The Porcine Prerogative: A Perilous Precedent

While not falling within the CNS arena per se, the consequences of Gilead Pharma‘s decision to platinum-price Sovaldi for Hepatitis C, to the tune of $84,000 per three month treatment cycle in the US, eventually will permeate health care in general. The  pricing seems born of Orphan Disorder modeling, for which tolerance in the US has been expansive, given the small sizes of these populations and the easily-discernible outlines of the scenario for sympathy; pediatric patients otherwise doomed before they ever really get to begin. But Sovaldi is applicable to far larger populations, given that 2% of the US population is estimated to have a Hepatitis C infection. Some estimates of the potential US market, were all HCV-infected patients to be treated, are over $200 billion. That is not going to happen, but where one draws the line in terms of eligibility–e.g. cirrhosis?–invokes an inevitable debate between reactive and proactive intervention models. The most extreme framework for reactive treatment would require that later-stage damage has been done and symptomatically apparent, where transplants might otherwise be part of the conversation. But that would be treatment that arrives too late: True pharmacoeconomic benefit would come from preventing large segments of the HCV population from progressing to serious–and very expensive–stages of hepatic dysfunction. But proactive therapy, intervening before that level of damage has been done, could be expanded to a scale of utilization and cost that would temporarily delight Gilead management and shareholders, and would–and should–horrify all other onlookers.

In fact, there won’t be any true onlookers here; this is the kind of gluttony for which everyone will pay, and which could present the tipping point on the other side of which awaits governmentally-governed pricing constraints, the kind of price-controls that the US has avoided, even as the rest of the developed and semi-developed world has embraced them. The topic of why the EU, for example, has been allowed to shift the true costs of drug development onto the United States by sharply limiting its reimbursement for drugs is a topic unto itself, but sets the context: At some point the cultural antipathy to top-down regulation of drug pricing will shift as the US realizes that it can no longer afford to be the World’s Deepest Pockets for Pharma.

The situation is also one where it will be relatively easy to manipulate the finite empathy of the American public, because rather than serving a population of innocent children, it is a simple public relations maneuver to paint the Hepatitis C population–even if unfairly–as being largely characterized by intravenous drug users whose illness can be traced to their own conduct, and a group more often covered by governmental insurance (e.g. Medicaid).

Once the precedent has been established, it cannot be undone. And it will eventually bring us to the biggest quandary of them all–Who will receive, and who will pay for–the first drugs to slow disease progression in Alzheimer’s? With over five million Alzheimer’s patients in the US, and many more who are on the cusp with MCI or ARCD, the potential scale of that market dwarfs even Hepatitis C. There, the additional socioeconomic argument will come into play regarding the costs of care for those approaching the end of their lives, and the degree to which younger generations should and can go into hock for them.

Any precedents set regarding access and price-controls will reverberate well beyond HepC and Sovaldi, yielding seismic changes in attitudes in the United States, as economic necessity begins to erode the American resistance to governmentally imposed restrictions–particularly when it comes to federally-funded insurance programs. The eventual advent of competing drugs might–at least in theory–set up price-competition that might attenuate the impact, but we would not count on it. By setting this bar so high, Gilead is hoping that the pricing game will be played at this stratospheric level, like MS, with all relevant entrants pushing the cost envelope to some degree. This may not be a crime, but it is also not victimless.  The old saying ends with, ‘Pigs get slaughtered,’ and in their greed, Gilead not only did not consider the damage that they could bring upon themselves, they almost certainly did not envision the likelihood that they could bring plenty of company with them down the kill-chute.

 

 

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Prana’s AD Gamble Falls Short

Prana just reported that PBT2 did not produce benefit vis-a-vis AB plaque load, cognition, or metabolic function in their latest Phase II trial in prodromal/mild Alzheimer’s. A nonsignificant trend towards slowed hippocampal atrophy (2.6% vs. 4.2%) over twelve months was reported, consistent with what was reported from their Huntington’s PhII.
What does this establish about PBT2 in AD specifically, and in neurodegeneration in general? About as much as might be expected from a 42pt trial–virtually nothing. Anyone who expected to see cognitive benefit from this size trial has not been paying attention, and had there been an impact on plaque volume, we would have been raising the question of whether this was good, bad, or irrelevant. Even the meaning of the hippocampal volume trend is impossible to establish–it was the  measure that NIR was more interested in, since we wanted to see if there was anything to substantiate the ‘signal’ suggested by the six patient(!) cohort in the HD trial–but even so, we have no idea whether it reflects a genuine effect upon the degenerative process or not.

One must question Prana’s judgment in running this study. AD trials these days look at eighteen-month duration effects in thousands of patients; this may be the most underpowered Alzheimer’s trial in recorded history. As we said in the January issue of NeuroPerspective: “It will be hard to find anything conclusive with just 40 patients, but they will be looking hard for trends.”

The net effect will be to undercut Prana’s already borderline credibility, and hinder–perhaps fatally–their ability to follow up on the hotly debated, ambiguous-at-best Huntington’s data. It would have been a near-miracle for it to be otherwise. Why did they bother?

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Zohydro’s Days are Numbered

(A courtroom in the United States, December 2016)
“Doctor…Why did you prescribe Zohydro to the plaintiff’s son in July 2015?”
“He was experiencing severe pain as a result of his fall, and I had positive experience in using Zohydro with this type of case.”
“Were you aware that he had a history of abusing opioid painkillers?
“No, I was not.”
“But were you aware that there was an abuse-deterrent version of hydrocodone, also acetaminophen-free, that was available?
“Yes, but since he was having good results with Zohydro, I did not want to take the risk of switching him to a new drug.”
“Doctor, isn’t it likely that, had you prescribed the abuse-deterrent form of the drug instead of Zohydro, that the plaintiff’s son would not have overdosed, and would be alive today?”
Silence.

As dramatized-for-TV as this vignette may be, it is the reason that Zohydro’s days and prospects are  on a finite downslope. There was a valid reason for approving an acetaminophen-free version of hydrocodone, and in spite of the self-serving harrumphs of outrage percolating out of Congress, the FDA was correct in doing so. Congress would be practicing well outside its nanoscale areas of expertise in legislating the components of any pharmacopaeia, and we hope that the FDA will not yield to them now. But with Purdue Pharmaceuticals having completed pivotal testing of an abuse-deterrent formulation that achieves similar analgesic results, the clock is ticking on Zohydro. There will be strong pressure for an accelerated review once that NDA is filed, and even though the Senate’s limited attention-span will doubtlessly have shifted by the time the Purdue drug is approved, prescribing physicians will have had their focus brought to the legal liability they would face if a patient were to overdose on Zohydro when a safer alternative was available–or if a patient driving-while-impaired after crushing and snorting Zohydro were to cross the median into an oncoming school bus–one can paint any number of ruinous malpractice/liability scenarios. The question is not whether the plug will be pulled on Zohydro, but by whom: The FDA, already on record stating that abuse-vulnerable drugs can be pulled from the market when an abuse-deterrent version is ready; or by physicians bent on avoiding the easily avoidable spectre of very public liability. Zogenix has to now decide whether putting resources into their own abuse-deterrent formulation is worth the investment when it would mean going up against a Purdue version that will have had a head start. But their strategic planning had better be predicated upon a rather brief window of opportunity for Zohydro, a window already narrowed by the controversy spurred by its approval and launch.

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Twitter and Prana

NIR has been asked on a few occasions why we do not utilize the social media potential offered by Twitter. The current contretemps around the Prana results in Huntington’s beautifully illustrate why we do not: Twitter is an effective venue for social media, true, but it also appears to be a direct route for communications that bypass the frontal lobes.

The Twitter micro-flame war that broke out between Prana’s scientific founder Rudy Tanzi, and Street.com‘s Adam Feuerstein after the release of the Phase II results for PBT2, illustrates this. Feuerstein has published the Twitter exchange on his Street.com thread, from which we quote a tweet from each:

Tanzi: <<adamfeuerstein seems set on seeing PBT2 fail in his biased blogs. PBT2 SIGNIFICANTLY improved cognition in pre-specified HD patients!>>

Feuerstein: <<RudyTanzi please save the spin for your analysts and gullible investors. PBT2 failed HD. Disgraceful you’d argue otherwise.>>

Both of these public statements are incorrect, both made by people who should know better. Tanzi’s statement regarding the improvement in “cognition” overstates the case: When it comes to the gold standard of p=.05, only one of the cognition measures utilized reached that level, and only one other measure (of functional capacity, not cognition) reached the lesser standard of a pronounced trend (Prana did not cite the p value, p=.10 is commonly utilized, p=.20 less often). We have previously published our opinion that the pattern of results from the trial suggest a preliminary signal–but a trial this size and duration proves nothing.

Feuerstein’s statement that “PBT2 failed HD” is also untrue. Meeting one (or with a lesser statistical criterion, two) endpoints on the efficacy testing is a mixed result. There is no universally accepted standard for  Phase II that decrees how many, or which, endpoints have to be met, at what p value, to declare success or failure. His willingness to make this a binary event that has been outright failed is just as arbitrary as Tanzi’s declaration of success.

It is understandable that both Feuerstein and Tanzi ended up on polarized ends of this Twitter fest. Tanzi’s scientific legacy is very much intertwined with the mechanism being tested here, regardless of his financial stake in Prana. Feuerstein has made his reputation partly on his willingness to confront pharma companies on their all-too-frequent willingness to cross the boundary from spin to deception.

We have to acknowledge that we have bias that could creep into our analysis of the situation, albeit on both sides: While lacking a financial stake in Prana, we very much want to see progress in addressing neurodegeneration. NIR also has its own history of challenging the practices of data-fracking and deceptive spin, and it feels a bit disorienting to be questioning this challenge.

In this situation, some restraint on both sides of the argument would seem appropriate, albeit somewhat too late. As we discussed in an earlier post, a trial this size rarely, if ever, proves anything.  We believe that there is reason to believe that there is a signal here, but one can not reasonably assume that it will be replicated and broadened across outcome measures in a larger, longer trial. By the traditional rubric of clinical trial progression, PBT2 should be going into PhIIb, to see if this signal emerges over a twelve or eighteen month treatment period, and a higher dose would be worth consideration.

Going into Phase III at this point is not a decision predicated upon science, it reflects the pressure to perform that is endemic to the pharma industry, impacting companies both large and small (e.g. Merck has gone into Phase III for Alzheimer’s with a BACE inhibitor that has never had efficacy testing done, the ‘Phase II’ component involved safety and biomarker assessment). NIR has previously written that “Phase IIb is not optional.” That continues to be the case, and making exceptions based on economics is a very high-risk bet. Saying that a product is ready for Phase III does not necessarily make it so. Saying anything on Twitter guarantees nothing more than brevity, and constitutes a threat to both credibility and civility.

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Prana followup

Having just participated in the Prana CC, there are a couple of informational pieces worth mentioning:

1) The statement that all trends seen on the range of measures administered were in the “positive direction” gives some reassurance that the two specific measures where benefit was statistically significant or approached significance (Trails B and the TFC test of functional capability) are not just straws randomly emerging from a haystack of molecular irrelevance. It supports the hypothesis–and that is what it is– that there is a trend towards improvement on a range of functions that may be more salient, and substantiated, in a trial that tests more people, for a longer duration. Six months may have not been long enough for the control group to decline in some areas to the degree that can be detected by the tests assessing those areas.

2) When one sees a neuropsychological testing result, it always begs the question of its relevance to real-world functionality. The good news here is that improvement was seen on both the Trails B neuropsych measure and the TFC functional composite score. The open question is whether the magnitude of benefit on the TFC (a decrease of 0.3 for the high dose group compared with a decrease of 0.6 points for the control group) would translate into tangible real-world benefit. One of the researchers on the call said that the TFC, which taps six different areas on a scale that ends up covering a range of 0-13, has subcomponents that would not be expected to decline over six months, and some that would (managing finances and occupation function)–the implication being that the benefit may have been in specific behavioral subsets, and that what looks like a small treatment effect may actually be more salient within that context.

3) The presentation reiterated a point made on this blog this morning: The fact that the greatest improvement was seen on the same measure where it was observed in an entirely different patient population (Alzheimer’s) makes it less likely that it was a fluke–because it was replicated.

As was noted earlier, this was a small n, short-duration trial, and should be thought of as a pilot study. But the report that the overall gestalt of trial results was of positive effects, even if not approaching statistical significance, makes it more likely that this is a real signal, not the product of ‘data-fracking.’ The results provide hint-of-concept, not proof-of concept, and now requires replication in a much larger study, hopefully one that would utilize at least a one-year treatment duration (probably with an open-label extension).

While we had been wondering whether a 40 pt Alzheimer’s trial (due to report next month) can shed much light on anything due to its small size, it does have an imaging component that might be very interesting.

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Making Sense of Prana

Prana Biotechnology finally announced the results from their Huntington’s Phase II trial today, and depending on who one reads, one might come away with the impression of great success–or abject failure. We think the truth is in between, but is closer to the former than the latter, and here is why:

It was a 109 pt trial (just 104 completers), which means one must look beyond the p=.05 criterion for establishing an effect. PBT2 did hit statistical significance on a measure of front area/executive functioning–based on Trailmaking B–and showed a trend towards improvement on a functional capacity measure. A tiny fMRI imaging substudy (six patients–four on PBT2) showed evidence of slowed atrophy in those areas where HD tends to produce the most degeneration. It is worth noting that the specific effect upon executive functioning measured by Trailmaking B (which is a simple but useful neuropsych screening measure) was also seen in the previous Alzheimer’s trial–which argues against the findings being fluky, and raises some intriguing questions about why the mechanism might be particularly important in that neuroanatomical area.

No detail regarding other cognitive measures was provided, which likely means that no trends were observed. Even so, it is in executive functioning that HD tends to display its more prominent impact on cognition, thus it is where one might expect to see an impact upon decline over a relatively short period (six months). It is worth noting that a 2011 Lancet Neurology report found that imaging was the best measure of disease progression–and this was over two years–and that progression as measured by other criteria is highly variable, which makes a six month timeframe all-too-short.

This brings us to the headline from Adam Feuerstein of Street.com: “Prana Bio Huntington’s Disease Drug Fails Key Efficacy Hurdles.” In general, we like Feuerstein’s work a lot–he punctures the balloons of PR hype with great accuracy and zeal. But not here, where his zeal remains, but his aim was off. He zeroed in on the lack of statistical significance for broad spectrum assessments of cognition and motor function and deemed the trial a failure–dismissing the signs of improvement as essentially irrelevant.

The problem with his conclusions is that they ignore some basic principles of assessing change in neurodegeneration: The duration of the trial, which here was quite short; the size of the sample, which here was very small; and the difference between prespecified and datamined divergences. Alzheimer’s studies tend to now cover at least twelve months, more often eighteen months of time, and enroll thousands of patients–even in trials where diagnosis is certain, like Lilly’s revamped solanezumab Phase III design. Had Prana’s study had that kind of size and duration, and yielded these results, it would be justifiably deemed a failure. It did not, and its results must be considered more akin to a Phase IIa trial, a pilot study that points to possible utility, albeit not establishing it. The positive findings were where previous data would suggest they would be found, not a random walk through the statistical thickets.

What can be said unequivocally here? That Prana’s financial constraints prevented them from running a more definitive study that enrolled enough people, covered enough time, and utilized sufficient measures (especially in the imaging component) to provide something approximating certainty. But we believe, particularly in concert with a similar cognitive effect shown in an entirely different neurodegenerative disorder, that there is a signal here worth pursuing, and that while PBT2 has a long road to proof ahead of it, it has earned that opportunity with some preliminary indicators of benefit.

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Setting the Bar Low

BioCentury Extra for 2/12/14, regarding a FDA/Institute of Medicine conclave:
<The second day planned for Thursday was postponed due to weather; FDA said it would be rescheduled for April or May and would focus on communicating uncertainty.>

An excellent example of setting an achievable organizational goal.

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