ROCHE (not Ariad) found that Iclusig can overcome resistance of tumors to targeted cancer chemotherapies. They published this finding in a top tier journal. Could adding low dose Iclusig to any of the above chemotherapies prevent drug resistance to the above chemos? Could adding Iclusig to the chemotherapy regimen of a patient whose tumor has already mutated and become resistant allow for the continued use (and therefore treatment) of the patient's cancer?
Partnership with Roche coming?
Scientific analysis: This journal is a top 3 cancer journal of the Cell press series. The authors of this article are from Genentech (Roche)... NOBODY from ARIAD is on this manuscript. So, they tested whether addition of ponatinib to tumor cell lines that have become resistant to drugs used to treat those tumors can overcome resistance to tumors.
They found an interesting phenomenon. In oncogene mediated cancers, they become addicted to the signaling pathway that is over-activated. When you give a drug like crizotinib or imatinib (CML), or vemurafinib (melanoma), the tumor starts to acquire additional mutations around the protein that is targeted by the inhibitor (like in melanoma, they acquire resistance to BRAF by acquiring Akt mutations or MEK mutations leading to continued oncogenic signaling). The theory of the paper is that activation of STAT3 in many cancer cells is the end product that the tumor needs to stay alive. This is mediated by two mechanisms, FGFs (fibroblast growth factors, there are 5 types of them) can directly activate STAT3, and PI3 Kinase/Akt signaling can also activate STAT3. They found adding ponatinib blocks both of these ways to activate STAT3.
Here are the drugs that addition of ponatinib in culture allowed killing of the resistant tumor cells the drugs to overcome cancer resistance: Lapatinib, Crizotinib, TAE684, and erlotinib.
Here are the pathways those drugs target: 1) EGFR, 2) HER2, 3) ALK, and 4) MET, as well as mutant 5) KRAS, and 6) MEK.
Here are the cancers this can be helpful in (corresponding to protein above):
1) Non small cell lung cancers (particularly squamous cell lung cancer 2) Breast and ovarian cancers 3) Some lung cancers that are ALK mutated and potentially ALK mutated lymphoid tumors such as ALCL (anaplastic large cell lymphoma). 4) Renal cell cancer, gastric cancers and non-small cell lung cancers. 5) Lung and head and neck SCCs, pancreatic carcinoma 6) Melanoma that has acquired resistance to vemurafinib
The data is good, Not fantastic, but good. I think they will need to add an adjuvant (IL-33 or IL-12) or add PD-L1 inhibition (ah hem, Roche, you gonna step up now?) eventually to get the results from good to great. This is a fantastic day for longs. The promise of INO will continue.
The clinical performance is AMBS's experience with the LymPro test. The analytic performance is BD's results with the tests, as BD was the outside lab paid to verify the results (prove another lab can get the same results as AMBS.)
I think if BD gets above a 90% specificity and a 85-90% sensitivity, this will be 0.25- 0.30 after the conference.
That's not how Quest works. They will pay AMBS a royalty for offering/performing the test on each test that is run, with a large up front fee (for exclusivity). Quest will get their share of the profit. Otherwise, what is the point for Quest offering/performing the test? In actuality, this is "going it alone." If AMBS would have given LymPro to BD, BD would have outsourced to Quest to make it available to everyone. I believe AMBS going it alone means, AMBS cutting out the middle man, and just offering it through Quest themselves rather than through Quest vis a vis BD. When money was tenuous (prior to Lincoln Capital money), AMBS's only option was going through a middle man and splitting profits 3 ways, so that they could get the money they needed to survive.
AMBS could never truly "go it alone," in the purest sense of the word, because that means they would have had to open up multiple CLIA certified labs across the country so that doctors offices could send them specimens.
The key here is making Lympro available to 313.9 million people in America. Only Quest or LabCorp could do that. Otherwise, AMBS would have to drop their lab slips to every doctors office in the country and tell them about the test, so that the doctor can run lympro. They, I'm sure, are looking at similar partnerships in Europe.
After the test goes public, it will be on every Quest lab slip (if Quest truly is the partner), and I am sure it will be publicized in the news as the first blood test for Alzheimers. There will be both good and bad PR with people claiming it works, and people refuting the claims of AMBS. Be prepared.
If you want your CLIA certified blood test to be available to a huge population, you need to go with Quest or LabCorp. Anytime I send a person to get their blood drawn, I ask them what do you prefer: Quest or LabCorp? I never say, go to BD. They will run your test for you. Basically to have Alzheimer's test on a Quest or LabCorp form that any doctor can check off, then the patient goes and gets their blood drawn is huge.
BD doesn't have that available. A partnership with Quest a partnership with BD... And Its not even close. For the purpose of LymPro is what I am talking about.
Very simple. Gerald discovered MANF and patented the gene,protein, and applications in disease. I can go in and patent MANF for use in wrinkle creams or in a car wax or whatever. My specific patent will fall under the umbrella patent of MANF, but if anyone wants to develop MANF in car waxes (including AMBS) they would have to get the license for the specific patent from me. I will get part of the money and AMBS would get part of the money from the actual people who make the car wax
For Urano, a scientist to go after MANF, a similar but unrelated protein, as a GENETIC therapy TO CORRECT cells in a genetic disease where the DISEASE IS CAUSED BY A MUTATION IN ANOTHER I REPEAT ANOTHER protein, wolframin, means the data with replacement therapy/treatment in animal models is better than replacing the mutant protein. It could be a dominant negative (scientists, you know what I am talking about) effect of mutant wolframin which would make any additional wolframin useless because of the dominant effect of the mutant protein.
Last part about the dominant negative is speculation on my part. First part with all caps for emphasis is speculation from Urano... Or is it... He said he had data coming out which would help him choose/decide between replacement therapy with wolframin or treatment with MANF for Wolfram's syndrome.
Looks like he chose.
I don't know what you mean by "A Wolfram's trial will use less MANF than an RP trial". Both are chronic diseases, so both will require repeated doses (after MANF is proven to be safe, etc). The pathogenesis of eye disease in Wolfram's is similar but not the same as RP, ZB.
RP is heterogeneous and many different mutations can cause RP. Its thought that the retina degenerates because of toxic accumulation of proteins and other things from degenerated rods and cones in the retinal pigmented epithelial (RPE) cells. It causes blindness because the retina becomes completely dysfunctional.
Wolfram's is caused by a defect in WFS1 gene (encoding wolframin). Loss of WFS1 causes blindness because the optic nerve atrophies. The retina is fine. Also, even though the Wolfram's patients have diabetes, they don't seem to get diabetic retinopathy.
I do concur that if they treat Wolfram's with MANF, it will be local eye treatment first, but not for retinitis pigmentosa. They will be treating the optic nerve dysfunction. If that is successful, they may try targeted therapy to the beta cells of the pancreas, or systemic therapy.
It will be like the Biomarin approach... Treat rare diseases because nobody else is doing it.
The only difference is, if MANF can treat retinitis pigmentosa, it may be a useful therapy for other forms or retinopathy. If it helps with retina degeneration, it may help with neuron degeneration in Parkinson's, Alzheimer's, and Huntington's. Also, if it can help with Wolfram's associated diabetes, it may help with protecting beta cells in type 1 or type 2 diabetes.
Zarc, you're funny but I respect you. I've been long since last August and added many times along the way, and I think you and I may have even argued as you used to bash to get in cheaper. To me (and others on this board) you are one of the "new longs" that you speak of. I saw in AMBS what you just posted above last August... But I thought it would happen quicker than it did (invested in INO in June, and that one happened pretty quickly). You obviously had much better timing than I did with AMBS, and you made money flipping, whereas I just held.
Here's to continued prosperity as you describe above for the next few months.
That is one of the indications on the back burner for MANF. Use as a perfusion solution in organs removed from patients prior to transplantation to preserve them. MANF protects the heart in animal models of heart ischemia (heart attack). The main injury there (and when an organ is removed from the body is ischemia repercussion injury
Not much. I am going to take a scientific realist approach.
They used a genetic Alzheimer's like mouse strain that overexpresses mutant amyloid precursor protein, which mimics several aspects of Alzhemier's because they get amyloid plaques.
However human Alzheimer's is more complex, and drugs that have targeted amyloid precursor protein or the processing of amyloid precursor protein by beta secretase (BACE-1) or gamma secretase (the proteins that cleave and modify amyloid precursor protein to form beta-amyloid plaques) have either led to no improvement in phase II trials, stoppage due to severe liver toxicity, or actual worsening of Alzheimer's when compared to doing nothing.
So why would using an antisense therapy to the RNA of amyloid precursor protein have an effect in human disease? Well obviously in an animal model where the disease phenotype depends on the over expression of amyloid precursor protein, knocking down the protein with antisense will improve the disease.
But in all actuality, the human disease is caused by many problems acting in concert, that we don't quite fully understand.
That's why the paper is published in Journal of Alzheimer's Research and not Nature or Science. It is an incremental advance at best, and likely won't amount to much.
I hope I am wrong for the patients' sake, but I am not getting my hopes up yet.
All gene therapy approaches thus far to correct a mutation/gene deletion have targeted the mutant protein. Urano thinks supplying MANF via gene therapy is better than supplying wolframin to patients with mutated wolframin. Do you see that yet? I do not know of one instance where a scientist has tried to do that yet. For instance, boys with SCID by mutation of adenosine deaminase. People give them adenosine deaminase gene therapy to fix their lymphocytes. Not MANF. That's why it's a huge deal. Urano has stated he is testing different proteins in his wolframin mice. He had to like what he saw with MANF
This manuscript has an expanded marker list including CD28. Although CD28 was not as useful as CD69. I agree, though, that if the new IP is better than 91/92 (by BD in the analytical performance abstract) that this will be a home run test, and a test that will be the gold standard (for now) for diagnosing Alzheimer's. The reason I say for now is that better tests will likely become available in 3-4 years. Remember, there is nothing else available until then so lympro will be the best. Then I don't care what happens to Lympro. Because eltoprazine and MANF will be getting in gear/goin full swing and that is where the real money is with this company.
Lympro is a temporary money maker to get the company the money needed to progress with the rest of the pipeline. Let's see what partnership news we get by year end for MANF and possibly eltoprazine
Your letter did not include the fact that the studies were completely performed within the Genentech group of Roche, and Ariad Pharmaceuticals had nothing to do with these studies. . Can you add that fact to the blog post, because knowing AF and Cramer, they will find some way to spin a study published in a Cell Press journal negatively
I am long since December 2013. Bought in at 6.60. Last Tuesday evening, PBYI announced positive phase III data on neratinib, a small molecule inhibitor of Her2 and skyrocketed over 200% on Tuesday after market and Wednesday during regular trading.
On Wednesday morning, someone with a fake twitter account posted a fake rumor that ARIA was going to be bought out, sparking a 5% increase in ARIA stock price.
It was found out that the account was fake, and the account was shut down. However, shorts were scared, and some started covering resulting in a +15% gain on Wednesday trading. On Thursday morning, ARIA share price gained another 11% during its intraday high, but by the end of the day, the share price was only up ~5%.
So here is my problem. On Thursday, the golden cross was imminent on the stock chart (The 50-day MA crossing over the 200-day MA), and was going to happen on Friday. This could have sparked a huge move in the stock, and trapped the 25% shorts in the stock on ANY news, seeing the moves of the two days before.
But did ARIA have any news to share with shareholders? YES!!!! An article published THAT DAY by Genetech/Roche scientists was published in a top cancer journal Cancer Cell, showing that Iclusig can be combined with many drugs targeting other pathways, including Her2, EGFR, MET, ALK, and prevent resistance to the pathway inhibitors targeting those pathways.
An announcement of this news on Thursday would have provided a way to break out of this downward trend in the stock price.
So why didn't Ariad even mention this publication? Is Harvey incompetent? Do they not care about shareholders? Do they want shorts to continue making huge amounts of money, while people like us shareholders suffer and hold the bag?
I am long for the science and the potential of Iclusig, but management needs to be more proactive to help shareholders out.