I think Orkambi will be approved, not due to excellent efficacy, but more because there is no alternative treatment for CF patients. GLPG's alternative to Kalydeco currently is in phase I, preclinical data are much better than Kalydeco's. End of year we will know first clinical data, if positive in less than 2 years it will substitute Kalydeco., Kalydeco is the back-bone of VRTX CF franchise, without it Orkambi and VX-661 are at risk. I will not exclude a repeat of the HCV disaster .
On approval and announcement of price of Orkambi I will unload most of my VRTX shares, which I have held for quite some time (average cost basis
that's VRTX key problem: poor decision management, too many compounds are lingering in pre-clinic. VRTX desperately needs clinical expertise and leadership.
GLPG has developed various assays to evaluate the impact of corrector molecules on the rescue of CFTR-F508del that allow insight into the influence of each component in combination cocktails. Info is available at GLPG website. Wonder how these assays compare to Van Goor's HBE assay.
in my interpretation of all available data VX-661 is superior to lumacaftor. On approval of 661 lumacaftor will become obsolete. Or do you see patients that will benefit more from luma than from 661? The future is ivacaftor+661 and iva+661+second gen corrector.
So in my view VRTX ought to focus on 661 and negotiate with FDA on as little as possible extra trials for lumacaftor.
cancer is a pretty crowded field, phase I trials don't excite investors, no matter how attractive the mode of action might be, all that counts is good phase II/phase III data, so it will take about two years before VX-803 and/or VX-970 will contribute to VRTX valuation.
I assume Orakambi will be approved. But it will have a short life. VX-661 is superior. Once approved, I guess VRTX will drop lumacaftor. Given the discussion at adcom meeting lumacaftor is a tainted product.This is the second short lived Vertex blockbuster. It will suffer the same fate as the HCV product.
VRTX seems to have problems selecting the most promising product from their pre-clinical compounds. Same might be true with the cancer candidates VX-970 and VX-803 which are both recruiting patients for phase I studies. VX-803 is recruiting since late 2012! Obviously they don't trust in 803 and want to see how it compares to 970.
A second generation corrector had been promised to be in the clinic in late 2014. Now VRTX talks about several correctors to be tested with iva and 661. Same picture: problems in selecting the most promising candidate. Is that the reason why Mueller had to quit? If that's the case his successor is the wrong guy. VRTX need more experienced clinical experts, not rocket scientists.
I am, too, still puzzled by fda's line of argumentation. Do I get it right that the combo trials show efficacy, but fda supposes that this efficacy is due to ivacaftor alone? If so, they ought to expand iva labels and VRTX is free to treat the expanded patient population. As fa as I know fda ought to be looking at efficacy and safety only, not why there is efficacy.
bottom line: fda has to approve the combo.
the fda presents results from a statistical analysis, why doesn't VRTX outline their own statistics? that would have been a more appropriate response, I sure do hope they will do that next tuesday.
I agree with your assessment, but I am disappointed by VRTX insubstantial response to fda criticism:
"excerpt from the response that was received.
1. The nature of the molecular defect caused by the F508del-CFTR mutation is well established and LUM is essential to address the underlying cause of disease in patients homozygous for the F508del-CFTR mutation.
2. Nonclinical data quantitate the contribution of each drug to the improvement in F508del- CFTR function, and show that there is minimal effect of IVA alone while superior improvement in F508del-CFTR function is provided by the combination of LUM and IVA compared to either agent alone.
3. The improvements in F508del-CFTR function in vitro translate to the sweat chloride response in subjects homozygous for the F508del-CFTR mutation, and confirm that superior improvement is provided by the combination of LUM and IVA compared to either agent alone.
4. Clinical evidence demonstrates that LUM/IVA combination therapy is highly efficacious and clinically superior to IVA monotherapy in homozygous F508del-CFTR subjects, confirming that LUM is an essential component of the combination product.
A robust Phase 3 clinical program demonstrated rapid, consistent, and sustained improvements in respiratory and systemic parameters with LUM/IVA combination therapy, notably including marked reductions in severe pulmonary exacerbations. LUM/IVA was well-tolerated, with a favorable safety profile in more than 1000 subjects. This positive clinical benefit/risk profile supports approval of the LUM/IVA combination therapy in patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene. In contrast, as indicated in the Kalydeco label, IVA monotherapy evaluated in this population did not show a consistent and meaningful clinical benefit."
from the briefing summary:
However, when the results of study 770-104 are now evaluated in the context of the relatively small treatment effects observed in CF patients who received LUM 400mg/IVA 250mg in studies 809-103 and 809-104, the question arises both whether lumacaftor contributes any added benefit over that of ivacaftor alone and whether ivacaftor monotherapy itself has a positive treatment effect that would have been able to demonstrated if study 770-104 were powered for efficacy similar to studies 809-103 and 809-104.
As such, an important discussion for the PADAC to have on May 12th is not only whether treatment with LUM 400mg/IVA 250mg demonstrates statistically and clinically significant improvements in CF-related endpoints compared to placebo but also whether treatment with LUM 400 mg/IVA 250 mg FDC q 12h offers additional benefit over ivacaftor alone.
This is an important discussion in light of the large population of CF patients affected and lack of alternative treatment options for cystic fibrosis patients homozygous for the F508del mutation in the CFTR gene. At the PADAC meeting, Vertex will present an overview of the clinical program, which will be followed by the Agency’s presentation of the efficacy and safety data. Please keep in mind the following draft topics that will be discussed and deliberated upon following the presentations.
"The similarity of the nominal treatment effects in study 770-104 for 150mg ivacaftor alone and studies 809-103 and 809-104 for the LUM 400mg/IVA 250mg dose raised the question of whether lumacaftor contributes any added benefit over that of ivacaftor alone and begs the question if study 770-104 were powered similarly to studies 809-103 and 809-104, would the treatment effects for ivacaftor monotherapy also have been statistically significant, especially in relation to improvements in lung function and reductions in CF pulmonary exacerbations. In the absence of an ivacaftor alone arm in the LUM/IVA combination studies, FDA conducted
￼￼￼￼￼￼￼￼￼￼￼￼￼￼￼￼￼￼statistical comparative analyses between ivacaftor monotherapy and the proposed LUM 400mg/IVA 250mg combination product dose in an attempt to determine whether the addition of lumacaftor to ivacaftor contributed to the overall treatment effect of the combination for lung function and pulmonary exacerbation endpoints. The results from these analyses could not exclude with any level of confidence that LUM/IVA was different from ivacaftor, i.e., the possibility that LUM/IVA not was equivalent to ivacaftor with respect to changes in ppFEV1 and pulmonary exacerbations."
is available at fad website, focus of concern is efficacy:
"Summary of Efficacy
Overall, the results from LUM/IVA studies 809-103/104 demonstrate that, compared to placebo, LUM 400mg/IVA 250 mg q12h had a small but statistically significant effect in terms of the primary endpoint of absolute change from baseline in PPFEV1 at 24 weeks with a difference from placebo of 2.7-3.0%. Improvement in the secondary endpoint relative per cent predicted FEV1 was also statistically significant in both studies. The secondary endpoints change in BMI and CFQ-R respiratory domain failed to show substantial evidence of a treatment effect. LUM/IVA response rate and number of pulmonary exacerbations demonstrated nominal improvements but are not considered statistically significant since the prospective statistical testing hierarchy stopped before the comparisons were made.
Results from study 770-104, originally conducted for the original ivacaftor monotherapy program demonstrated a small statistically significant change in sweat chloride compared to placebo. While nominal treatment effects for lung function endpoints and pulmonary exacerbations were comparable to those for the LUM/IVA combination, the study was not powered for efficacy and statistical significance was not achieved."
normally the FDA publishes a documentation a few days ahead of the adcom meeting. Therein it describes potential concerns with the drug to be discussed. This documentation ought to be published tomorrow.
about a year ago researchers from the Gladstone Institute reported that VX 765 offers a new approach in treatment of HIV. There were speculations on corresponding phase II studies to be conducted by VRTX. It never happened. VRTX pipeline beyond CF remains a conundrum.
VRTX must have done a great job in the negotiation with FDA:
Thanks for the question. It's a little bit different in the US than Europe so it's important, I think, that we clarify that. In the US the safety PK study, which is fully enrolled now, we believe -- we know -- is the only study that we're going to need -- assuming, of course, it's successful -- to apply for approval in the US."
no efficacy trial, just PK !! - that's a no-brainer !!!
that does not mean that VRTX will receive that much:
"According to some number-crunching from a pair of Prime employees, the Vertex med--if priced roughly on par with solo Kalydeco--will cost the PBM $367,000 per year with medical and pharmacy costs included"
most likely the VRTX combo price tag will be about 300k
would be nice to get comments on non-CF pipeline drug candidates but I guess VRTX will not release corresponding news. Oncology candidates 803 and 970 are just recruiting patients for phase I studies (VX-803 trial already started back in 2012!), there are no trials in other indications yet.