Prion-like behaviour and AD

Corrupted Proteins Spread Disease/ By Ed Yong | June 18, 2012

A protein fragment involved in Alzheimer’s can seed new clusters throughout the brain, pointing to prion-like qualities of the disease.

http://the-scientist.com/2012/06/18/corrupted-proteins-spread-disease/

ORR in ITT population is 22.9% in the FDA analysis, and in the 'truly' unmet need (patients unresponsive or intolerant to approved agents) is above 20% in all subgroups, so I think the efficacy demand is met but seems it may not justify the risk for cardiotox in the FDA's view and chances are quite high they will want more data.

Brivanib is a selective receptor tyrosine kinase inhibitor that targets VEGF-R2 and FGF-R1/2.

Pegdinetanib is a highly specific VEGF-R2 inhibitor.

Cediranib inhibits all three vascular endothelial growth factor receptor (VEGF-1,-2,-3) tyrosine kinases and has activity against c-Kit, PDGFR-ß and FIT-4.

Pazopanib selectively inhibits all three VEGFRs, c-Kit and PDGF-R.

Lenvatinib is a specific VEGF-R2/3 inhibitor.

Motesanib selectively targets and inhibits all three VEGFRs, PDGFR, kit, and Ret receptors

I wanna hear what you were not too whacked out to say :)

Lapatinib is a reversible, dual inhibitor of EGFR/HER2 while the others are irreversible, pan-HER TKIs, so they should be more potent (more complete and sustained inhibition), but also with more/higher grade AEs I expect. It is not yet known which is the more potent, selective, less toxic agent plus there's the question of the best combo and in which patient populations. For instance, one combo Puma is testing (and Boehringer is not), is with Torisel, which make a lot of scientific sense but you never know if for real plus it could be too toxic.

JNJ submitted sNDA filings for Zytiga in chemotherapy-naive CRPC:

http://www.investor.jnj.com/releaseDetail.cfm?ReleaseID=683472&year=2012

Teva will try and get a formulation patent.

If approved, and I think it will, the thrice-weekly Copaxone will be strongly promoted by Teva but I think they might have too little time to convert before it goes generic.

Bet it would be easier to co-formulate Fovista with AGN's DARPin :)

Do you think patients will have a say? I mean, if they ask for the more convenient formulation. Wonder what the pricing would be.

Also data are for one year so far.

I don't know of any. Aptamers can be easily modified chemically with a variety of functional groups and can bind to antibodies (this is used in the design of an aptamer-antibody hybrid sandwich ELISA), so while not trivial, I don't think it's impossible.

Probably.

Amgen/Daiichi AMG 888 is one such antibody currently in phase II in NSCLC similar to MM-121 as well:

http://clinicaltrials.gov/ct2/show/NCT01211483

Agree that long term Eylea/Fovista should work just as well but if Roche or Novartis buy Ophthotech they can coformulate Fovista&Lucentis and have a unique new product.

It has to be the trial cause it's the only one testing combo with Tarceva in NSCLC. Seems likely that MM121 would at least prevent one escape mechanism for tumor growth under the pressure of anti-EGFR therapy, via EGFR/ErbB3 heterodimers. Wonder if overexpression of ErbB3 and/or heregulin in tumors from naive patients could be a biomarker for treatment success with MM121 or perhaps it only develops after resistance to treatment has occurred.

Well, it makes picking up the diamonds from the piles of dirt more challenging.

Abraxane's phase I/II pancreatic results were published here:

http://jco.ascopubs.org/content/29/34/4548.abstract

Looking at data from GSK's dabrafenib monotherapy in phase III melanoma trial, efficacy seems similar to that of Zelboraf but AEs seem better.

http://abstract.asco.org/AbstView_114_96291.html

One more important detail on BMS-936558, BMY’s anti-PD-1 cancer drug:

http://abstract.asco.org/AbstView_114_91353.html

Factoids—There are over 4500 disorders with known molecular basis and only 250 of them with therapy.
Source: NIH Director Francis Collins talk (

! )

I haven't heard the call either but think I found the problem after looking at the two tables here:

http://services.corporate-ir.net/SEC.Enhanced/SecCapsule.aspx?c=142125&fid=8226167

Efficacy Results came from 612 patients while Most Common Adverse Events data came from 832 patients, meaning efficacy analysis wasn't done on ITT population. No idea if the FDA will accept their analysis.

I knew something was missing in Peter's answer

AUXL/BSTC/Xiaflex data in Peyronie disease. Stock is up 10% pre market.

http://www.reuters.com/article/2012/06/04/auxiliumpharma-study-xiaflex-idUSL3E8H45YY20120604?type=companyNews&feedType=RSS&feedName=companyNews&rpc=43

MACK's MM-121 should work quite similarly to pertuzumab imo, and the latter is likely to be approved in a few days.

Eisai also has one c-MET inhibitor in a bunch of phase I/II studies (looks like phase II are all combos)

http://clinicaltrials.gov/ct2/results?term=E7050

Peter, don't you think there's a risk that the PREVAIL trial of MDV3100 in chemotherapy-naive CRPC patients will not hit stat-sig on OS because of crossover?

Lilly has c-MET program with one MAb in phase II and one inhibitor in phase I:

http://newsroom.lilly.com/releasedetail.cfm?sh_print=yes&releaseid=661261

I found the data from phase II of the two BRAF inhibitors and with the caveat of comparing results from different trials, they seem to be in the same ballpark.

BRIM2 phase II data for Zelboraf (vemurafenib)

http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=84075

BRF113710 phase II study of dabrafenib (GSK2118436)

http://www.gsk-clinicalstudyregister.com/result_comp_list.jsp?phase=Phase+2&studyType=All&population=All&marketing=All&compound=dabrafenib

While it is already known that synonymous changes in codons are not so silent as once thought, you are rightly wondering about the importance of the phenomenon. Not enough work has been done yet but this one by Chen et. al. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962641/?tool=pubmed found that nsSNPs and sSNPs shared similar likelihood and effect size for disease association.
One note on the the measurement of relative synonymous codon usage (RSCU) used in the paper before I go on:
RSCU values show the number of times a particular codon is observed relative to the number of times that the codon would be observed if all the codons for a given amino acid had the same probability.
Change in RSCU = deltaRSCU, might be associated with a change in local translation elongation rates i.e. the speed of translation. So it represents only this parameter and does not capture others like the location of the mutation, failure of splicing, exon skipping, mRNA stability, microRNA binding, all of which can also be crucial.
My view is that the surface has only been scratched but I think synonymous changes in codons can sometimes have a dramatic effect on phenotypic outcome.

I have high hopes for the anti PD-1 class not only from the scientific point of view but also since a friend has been enrolled to the CureTech/CT-011 phase II metastatic melanoma clinical trial.

TEVA was another one of the few stock that rose yesterday (+2.89%) perhaps on the stock move from NASDAQ to NYSE and a possible tax relief

http://www.globes.co.il/serveen/globes/docview.asp?did=1000753153&fid=1725

This part is present in Jellybean's post but a bit hard to notice

This is a more convenient way imo, of looking at Table S-2 from the paper:

http://www.nature.com/nrg/journal/v12/n10/extref/nrg3051-s2.pdf

If he has a few risk factors for atherosclerosis in addition to resisting statins therapy, I have a bad feeling he might lose a lot more than just credibility...

Here's a short-easy-summary on the issue that further directs you to the actual Nature review, written by researchers from the Center for Biologics Evaluation and Research (the review itself isn't free but I think the summary is good enough):

Synonymous (“Silent”) Mutations in Health, Disease, and Personalized Medicine: Review

http://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/ucm271385.htm

Thanks for the pointer, I've skipped it as the abs. isn't available yet. I don't think GSK ever presented PFS and OS data from phase II, so are you talking about phase I data?

GSK will present data from phase III of trametinib but its value in monotherpy is low

http://abstract.asco.org/AbstView_114_96304.html

The conbo is in phase III but i could only find an update from phase I/II to be presented in ASCO

http://abstract.asco.org/AbstView_114_97785.html

Apropos to Zelboraf, the GSK BRAF inhibitor - dabrafenib has shown activity in brain metasteses, something I don't think was seen with Zelboraf:

http://abstract.asco.org/AbstView_114_97727.html

#msg-54584465 and the following emails :)