Thank third! It's clear to me from the abstract you posted that the use of the term "null responder" will be redefined by the specialists treating the treament naive hep C population with boceprevir based therapy, as those who respond poorly to SOC in the lead-in 4 weeks prior to adding boceprevir.
Since none of the telaprevir clinical trials used this protocol in the treatment naive population, there can be no direct comparison of telaprevir vs. boceprevir in the Phase 2 studies (PROVE 1 and 2) or the ongoing Phase 3 studies involving the treatment naive patient group. In the prior SOC treatment failure patient group, there is only one arm in the ongoing Phase three telaparevir clinical trial that looks at the effect of a lead-in of four weeks of SOC prior to adding triple therapy for the next 24 weeks, and then continuning SOC for another 24 weeks.
Final Prove 3 results being presented at AASLD this month will show in detail how well telaprevir works in prior SOC treatment failure patients, witout the benefit of a four week lead in treatment with SOC. Also, Study 107, whose results should be available soon, will also confirm telaprevir's efficacy without the need for SOC lead in treamtment in the various types of prior SOC non-repsonders.
Finally, Study C208, will show telaprevir's effectiveness in treatment treatment naive patients with twice a day dosing compared to three times a day dosing requried with boceprevir (an important differentiating advantage for Vertex).
Bottom line: Boceprevir based treatment will be touted at AASLD as efficacious in treatment of hep C, and you are right that the term 'null' in treatment naive patients, simply refers to a poor response in the first four weeks of lead-in SOC therapy that are required to get an optimal response from boceprevir based therapy that lasts 48 weeks, since it is a weaker agent than telaprevir.
The abstract does not address the number of patients requring EPO to complete therapy. The fact that SGP has been reported to be planning a Phase 3 study looking at the effect of EPO on SVR rates in boceprevir based treatment, may delay FDA approval of boceprevir as a treatment agent for up to two years until that study is completed, or at least highlight the additional cost and morbidity associated with the longer and more complicated treatment requried when using bocepreivr instead of telaprevir based treatment.
Wow, pretty creative results. Did I read that right? Did they just take the patients that werent responding as well out of the results of the original arm of the trial, and create a new arm giving it a misleading label of "null-responders"? Hey, taking those pesky not doing well people out of the results sure makes for better numbers.
The main text of the abstract is:
HCV SPRINT-1 had two arms with a 4-week lead-in of P (1.5 μg/kg/QW) plus R (800-1400 mg/day) prior to the addition of Boc (800 mg TID) for an additional 24 or 44 weeks of therapy
in naïve G1 patients (pt). This design allowed the determination of viral response based on precisely defined P/R response. Data from IDEAL demonstrating that a 1 log10
decrease in viral load at W4 corresponded to a ~2 log10 decrease at W12, permitted definition of a ‘null’ response to P/R therapy (<1 log10@W4). Viral response was assessed by
Roche Taq-Man (LLD=15 IU/ml) at multiple times including 24-week post-treatment (SVR). Results: Pts were all G1 (1a>1b) with 15% Black, 7% cirrhotics and 90% high viral load. W4
virology was available for 96 and 101 patients in the 28W and 48W arms, respectively. Combining these 2 arms 60% of null responders (30/50) had undetectable HCV-RNA at W24,
including 56% (9/16) of those with the poorest W4 response (<0.5 log drop). SVR was 55% (12/22) and 25% (7/28) in the 48W and 28W arms respectively, with 44% (4/9) of the worst
responders achieving SVR after 48 weeks of Tx. SVR for the ‘non-null’ responders was 81% and 72% for 48W and 28W arms. Multivariate regression showed W4 response to be a
predictor of W24 response (All) and SVR (48W Tx; OR=8.2, p<0.005). We could not define a minimal P/R response at W4 that reliably predicted poor viral response. In >95% of pts,
addition of Boc for 4 weeks led to a >1.5 log decline in viral load, and only those who never became undetectable had a poor SVR.
Conclusion: Null responders to P/R (lead-in) therapy had a high SVR after 44 additional weeks of Boc plus PR therapy. Response is higher in ‘non-null’ patients, but no factors
could clearly define a group of patients who do not achieve SVR. Since null responders to P/R responded well to the addition of Boc, and benefited from longer Boc/P/R therapy, the
ability to treat these pts for up to 44 weeks with all 3 drugs is likely an important therapeutic advantage.
The most surprising is the title:
HIGH SUSTAINED VIROLOGIC RESPONSE (SVR) IN
GENOTYPE 1 (G1) NULL RESPONDERS TO PEG-INTERFEON
ALFA-2B (P) PLUS RIBAVIRIN (R) WHEN TREATED
WITH BOCEPREVIR (BOC) COMBINATION THERAPY.
It sounds as if they looked at the TRUE null-responders. But the truth is that they redefined the term NULL-RESPONDERS as the treatment naive patients who did not achieve their viral decrease better than one log at the end of the 4 week lead-in period of its P/R dosing.
The SVR values for this group of patients was 25% for the 28wk arm and 54.5% for the 48wk arm. But, the total number of patients belonging to the 48wk arm was only 22, out of whom 12 achieved SVR. They were dealing with a small sample of patients because the patient group was treatment naive and only a small fraction of them belongs to their <<Null-responders>>. Of course, the small sample makes the figure very unreliable. Nonetheless, the presentation may hit the media headline.
I tried to paste the table here without success. It is not possible to compare with PROVE 3 because the definitions of null or non-responders were different.
bad timing? or good timing? Maybe this signals a top for the stock? With boehringer ingelheim about to present interim Phase 2b results of a once daily (one small pill instead of 6 big telaprevir pills (bid or tid doesnt matter still 6 pills)), more potent protease inhibitor than vrtx, which also looks to be much better tolerated and only 1-2 yrs behind, it will be interesting if investors start to worry that telaprevir could only be around for less than 2 yrs before being completely replaced by something much better (see late breaker abstract on boehringer compound at aasld website for details). This is why, in my view, it is very unlikely pharma ever buys vrtx, they would need to pay over $10 billion for a company with a drug that could be very short lived (remember crixivan?) and the valuation simply doesnt work unless one thinks sales persist for years, which seems highly unlikely given that boehringer, JNJ/Medivir and others are likely less than 2 years behind with once-daily, more potent, and likely much better tolerated drugs. with so many retail investors and generalist mutual funds piled into this stock this could get interesting. But good news for patients as much better drugs are fast around the corner, but not sure this will be good for vrtx. Perhaps Kurt Graves departure will prove to be good timing on his part. time will tell
I got hold of the abstract you referred to. Are you judging this BI drug by the convenience of swallowing alone? Read its RVR and EVR determined with the better sensitivity. First, it is a slow acting drug like Boceprevir... certainly lower than TVR data. This means that there will be a large relapse after PI dosing. Even the EVR is not as good as the EVR of Telaprevir (compare against Study C208 which will be reported at the Presidential Plenary session)
Here's an excerpt from the link below explaining the likely reason for Kurt's departure:
At the same time as Graves was hired, then Vertex CEO and founder Joshua Berger step back a bit from being the prominent and very public face of the company, especially to investors. This led to some speculation that Graves was being groomed for the CEO role if/when telaprevir was approved. But when Berger did step down from his CEO post (retaining the chairman's role), Vertex went out and hired Shire CEO Matt Emmens as its new chief executive.
Emmens has a lot of commercial expertise of his own, which probably left Graves with little chance of advancement at the company. A source familiar with the situation says Graves coveted Vertex's CEO post, so when Emmens was hired, it was only a matter of time before he left.