cells as foreign. How this plays out will depend on if the Pharmaceutical companies like Bristol-Myer Squibb, Novartis, Pfizer, Hoffman La Roche, Plexikkon and other come together as one, to fight this Monster of a disease. Time will only tell. We owe it to the Patients.






Take care

Jimmy B

Melanoma_Missionary


"Today might be the worst day of your life...but tomorrow could be the best. You just have to get there."
~Unknown~

http://www.box.net/shared/kjgr6dkztj

Melanoma and The Magic Bullet (Monoclonal Antibodies)

There is No Magic Bullet to Cure Melanoma, And We Must Develop Multimodality Strategies..Melanoma..Jim Breitfeller

Expert opinion
“The research efforts directed towards the development of novel therapies for patients with metastatic melanoma have been intense despite disappointing clinical outcomes. It is clear that monotherapy for metastatic melanoma will not be successful, with every study to date yielding minimal clinical outcomes
data. Therefore, we must realize that there is no magic bullet to cure melanoma, and we must develop multimodality strategies to enhance the immune response to melanoma from different angles. This will require an unprecedented collaborative effort by many in order to overcome the historical competition between large pharmaceutical companies striving for ‘total cure’ with their drug.”

~ Dr.Adam I Riker~

We should realize that the future of drug development and design will depend heavily on the recent trend towards molecular medicine, and in particular, gene profiling efforts using gene microarray analysis. We are entering an entire new field of research dedicated to the molecular basis of cancer. Such research has the greatest potential to impact the way we treat patients with melanoma, focusing results on the prognostic significance of particular genes from a melanoma patient and basing clinical decisions as to whether such patients will (or will not) respond to a particular agent. The development of molecular signatures using gene microarray analysis has come to the forefront of existing research efforts identifying patients who may have an aggressive (versus indolent) form of melanoma and those patients with particular prognostic gene
signatures that may predict the response to forms of immunotherapy. The identification of such gene signatures has had important implications in the development of targeted immunotherapies for patients with metastatic disease. Thus, we must focus our efforts towards an improved understanding of the molecular and immunologic events involved in melanoma development and progression. We should also re-evaluate our present approach to immunotherapy and trial design, with many past trials failing to show clinical efficacy because of a lack of appropriate preclinical data that provide the essential rationale to perform such studies.

Source: http://www.southalabama.edu/mci/spf90/riker2.pdf

Immunotherapy of melanoma: a critical review of current concepts and future strategies








Take Care,

Jimmy B

Combinatorial Therapy, Will the Big Pharmaceutical Companies do what Is Ethically Right?Melanoma..Jim Breitfeller

Combinatorial Therapy, Will the Big Pharmaceutical Companies do what Is Ethically Right?




They include Plexikkon,Bristol-Myer Squibb, Pfizer, La Roche and Novartis.


I and other researchers have come to the conclusion that Combinatorial Therapy may be the only way to beat The BEAST, Melanoma



“A very obvious combination that we are trying to move forward now is PLX4032 with ipilimumab. There is unanimity among the academic researchers that this must be investigated. Both companies see the logic, but are reluctant with neither of their drugs yet being FDA approved. As you know ipilimumab (and tremelimumab) have not overwhelmed the FDA yet as they were told to show a response rate greater than 10% and neither drug could do so. Most melanoma researchers believe that there are additional patients who get real and long-term benefit without having their tumors shrink significantly in size, but the randomized trials are needed to show that. The worrying sign is the outcome of the tremelimumab randomized trial. So, now we are down to waiting for the results of the dacarbazine vs. dacarbazine plus ipilimumab phase III trial. If this is negative, we are in trouble as ipilimumab will have no clear path forward with the FDA. If it’s positive, then the idea of moving ahead with combinations becomes much, much easier. But, even it that trial is negative, we know that CTLA-4 blockade can induce phenomenal responses in some. So, in that case, we have to figure out (1) who those patients are and, (2) how to make those responses happen in more patients. The other way of thinking of #2 is that PLX4032 doesn’t work for as long as we would like and that making those responses more durable would be desirable.”


~ Dr. Keith Flaherty ~


“ Mike Weber was kind to forward your paper and email. It appears that you have a very good sense of, and interest in, the immune response to melanoma and to cancer in general. I believe you are right that timing of the various components of the immune response, especially with combination therapies, is important, just as it is in the orchestration of a beautiful symphony.”


~ Dr. Craig Slingluff ~



Dr Markovic,. I thought you might be interested in this combinatorial therapy

“We actually just submitted a paper to this affect in a small clinical trial where we used a conventional chemotherapeutic agent to induce a systemic anti-tumor immune response by simply timing drug delivery. And, it worked! It was a small study, so the data is only descriptive. I'm gearing up to move to a large trial right now.”


~Dr. Svetomir Markovic~



“To answer your last question first: Mutations in B-Raf and N-Ras have been shown to cluster at specific nucleotides. This strongly suggests that there is a cellular mechanism which targets these sites in each gene. However, you are probably right, that anti-CTLA4 and IL2 are working by enhancing immune surveillance of your melanoma.”


~Dr. Natalie Ahn~



“In conclusion, the combination of MART-1/DC with concomitant tremelimumab is feasible in patients with metastatic melanoma, especially when tremelimumab is administered every 3 months, and results in durable objective clinical responses at the higher range of the expected objective tumor response rates with either therapy alone. Therefore, this combination warrants further study in patients with advanced malignant melanoma.”

~Dr. Antoni Ribas~


The rationale for the CTLA-4 and IL-2 combination is once you activated the CD4+ Tcell and it crossprime the CD8+ Tcell , the IL-2 needed for the maintenance and functionality of the CD8+ T-cell.
If lymphocytes are cultured in the presence of Interleukin 2, it results in the development of effector cells which are cytotoxic to tumor cells.

“Fine theory but just theory that has never been tested in relevant clinical setting…”

~Dr. John M. Kirkwood~

"Glad to see your post on this series. From our perspective, the melanoma community isn’t waiting for a “miracle” to fall out of the sky to help patients. It’s clear that no single drug will likely effectively treat the disease; instead, a combination of drugs may be the answer. The Melanoma Research Foundation (MRF) is coordinating the Melanoma Breakthrough Consortium to accelerate research by bringing together leaders in drug development, laboratory and clinical research to find effective treatments. This collaboration will take years off the process. Patients with advanced melanoma have few or no treatment options and there’s no doubt in the urgency of moving forward to test new therapies today. More information is available at http://www.melanoma.org."

~Tim Turnham~
Executive Director
Melanoma Research Foundation




This is why we the patients need the Pharmaceutical companies to work together. Each therapy will not work alone as a single agent. The response rate is between 10 and 22 percent for each therapy. If you do a sequential treatment with the proper dosage and timing, you will see a synergistic outcome.

“There are three parts of the equation in a clinical trial. There’s who has control, who gets the reward, and who takes the risk. Patients take all the risk, they have no control, and they get no reward. Patients ought to be the ones driving the process and get the reward out of it and have the control, since they are the ones that take the risk.”


~Greg Simons~


If we are taking all the risk, shouldn’t we have a say in our Destiny?
“We need to all work together for the common good of the Melanoma Patients”
“We need to take greed out of the equation and just do what is ethically for humanity”

~Jimmy B~

Which elevator will you, The Pharmaceuticals Companies will Take?



Take Care,

Jimmy B

What If you combine Therapies? Response from Dr. Keith Flaherty..Melanoma ..Jim Breitfeller

What If you combine Therapies? Response from Dr. Keith Flaherty

Jim,


Thanks for the note.




"It is actually critical “patient advocates” which obviously includes patients, as well as those who are motivated to advocate on behalf of patients get involved in this process. One of the very reasons why I thought that a consortium was important to form, so that there could at least a body of researchers to point to as a group jointly focused on this direction. You see, companies find it very easy to say no to individual investigators when it comes to “difficult” requests. We need to make it harder for them when it involves losing time that our patients don’t have."



A very obvious combination that we are trying to move forward now is PLX4032 with ipilimumab. There is unanimity among the academic researchers that this must be investigated. Both companies see the logic, but are reluctant with neither of their drugs yet being FDA approved. As you know ipilimumab (and tremelimumab) have not overwhelmed the FDA yet as they were told to show a response rate greater than 10% and neither drug could do so. Most melanoma researchers believe that there are additional patients who get real and long-term benefit without having their tumors shrink significantly in size, but the randomized trials are needed to show that. The worrying sign is the outcome of the tremelimumab randomized trial. So, now we are down to waiting for the results of the dacarbazine vs. dacarbazine plus ipilimumab phase III trial. If this is negative, we are in trouble as ipilimumab will have no clear path forward with the FDA. If it’s positive, then the idea of moving ahead with combinations becomes much, much easier. But, even it that trial is negative, we know that CTLA-4 blockade can induce phenomenal responses in some. So, in that case, we have to figure out (1) who those patients are and, (2) how to make those responses happen in more patients. The other way of thinking of #2 is that PLX4032 doesn’t work for as long as we would like and that making those responses more durable would be desirable.

The companies need to hear it from patients and all patient-advocates that fairly obvious directions need to be pursued to find multiplicative effects. For the first time in melanoma, we have the building blocks in front of us and scientific rationale to guide us for the next steps.


Best regards, Keith

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Keith,


Base on my research, Ipi doesn’t work well is because it is lacking the tumor-specific antigens. DTIC+ Patrin-2, Irradiation, Oblimersen and others. We need the tumors to shed antigenic protein. To get the immune response into motion.


By using PLX-4032, my guess it will shed the protein needed. Then Anti-CTLA-4 Blockage comes in. It leaves the cd4+ T-cell activated and at the same time suppresses the Treg function allowing the CD8+ T-cells to get crossed primed and have them break though the tumor microenvironment. The HD IL-2 is added at the peak expansion of the CD8+ T-cells ( 50 days after Ipi is introduced into the host.). IL-2 is essential in the survival and function of the CTLs.


The above is my take on this combinatorial therapy. If you want, I can send you all the supporting papers of this theory.


Also, Can I get your permission to post your reply on my Blog?

Best Regards

Jim

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

What If you Combine three Therapies? PLX-4032 after remission, to let the tumor burden be low, Than add one dose of Anti-CTLA-4 Blockage. Wait 50 days so the CD8 T-cells would be at their maximum expansion. Then add two cycles of HD IL-2 to help grow and differentiate the CD8 T-cells into Cytotoxic T Lymphocytes (CTL's). You use the PLX-4032 to lower the tumor burden and shed the antigenic protein from the tumor.



For the patients that have the Braf mutation, use PLX-4032 to shed the antigenic protein and lower the tumor burden.

If you don't have the mutation, use radiation, chemo DTIC+ Patrin-2, Oblimersen and other small molecules to shed the antigenic protein.







Take Care,

Jimmy B

A note To Dr. Keith Flaherty.. Combinatorial Therapy..Melanoma..Jim Breitfeller..2-25-2010

"One year, Dr. Flaherty thought, when he heard the news. Certainly no triumph. But it was something. Something to be built on.

Novartis and Bristol-Myers had agreed to schedule teleconferences for later in the month to talk about combination trials. He checked the dates on his electronic calendar. A meeting with Pfizer was also pending."



Dr. Flaherty,

As early as May of 2009 I had come to the conclusion that the drug companies must work togther to come up with a stabilization/cure.

As a fellow researcher and Blogger, What can I do to help convince the pharma this it is in their best interest to work together. It would be a win, win for all, including the Patients like myself.

Keith, Please let me know what I can do to Help?

Best regards



Jim Breitfeller





Friday, May 8, 2009

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space Melanoma.. Jim Breitfeller

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space.

With ASCO Annual meeting coming up at the end of May, I believe that there will be some excitement around monoclonal antibodies. In particular, anti-CTLA-4 blockage treatment will be under the spotlight. What will the overall survival rates look like? Well, speaking from my experience, anti-CTLA-4 has prolonged my life for over 27 months where as a stage IV Patient, I was given 6 to 9 months. This could not have happen with out the extra help from Interleukin -2.

See, once the CD4+ T-cells activated, they need to grow and cross-prime the CD8+ T-cells. While activated T-cells secretes IL-2 at a certain concentration to help promote proliferation of the CD4+ T-cells. If there is too much IL-2 at the beginning of the immune response, I believe that the ratio of CD4/CD8/CD3 would be altered causing
the Tregs (CD4+ CD25 fox P3) to gain the upper hand of suppression of the immune response. A subset of CD4 + cells called CD4 + CD25 + regulatory T (Treg) cells that expresses Forkhead box P3 (Fox P3).

With just adding Anti-CTLA-4 first, It has been reported that it suppresses the T regs and pushes the balance towards an immune response. Once the immune response is in progress, the CD4+ T-cell is needed to co-stimulate the CD8+ T-cell. A source of these cofactors for effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts of IL-2.

Once the CD8+ T-cell is activated, and is cultured in the presence of Interleukin 2, it results in the development of effector cells which are cytotoxic to tumor cells.

This is why we the patients need the Pharmacitical companies to work together. Each therapy will not work alone as a single agent. The response rate are between 10 and 22 percent for each therapy. If you do a sequential treatment with the proper dosage and timing, you will see a synergistic outcome.


“There are three parts of the equation in a clinical trial. There’s who has control, who gets the reward, and who takes the risk. Patients take all the risk, they have no control, and they get no reward. Patients ought to be the ones driving the process and get the reward out of it and have the control, since they are the ones that take the risk.”

~Greg Simons~


If we are taking all the risk, shouldn’t we have a say in our Destiny?

“We need to all work together for the common good of the Melanoma Patients”

“We need to take greed out of the equation and just do what is right for humanity”




Melanoma and The Magic Bullet (Monoclonal Antibodies)




Take Care,

Jimmy B

Medarex is Giving away the Company without it's Shareholders Consent at a Fireside Sale to Bristol-Meyer Squibb of 50 % off! Melanoma Jim Breitfeller

Headline Pfizer's melanoma disappointment compounds Medarex misery

Source EP Vantage

Company Medarex

Related: Bristol-Myers Squibb, Pfizer

Date April 02, 2008

The termination of a phase III trial of tremelimumab in melanoma, after interim data suggested the drug was no better than standard chemotherapy, could mean Pfizer has lost one its most promising pipeline products.
While the company is not abandoning the antibody, which is in trials for a range of solid tumours, the prognosis is not good, and is the last thing Pfizer needs as it attempts to drive through new products ahead of the looming loss of Lipitor. For Medarex, the news is an even bigger blow, because it makes potential future royalty payments look more uncertain, and adds to concerns around a similar antibody the biotechnology firm is developing with Bristol-Myers Squibb.
Tremelimumab, or CP-675,206, is an anti-CTLA4 antibody which targets a molecule found on the surface of T-cells, and has been shown to diminish the immune response to tumours. By using a human antibody to block the activity of CTLA-4, immune systems may attack tumours more strongly.
There are two anti-CTLA4 MAb’s under development, tremelimumab and ipilimumab, both in final stage trials for melanoma. The Pfizer drug was developed using technology similar to Medarex’s, hence the royalties due on future sales. The latter, also known as MDX-010, was developed by the biotechnology group, and is being progressed under the alliance with Bristol-Myers Squibb.
The consensus net present value of MDX-010 to Medarex is $1.23bn, according to EvaluatePharma’s NPV Analyzer, which represents just over a third of the total value of the group’s pipeline. CP-675,206 is valued at $547m, accounting for just under a fifth, meaning half of the company’s pipeline value is tied up in the success of anti-CTLA4 MAbs.
Medarex shares were trading 15% lower, at $7.88, in early trade.

Second most important

Pfizer shares also opened weaker, down 1%. The consensus NPV of the product is $2.29bn, representing 2% of the company’s share price. That makes it the second most important pipeline project, after axitinib.
Analysts had penciled in sales of $499m by 2012, and were anticipating launch this year. The product is phase II trials in non-small cell lung cancer, colorectal and breast cancers, among others.
Melanoma would be a big opportunity for both CP-675,206 and MDX-010, because the cancer represents a significant unmet medical need. The main drugs used to fight the disease are the interferon alphas, sales of which are in decline as newer, more effective products have been developed for other tumour types, with melanoma remaining hard to treat.
If the antibodies fail to make the grade, the indication will lose two its most promising looking new candidates.

Diminishing hopes

Hopes that the anti-CTLA4 MAbs would prove to be a significant new treatment options were lowered when Bristol-Myers and Medarex released mixed results from three registration phase III trials of ipilimumab in December. One study did not meet the primary endpoint, although the companies have stressed that response rates across the trials were positive.
MDX-010 is due to be filed with the FDA in the first half of the year, and Medarex has expressed confidence that the regulator will approve the drug on the data. Sales forecasts commence in 2008, given the fast track status the drug has been granted, but confidence in straight-off approval has diminished, with many analysts believing further trials will be required.
A sign that Bristol-Myers is also less than confident came in a December slide show given by the company, which showed sales of MDX-010 starting in 2010.
Consensus for 2012 sales sits at $389m recorded by Bristol-Myers. A key event for defining the potential of the drug will come when full data from the three phase III trials is presented at this year’s ASCO conference at the end of May.
With today’s set back, that presentation takes on even greater importance for the biotechnology group. Its shares fell 21% when the news on MDX-010 was announced in December, and aside from a recent small rally, have been falling since.
With the stock now trading at three-year lows, significant progress with the remainder of its pipeline is needed to restore confidence.

This content is written, edited and published by EP Vantage and is distributed by EvaluatePharma Ltd. All queries regarding the content should be directed to: news@epvantage.com
EP Vantage is a unique, forward-looking, news analysis service tailored to the needs of pharma and finance professionals. EP Vantage focuses on the events that will define the future of companies, products and therapy areas, with detailed financial analysis of events in real-time, including regulatory decisions, product approvals, licensing deals, patent decisions, M&A.
Drawing on EvaluatePharma, an industry-leading database of actual and forecast product sales and financials, EP Vantage gives readers the insight to make value-enhancing decisions.



Source: EvaluatePharma®
Source:
http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&lType=modData&id=10530&componentID=1002#&&_ViewArgs=%7b%22_EntityType%22%3a0%2c%22_Parameters%22%3a%7b%22_ContextData%22%3a%22%7b%5c%22isEPVantage%5c%22%3atrue%2c%5c%22percentage%5c%22%3a-1%2c%5c%22searchWords%5c%22%3a%5c%22%5c%22%2c%5c%22sectionID%5c%22%3a%5c%22%5c%22%2c%5c%22storyID%5c%22%3a%5c%22152431%5c%22%7d%22%7d%2c%22_Type%22%3a1%7d


Based on this information plus 1.5 bn for the othe 39 drugs in the pipeline plus 1.23 for mdx-010 and 2.29 for Tremelimumab, or CP-675,206 equals 5.02 bn

Lets do the math 2.4 bn/16per share = 5.02 bn/X X= 33.5 dollars per share

BMY got a half off deal.


Show us the $$$$$$$$$$$!!!!!!!!!!

Medarex List of products in the pipline!!!! 14-Aug-09 10:13 pm
Product Count
Medarex
Marketed 3
R&D 62
Suspended in R&D 1
Abandoned in R&D 42
Disposed in R&D 1
Total (Medarex) 109

DEPTH COMPETITIVE INTELLIGENCE AVAILABLE ON

Product Generic Name
Medarex
aB7H4
-
ADC Research Program
-
AFP-VAC
-
ALT-212
-
AMG 714
-
Amgen Antibody-1
-
Amgen Antibody-2
-
Amgen Antibody-3
-
Amgen Antibody-4
-
Amgen Antibody-5
-
Anti-bacterial MAb
-
Anti-CD70 MAb-MGBA conjugate
-
Anti-Cripto-1 MAb
-
Anti-CTLA-4 project
-
Anti-SDF-1 MAb
-
aPtk7
-
ARIUS/Medarex Cancer Research Project
-
AutoImmune MAb Collaboration
-
Avalon Cancer Antibody Collaboration
-
BMS-66513
-
Cancer antibody collaboration
-
Cancer MAb Project
-
Cancer Research Project
-
CDX-110
-
CDX-1307
-
CDX-1401
-
CDX-2101 (inc. Ribi-529 adjuvant)
hepatitis B vaccine

CDX-2301
anthrax vaccine

CDX-2401
-
CDX-2410
-
CDX-S03
-
CNTO 95
intetumumab

COL-VAC
-
Compugen antibody collaboration
-
CP-675,206
tremelimumab

DTS-201
-
Duocarmycin B2
-
Eos/Medarex/Biosite Cancer MAb
-
Euroscreen MAb collaboration
-
FG-3019
-
Fully-Human RSV MAbs
-
Graft versus Host Disease Project
-
GVHD-TOX
-
Haematological cancer MAb collaboration
-
HGS-TR2J
-
HuMax-CD4
zanolimumab

HuMax-Inflam (MDX-018)
-
IL-13 Antibody
-
Ilaris
canakinumab

IMC-18F1
-
IMC-3G3
-
Immunology MAb collaboration
-
Infectious Disease Research Project
-
Ipilimumab
ipilimumab

KW-2189
pibrozelesin

LOR-A04
-
Lung Cancer MAb
-
MAb Research Project
-
MAGE3
-
MDX 1097
-
MDX-060
iratumumab

MDX-066
-
MDX-067
-
MDX-070
-
MDX-11
-
MDX-1100
-
MDX-1105
-
MDX-1110
-
MDX-1185
-
MDX-1203
-
MDX-1204
-
MDX-1338
-
MDX-1342
-
MDX-1388
-
MDX-1401
-
MDX-1411
-
MDX-1414
-
MDX-214
-
MDX-22
-
MDX-220
-
MDX-240
-
MDX-33
-
MDX-44
-
MDX-447
-
MDX-RA
-
Medarex/Pfizer UltiMAb Antibody
-
Medarex/Raven MAb
-
MEDI-545
sifalimumab

MEDI-546
-
MelanA
-
MEL-VAC
-
NI-0401
-
Novartis Antibody 2
-
NY-ESO-1
-
OGeS cancer antibody collaboration
-
ONO-4538 / MDX-1106
-
Organon/Medarex MAb
-
Osidem
-
Ovarian Cancer MAb
-
PSA-VAC
-
Resiquimod (inc. CDX-1307 adjuvant)
-
SARS MAb
-
Second-generation MDX-070 toxin conjugate
-
Simponi
golimumab

Stelara
ustekinumab

Transcobalamin MAb
-
Valortim
-
VAP-1 Antibody Program
-
Vitamin B12 Receptor Blocking MAb

Take Care,

Jimmy B

Here is what Anti-CTLA-4 blockage can do!!!! Melanoma..Jim Breitfeller

Source:FORBES.COM

On The Cover/Top Stories

Targeting Melanoma

Robert Langreth 10.15.07, 12:00 AM ET

A new arsenal of therapies is aimed at a widespread and lethal skin cancer.




"Until recently researchers had little clue what molecular changes drive melanoma's rapid growth. But that has changed in a flurry of basic biology findings. "In terms of understanding what makes melanoma tick, in the past five years there has been an utter revolution," says Keith Flaherty, a physician at the University of Pennsylvania.

In 2002 gene researchers in the U.K. discovered that two-thirds of melanomas have a mutation in a growth-promoting gene inside skin cells called BRAF. The mutation causes the BRAF protein to become stuck in the "on" position, so it constantly sends a signal to the nucleus that it is time to proliferate. BRAF blockers are now in early-stage human trials at Novartis and separately at Roche, which works with partner Plexxikon. AstraZeneca is in midstage trials with 180 melanoma patients for a drug that hits a related target called mitogen-activated protein kinase kinase. "Every company I know of is interested in this," says Plexxikon Chief Executive Peter Hirth.

Therapies that trick the immune system into attacking melanoma are further along. Such immune system boosters have the potential to treat many types of cancer, but melanoma is one of the prime initial targets because it is one of the few cancers known to go into spontaneous remission on its own, indicating a possible immune response at work. The immune system activator interleukin-2 helps 15% of advanced melanoma cases and cures a few, but it produces such devastating side effects that patients must be hospitalized.

Pfizer's drug tremelimumab and Bristol-Myers Squibb's ipilimumab are antibodies to a protein called CTLA-4 (cytotoxic T-lymphocyte antigen-4) that acts as an emergency brake to prevent killer T cells from attacking healthy tissue. The antibodies bind to the CTLA-4, found on a cell's surface, and shut off the brake. Killer T cells then attack the cancer cells. Both drugs are in final-stage trials on hundreds of melanoma patients.

Much credit for the concept goes to immunologist James Allison, now at Sloan-Kettering. In the mid-1990s he theorized that CTLA-4 might prevent the immune system from mounting an effective response against tumors. Others were skeptical. But Allison showed in 1996 that he could shrink tumors in mice by injecting them with antibodies to CTLA-4.

Both Pfizer and Medarex, a biotech firm in Princeton, N.J., subsequently produced human antibodies to CTLA-4 and began testing them in patients a few years later. In 2005 Bristol-Myers Squibb paid Medarex $50 million in cash plus up to $480 in payments contingent on the success of Medarex's antibody.

At a meeting of cancer specialists last June Bristol-Myers and Medarex reported their drug shrank tumors in 46, or 13%, of 356 melanoma patients. The Pfizer antibody shrank melanomas in 7 of 84 patients in a midstage trial. The success rates were modest, but cancer doctors say that some patients may have had delayed responses. In some people tumors started to regress months after they had been declared treatment failures, says Bristol-Myers Vice President Renzo Canetta.

UCLA's Ribas calls the response rates "very low" and cautions that the anti-CTLA-4 drugs are just a first step. But even if the drugs improve survival only minimally, they are likely to be approved, he says. Bristol-Myers and Medarex are expected to finish key trials this fall. RBC Capital Markets analyst Jason Kantor pegged the odds of disappointing results "relatively high" in a recent report and rated Medarex an underperform; if the response rate is under 10%, it would make near-term approval "iffy", he says. Side effects of the drugs can include inflammation of the colon, thyroid or pancreas, or other autoimmune problems.

One reason for the limited response rate may be that some patients' T cells do a poor job of recognizing melanoma. To improve this situation, researchers are combining new antimelanoma vaccines with anti-CTLA-4 drugs. The idea is that the vaccines will train T cells to spot cancer, while the antibody will make sure the T cells remain activated long enough to do their dirty work.

Sharon Belvin was one of the first to try such a combination therapy. In May 2004, just a week before her wedding, she had developed a melanoma metastasis in her left lung. Belvin was only 22. The tumor grew through her chest cavity underneath her collarbone. Various chemo drugs and interleukin-2 produced nerve damage and other nasty side effects and didn't solve the problem. By June 2005 she had tumors in both lungs and could barely breathe or walk. Then Wolchok put her in a trial testing ipilimumab with an experimental Medarex vaccine. After only four treatments the tumors started to melt away. They were gone by mid-2006. The Jamesville, N.C. resident has been off therapy for a year and is pregnant with her first child, a girl due Feb. 10 2008."




By the Numbers

59,940 annual cases of melanoma in the U.S.

8,110 annual deaths.

99% five-year survival rate, localized disease.

15% five-year survival rate, widespread disease.

Source: American Cancer Society



Take Care,

Jimmy B

Please give and show your Support..Melanoma..Jim Breitfeller

I am writing to you today for your help and support. As you know Melanoma therapy depends on cutting edge drugs. These drugs take years to go through the FDA process and most of them fail. This is what happen to Tremelimumab (from Pfizer) is an IgG2.
It was compared to the “gold standard” Dacarbazine as a single agent. The trial was setup to fail at the beginning. Pfizer wanted to go it alone instead of using the research that was published stating it would be better in combination of other therapies. This drug
saved my life.

We need organizations like the Abigail Allaince to help us in the quest to get these and other cutting edge drugs. Our lives depend on it. So won’t you please Donate today. If you have loveones that are fighting cancer, don’t you want them to have access to these cutting edge drugs?

Here is happen to one family “My husband fought Stage IV Mel for two years and one week... The last year was spent waiting for the Ipilimumab that never came...”

There are many stories like this.


Please give generously to this organization. You can use paypal on the website
Abigail Alliance website


Thanks for Caring

Jimmy B … Melanoma Missionary

Patient/Survivor of Stage IV Melanoma Cancer


Take Care,

Jimmy B

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space Melanoma.. Jim Breitfeller

There is Enough Room for Novartis, Bristol Meyer Squibb and Pfizer for each to take part in the Melanoma Space.

With ASCO Annual meeting coming up at the end of May, I believe that there will be some excitement around monoclonal antibodies. In particular, anti-CTLA-4 blockage treatment will be under the spotlight. What will the overall survival rates look like? Well, speaking from my experience, anti-CTLA-4 has prolonged my life for over 27 months where as a stage IV Patient, I was given 6 to 9 months. This could not have happen with out the extra help from Interleukin -2.

See, once the CD4+ T-cells activated, they need to grow and cross-prime the CD8+ T-cells. While activated T-cells secretes IL-2 at a certain concentration to help promote proliferation of the CD4+ T-cells. If there is too much IL-2 at the beginning of the immune response, I believe that the ratio of CD4/CD8/CD3 would be altered causing
the Tregs (CD4+ CD25 fox P3) to gain the upper hand of suppression of the immune response. A subset of CD4 + cells called CD4 + CD25 + regulatory T (Treg) cells that expresses Forkhead box P3 (Fox P3).

With just adding Anti-CTLA-4 first, It has been reported that it suppresses the T regs and pushes the balance towards an immune response. Once the immune response is in progress, the CD4+ T-cell is needed to co-stimulate the CD8+ T-cell. A source of these cofactors for effective CD8+ T-cell stimulation can be provided by CD4+ T cells that release critical amounts of IL-2.

Once the CD8+ T-cell is activated, and is cultured in the presence of Interleukin 2, it results in the development of effector cells which are cytotoxic to tumor cells.

This is why we the patients need the Pharmacitical companies to work together. Each therapy will not work alone as a single agent. The response rate are between 10 and 22 percent for each therapy. If you do a sequential treatment with the proper dosage and timing, you will see a synergistic outcome.


“There are three parts of the equation in a clinical trial. There’s who has control, who gets the reward, and who takes the risk. Patients take all the risk, they have no control, and they get no reward. Patients ought to be the ones driving the process and get the reward out of it and have the control, since they are the ones that take the risk.”

Greg Simons


If we are taking all the risk, shouldn’t we have a say in our Destiny?

“We need to all work together for the common good of the Melanoma Patients”

“We need to take greed out of the equation and just do what is right for humanity”


Take care

Jimmy B

Response from Pfizer!!!!! Melanoma ..Jim Breitfeller

Dear Jim,

Thank you so much for sharing your experience and thoughts.

Some patients have indeed experienced tantalizing responses after treatment with CTLA4 antibodies. Let me assure you that many of us in the field keep working hard on figuring out what explains those successes so that, armed with that knowledge, we can extend the benefit to many cancer patients. Experts agree that the way forward requires combinations of immunotherapies. Despite the many obstacles (scientific, regulatory, operational, intellectual property, economic, etc), Pfizer Oncology is moving decisively in that direction.

Warm regards,

Jesus

Jesus Gomez-Navarro, MD
Senior Director, Pfizer Oncology
Immuno-oncology Clinical Lead

Will the real Dosage of CTLA-4 Please stand up???Melanoma ..Jim Breitfeller

In tring to figure out why my therapy has worked so far, I came across a major discrepancy in dosage used compared to the clinical trial by Dr. Rosenberg. His maximum was 3.0 mg/Kg of CTLA-4 and I did 15 mg/Kg.

That is a 5 fold increase. I do know he used Ipilimumab and I used Tremelimumab (from Pfizer). They are both anti-CTLA-4. They both have a molecular weight of 145.4 kDa. and ~150 kDa respectively.

Half lives of 15 days and 21 days simular. So why the great Disparity in dosage. Could that be a flaw in the trial?


Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.

Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Haworth LR, Levy C, Kleiner D, Mavroukakis SA, Yellin M, Rosenberg SA.

Surgery Branch, National Cancer Institute, National Institutes of Health, CRC Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, MD 20814, USA.

BACKGROUND: Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma.

METHODS: Thirty-six patients received anti-CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses). RESULTS: Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti-CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis.

CONCLUSIONS: There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.


Hi Mr. Breitfeller,


As this study is currently closed, I am now in charge of follow-up so your request was directed to me (I worked with Heather Blair while she was here so I’m familiar with your case). Hopefully this excerpt from the full protocol (UPCI #05-120) answers your question, but please let me know if you need further information. (CP-675,206 is the technical name for anti-CTLA-4)


Patients will receive intravenous administration of CP-675,206 at a dose of 15 mg/kg on Day 1 ofevery 90-day cycle. For purposes of treatment visits and scheduling, each cycle is defined as a 90-day (3 month) period. Patients may receive up to 4 doses (4 cycles) in a 12-month period
until progression of disease or intolerable toxicity. At a minimum, scheduled visits for clinical study safety assessments will occur monthly. Additional visits may be necessary at the discretion
of the Investigator.

Long term exposure to CP-675,206 is not known to be required to sustain clinical benefit.

Patients will be allowed to receive up to 4 doses in a 12-month period. By mutual agreement

between the Investigator and the Pfizer Clinician, patients exhibiting clinical benefit after 12 months may be eligible to continue therapy with CP-675,206 up to 2 additional doses for patients with a

Complete Response or 4 doses for patients with a Partial Response or Stable Disease up to a maximum of 24 months after enrollment


So I contacted Dr. Oncologist

Dear Mr Breitfeller,



"I don’t think we can draw any conclusions yet based on your experience with a single dose. However, one thing we do know is that dose does matter. Last year at ASCO, we presented data showing that higher doses of ipilimumab (10 mg/kg) were better than 3 mg/kg or 0.3 mg/kg. I once again applaud you for your efforts to understand the excellent response which you have had."


So, If a higher dose is better, don't you think we should repeat the trial with higher doseage of CTLA-4

Jimmy B

April 14, 2008 Pfizer Anti-CTLA4 antibody trial for melanoma stopped for futility ... Jim Breitfeller's point of View

April 14, 2008 Pfizer Anti-CTLA4 antibody trial for melanoma stopped for futility.

"The Data Safety Monitoring Board halted the Phase III randomized open label trial comparing the Pfizer anti-CTLA4 antibody, tremelimumab, to "standard" (and generally ineffective) chemotherapy for metastatic melanoma. The Board has reported that there is no statistical difference between the primary endpoint, overall survival, between the two study arms. Further, statistical analysis reportedly shows that further examination is "futile" or basically unlikely to ever show a statistical difference.

This is a major setback for the hopes of many investigators and patients who felt that the anti-CTLA4 antibodies represent an encouraging potential new therapy for metastatic melanoma, a disease for which there is no universally accepted or generally effective therapy.

Will this completely halt all efforts by Pfizer to develop this drug in melanoma?"

Authored by:
Eric Whitman, MD, is a Medical Director of the Office of Grants and Research for Atlantic Health System in Morristown, New Jersey

The A3671009 Phase III trial in 630 advanced melanoma patients was investigating tremelimumab compared to standard chemotherapy, consisting of dacarbazine and Schering-Plough's Temodar (temozolomide).

I for one, Believe it works but it must be in combination with Interluekin-2. See the Phase III trial was a administered as a single agent.

With my first hand experience, I did one cycle of CTLA-4 therapy and then switched to Interluekin-2. Base on the immune system pathway, the CTLA-4 blockage only activated one signal by attaching to the B7 receptor. It is all in the Medical literature. To get the Immune system to respond, it needs second signal (cell to cell). That is done with IL-2. It is my belief, that there must be time in between therapies to set the pathway and the microenvironment in motion.

I hope Pfizer doesn't give up on this therapy.


Jimmy B