this book really is worth reading for all that are interested in insights on Vertex! fascinating facts on the discovery of cf compounds and lots more.
Ian F. Smith - Chief Financial Officer and Executive Vice President
And Robyn, on types of transactions or collaborations that we're looking for, clearly, our focus right now is on what the VX-509 and VX 787, 787 being the molecule for, potentially, to help with flu. So we'll continue to have discussions. In particular, we've just recently received the 24-week data for VX-509, that allows us to continue those discussions. And as those progress through this year, we'll advise you appropriately.
Adam Feuerstein@adamfeuerstein$VRTX no swagger, no cockiness from these guys. The magnitude of the importance of Traffic/Transport weighs heavy. #JPM14
It should be noted that while several rounds of analogue synthesis and testing were required to go from the hit VRT-532 to drug VX-770, compounds were strictly assessed for an effect on ion transport in mutant CFTR- expressing cells, rather than CFTR binding or other assays of isolated CFTR protein. While ivacaftor is unable to restore normal CFTR function to cells with the ΔF508 mutant CFTR, due to its dual defects in trafficking and gat- ing, it restores normal CFTR function in cells with G551D, as this mutation only affects gating.107 For this reason, iva- caftor was moved into clinical trials for the treatment of patients with cystic fibrosis with the G551D mutation and found to improve not only sweat chloride measurements, reflecting the improvement in CFTR function, but also lung function and nutritional status, both important clinical parameters, leading to its approval for the treatment of patients 6 years and older with this mutation in January 2012.103
This would represent a triumph for target-based drug discovery had ivacaftor been developed with the CFTR as a target, based on structural studies of the CFTR protein— developing a precise molecular mechanism of action to repair the defects in the mutant channel. Instead, ivacaftor represents the development of a genotype-specific person- alized therapeutic using phenotypic drug discovery meth- ods and, as such, provides a counterexample to the widely held assertion that personalized medicine is only possible using the target-based drug discovery approach. Indeed, the exact mechanism by which ivacaftor exerts its beneficial effects on CFTR gating is still unclear, and although recent work suggests direct action on CFTR itself,108 this was not by design. Phenotypic drug discovery can yield targeted, personalized therapeutics.
copied from "Clinical Relevance of Target Identity and Biology: Implications for Drug Discovery and Development" J Biomol Screen 2013 18: 1164
Recent advances in the treatment of cystic fibrosis provide an example of how personalized medicine can occur with- out knowing the precise target of a novel therapeutic and can be applied with limited provider understanding of the biology at work. Cystic fibrosis is a fatal genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a mul- tifunctional protein whose primary role is as an adenosine triphosphate (ATP)–gated chloride channel essential for normal salt and fluid transport in multiple organs, including the lung.102 The discovery of the CFTR gene in 1989 prompted the development of therapeutic approaches to restore normal CFTR function, either through replacement of CFTR through gene therapy or by improving the function of the mutant CFTR.103 The latter is complicated by the fact that different mutations predictably affect the CFTR protein and its function in different ways.102,104,105 While the most common CFTR mutation, ΔF508, results in both impaired trafficking to the cell surface and problems with channel gating, other less common mutations, such as G551D, affect only channel gating.104–106
Using cells expressing mutant CFTR genes, Van Goor and colleagues106 at Vertex Pharmaceuticals screened 228,000 compounds for compounds that would enhance CFTR function using a cell-based fluorescence membrane potential assay. Specifically, they screened for two types of compounds: CFTR correctors, which improve ΔF508 CFTR trafficking, and CFTR potentiators, which improve ΔF508 CFTR gating at the cell surface. From the CFTR potentiator screen, hit selection and lead optimization yielded ivacaftor (VX-770).
" I think a key study deliverable would be determining what that upper limit is."
you are right, two important data to be determined in clinical trials are NOEL (no effect level) and MTD (maximal tolerated dose). So in principle it is not negative to have a dose that is above MTD (i.e 400 mg for VX 135), the development consequently has to focus on 100 mg and 200 mg.
Almost one year of Kalydeco
Decided it was time for a summary post about my new health on Kalydeco.
I have been on Kalydeco for 11 months through the Named Patient Program, a program where Vertex supply Kalydeco to those who are very unwell. Kalydeco is the first medication that treats the underlying cause of Cystic Fibrosis in patients with the G551D mutation.
Before Kalydeco my lung function was 41% and very unstable. I was in hospital every 3-4 months. I was on medications that treated the CF symptoms; these were becoming less effective as I grew older.
For the last 11 months my FEV1 has been stable at approx 70%. This is amazingly stable compared to before; for 20 years my lung function has varied up to 20% from month to
month, now I am stable for the first time in my life. This is my highest in 3 years.
I have stayed out of hospital for 11 months, which is a 20 year record (I am currently on IVs for mostly prophylactic reasons, I will post about this soon). Before Kalydeco I had over 60 hospital admissions, equalling 3 years of my life.
Every aspect of my health has improved with Kalydeco, I have gained 6kg, I can run up stairs, I can sleep without coughing and I’m attending uni more often. My sweat test results have improved from 102 to 40. This is much lower than the point (60) associated with the CF diagnosis.
Previously I did not plan further ahead than 5 years. At the age of 28, with a life expectancy of 37, I knew transplant was edging closer. Thanks to Kalydeco I now don’t have to plan around hospital and CF, instead I can plan to have a family, a career and to grow old with my lungs.
here is how Vanda got fanapt approved.
The strategy has worked for Vanda in the past. After FDA rejected the schizophrenia drug Fanapt, Vanda "engaged" a regulatory consultant -- also never identified -- to assist the company in convincing the agency to change its mind. The FDA ultimately approved Fanapt and for his efforts, the regulatory consultant was paid a "success fee" totaling $6 million, according to Vanda's SEC filings.
"sofosbuvir in combination with RBV and peg-IFN for treatment-naïve patients with genotype 1, 4, 5 and 6 HCV infection."
this is not an all-oral combination! just like incivek it relies on inf - it took Gilead quite some time to admit that the all-oral combo so far is just hype!
VRTX still is one of my core holdings, I am still confident that it will continue its climb, there is substantial stuff in the pipeline that makes it worth holding.
a stock that I have been successfully playing with over the years is TTNP, pdufa for its drug is 4/30, so just a couple of days away, I am betting on at least a doubling of its current share price in case of a positive decision by FDA, which I consider most likely.
disclaimer: do your own due dilligence, do not rely on recommendations by anonymous posters!
Sentiment: Strong Buy
seems to be an extension of previous studies:
"This study is designed to evaluate the long-term safety and tolerability of VX-509 in subjects with active rheumatoid arthritis (RA) on DMARD therapy. This study will enroll subjects who completed a previous designated study with VX-509 (e.g., Study VX12-509-103)."
since VRTX intends to outlicense VX-509 it may well be that potential partners have ask for more safety data.
there is not enough data to make any conclusion, the trial will continue because "the observed SVR4 rates exceeding the predefined threshold of 60 percent and the absence of significant safety issues. Enrollment of the remaining 600 patients in ION-1 is now underway."
because it says "Exercise Price of the Warrants may be satisfied" and not "Exercise Price of the Warrants has been satisfied"
this is from the 8k:
(i) the Exercise Price of the Warrants may be satisfied by a Lender, without limitation, through a reduction of the principal amount outstanding under such Lender’s Note with such amount being applied in the reverse order of repayment provided for in Section 2.2(a), and (ii) a Lender shall not be required to physically surrender Warrants in connection with a partial Exercise of the Warrants held by such Lender.”
if warrants had been exercised there would not be a need to refer to "a partial Exercise of the Warrants held by such Lender.”
what makes you think the warrants have been exercised? All the 8k says is that in case the warrants are exercised the debt will be reduced, also the 8k mentions that this applies to partial exercise of the warrants as well
Big Pharma first grew enamored with China for its arbitrage opportunities: Cheap labor, abundant resources and manageable regulations. Now, however, the country is churning out Ph.D.s faster than the U.S., and its incoming government wants to transform China into a knowledge-based economy. Peter Mueller, Vertex's executive vice president for R&D, said we're on the verge of a golden age in Chinese pharma innovation, and his company has gone from looking to the country for manufacturing to partnering with its universities, contractors and drugmakers to better develop treatments suited to its unique and diverse population.
source: fierce biotech
Leiden on VX-787 in an interview:
The company will look for outside funding for the flu molecule VX-787. “It’s not a specialty disease,” Leiden said. “We’re going to find external funding” for that molecule, and stop funding it internally, he said.
but no info on results of the phaseII study!
re VX 787: he mentioned it only once, telling that data will be available shortly, no hints on how to continue with that drug