Academic Opioid Leapfrogs Field–Perhaps

Nature was the venue (8/18/16) for the publication of a paper from academic collaborators at UCSF, Stanford, UNC, Friedrich-Alexander-Universität Erlangen-Nürnberg, and Parelcus Medical University, a paper that reported the development of a highly refined, selective mu opioid agonist that–in animal models–came close to morphine’s analgesic efficacy while not generating abuse potential on ‘liking’ measures and without morphine’s risk of respiratory depression (RD). Perhaps.
The group screened over three million molecules against a subunit of the mu opioid receptor crystal structure, parsing out those which activated beta-arrestin activity (thought responsible for RD) versus those which were biased towards Gi protein signalling at the mu opioid receptor, believed to be the basis of analgesic activity. Via a number of sophisticated optimization steps, the group developed a prototype drug, PZM21, that fit the criterion of similar efficacy with reduced side effect/abuse risk. In term of selectivity vis-vis other opioid receptor subtypes, the compound lacks nociceptin receptor activity, is a mild kappa opioid antagonist, and has very weak delta-opioid binding. In animal testing, PZM21’s effect in pain models showed efficacy similar to morphine’s; did not trigger sustained respiratory depression, though the paper’s authors failed to mention (and Nature’s peer reviewers overlooked) that the drug had the same RD effect after 15 minutes as morphine* (though morphine’s suppressive action became profound and persistent), and thus at least temporarily separated from vehicle (which raises the question of whether an overdose might in fact be potentially lethal in that timeframe); had less impact on GI motility than morphine; and was not observed to activate reward pathways and behavioral ‘liking.’ This is a unique profile, though this compound has yet to be tested in humans, and thus has a long developmental journey ahead of it. Trevena’s TRV130 is also a biased Gi opioid agonist, and is in Phase III. However, that compound differs from PZM21–it does have kappa opioid agonist activity (which can have aversive affective effects in males)–and it does briefly stimulate respiratory depression (albeit not much more than PZM21)–though there is evidence suggesting decreased abuse/risk.
Though the minefield of human testing remains ahead for PZM21, the animal models used in the analgesia context are more predictive than are models in most neuro-contexts, and the compound differentiates itself on a number of important features that would be relevant to safer, more efficient, less abuse-prone analgesia. We expect that this will be a sought-after licensing asset, though several major pharmas have deleted acute pain relief from their licensing interests; in spite of their flaws, standard opioid analgesics constitute a challenging competitive environment. PZM21 appears, at least preclinically, to address many of the shortcomings that are pervasive in the current offerings. However, the published report somehow overlooked the possibility that the compound may have a window of vulnerability to respiratory depression–a highly experienced neuroscientist suggested to NIR that an animal study be done comparing the potential lethality of PZM21 at 15 minutes post-administration to that of morphine and oxycontin (and we would add, TRV130), in order to ascertain whether the compound has a short-lived but potentially lethal Achilles Heel.
*noted by the LA Times’ Karen Kaplan


Also: TauRx Claims Posthoc Victory Prematurely

A couple weeks back, TauRx released results from the first of three clinical trials (two in AD, one in FTD)  for LMTX, reporting that it failed overall in AD, but they then claimed success based on a subset of patients not receiving concurrent ChEis who appeared to outperform placebo patients (both on and off ChEis). At best, this represents an interesting hypothesis that can only be proven, or disproven, by further prospective testing. Management’s claim that this established LMTX as an efficacious monotherapy was sloppy and specious–other explanations are as likely or more so. These results for the most clinically advanced tau-targeting therapeutic will be discussed in much more detail in the upcoming September/October issue of NeuroPerspective, which covers Alzheimer’s.

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SAGE Therapeutics’ remarkable run with tiny-n pilot studies as predictors of Phase II results continued when SAGE-547 separated remarkably well in a larger (albeit still very small, 21pt study) trial in severe Post-Partum Depression. A single injection provided remission of symptoms in seven of the ten patient SAGE-547 cohort (mean 20pt reduction or more in HAM-D) compared with one patient out of eleven (a mean 8pt HAM-D reduction) receiving placebo. MADRS score changes were similar. The impact was rapid, significant at 60 hours, and just as important, the impact was durable, remaining significant at thirty days. The initial pilot data had been viewed with skepticism by some, but as we noted in our March/April review of depression: “there was some appropriate skepticism about the predictive value of results from four depressed patients receiving an IV infusion of an experimental drug, a set-up for a placebo effect if ever there was one. But the premise for SAGE-547 in PPD has a solid biological basis: SAGE-547 is, after all, a form of allopregnanolone, and women with PPD have been reported to have lower levels of endogenous allopregnanolone than their nondepressed post-partum peers. It has thus been suggested that allopregnanolone may be protective against PPD.”  And so it appears to be, though it remains to be seen what scale of pivotal testing will be required by the FDA. This is not a large patient population (200,000-600,000 US cases annually), but when one considers the locus of PPD’s effect on a critical developmental time period for a newborn, the human impact of the disorder, and the potential of a successful treatment, are considerably magnified.

from NeuroPerspective March-April 2016
Pregnancy and new motherhood are often very different from the idealized, bucolic images conveyed by advertisers, churches, and aspiring grandparents. Indeed, somewhere between 5% and 25% of women experience some degree of post-partum depression. Some of them may have had a history of depression, and because of lingering worries about the safety of perinatal exposure to antidepressants, discontinued their antidepressants during pregnancy. Similarly, women who are nursing may be reluctant to use antidepressants, leaving them ill-equipped to content with their affective disorder. Combine that with the hormonal and experiential upheavals that go along with childbirth and new motherhood, these women can be vulnerable to a dramatic return and exacerbation of depressive symptoms. For a very tiny percentage, this can turn into a psychotic depression, with rare, but on highly-publicized occasion, horrific results.
In June 2015, SAGE Therapeutics announced results from their pilot data in Post-Partum Depression (PPD) and temporarily boosted their market cap by about $420 million. A planned fifteen patient study was cut short after the first four patients showed a complete reversal of their depression, their Hamilton scores nearing zero 60 hours later. SAGE immediately recognized that this radical improvement in PPD symptoms was well-deserving of a placebo-controlled study. At the same time, there was some appropriate skepticism about the predictive value of results from four depressed patients receiving an IV infusion of an experimental drug, a set-up for a placebo effect if ever there was one.
But the premise for SAGE-547 in PPD has a solid biological basis: SAGE-547 is, after all, a form of allopregnanolone, and women with PPD have been reported to have lower levels of endogenous allopregnanolone than their nondepressed post-partum peers. It has thus been suggested that allopregnanolone may be protective against PPD.
SAGE will develop a different, orally bioavailable molecule for PPD, once the signal has been confirmed. That confirmation is hoped to come from a 32pt Phase II placebo-controlled trial that should be completed by midyear.

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Purdue’s Potemkin Village of Addiction-Prevention: Make Them Pay

The Los Angeles Times has published an appalling albeit impressive investigative piece (; by Ruan, Girion, Glover) regarding Purdue Pharma’s handling of fraudulent Oxycontin prescriptions, and the part that this played in the opioid abuse crisis that has burgeoned in the United States. The piece described in detail the activities of  one such ‘pill mill’, which the reporters estimates provided 1.1 million pills to drug dealers, largely affiliated with LA street gangs and organized crime.The article is titled ‘Inside an L.A. OxyContin ring that pushed more than 1 million pills. What the drugmaker knew.’  As it turns out, they knew quite a lot, and looked the other way as millions of pills were diverted to dealers who then resold them to those who had become addicted. The story depicts a corporate culture that masqueraded concern about Oxycontin’s abuse potential; Purdue had even hired a former US-Attorney and a DEA veteran to be part of a team that had the prevention of Oxycontin diversion as its ostensible mission; this group tracked patterns in Oxycontin prescribing that flagged the near-certainty of fraudulent prescription practices on the part of unethical physicians. We are not going to replicate the Times story here, it is well-written and documented, worth reading in its entirety. We will instead cut to the chase: “Crowley (the ex-DEA agent working in Purdue’s anti-diversion ‘effort’) said that in the five years he spent investigating suspicious pharmacies, Purdue never shut off the flow of pills to any store(emphasis ours).
One might well wonder–why set up a group tasked with identifying and responding to illegal diversion of Oxycontin supplies and then make no attempt to effectively intervene? Even though the DEA had specifically pointed to manufacturers as sharing in the responsibility for the prevention of opioid diversion; and even though Purdue had previously been fined $635 million for misleading physicians regarding the abuse risk presented by Oxycontin; the story quotes Crowley as saying “company policy prohibited employees from reporting pharmacies to the DEA without first consulting their distributors.”  Purdue acted as if it was not their problem to solve, as if their hands were tied, albeit by their own Company policy. The obvious explanation is that they hewed towards the letter of the law without doing anything that would actually impede the flow of profits to Purdue’s bottom-line. Those profits were gargantuan: The reporters state that Purdue has “earned more than $31 billion from Oxycontin” (Forbes estimated that the total is $35 billion, but let’s not quibble about $4 billion). It is not as if Purdue is one of those pharmaceutical companies whose outsize profits on one drug are offset by the losses engendered by other research efforts that went-for-naught; Purdue’s business model is totally focused on opioid analgesia. Of the 67 Purdue Pharma-sponsored clinical trials cited on, 64 were for opioid-based analgesics, i.e. Oxycontin, its XR and abuse-resistant progeny, and its chemical cousins. Just three clinical trials were for non-opioids, those three were part of a partnership with Rhodes Pharmaceuticals regarding the clinical development of a new extended-release version of methylphenidate, for ADHD. In other words, Ritalin–not exactly a high-risk, innovative, expensive research endeavor. Neither ethics, legal obligations, or research activities were allowed to detract from Purdue’s bottom line.
Thus Purdue Pharma made tens of billions of dollars in profit on the sales of a drug whose abuse was noted and ignored, with few or no corrective actions taken. Purdue and its legal advisors of course publicly state that their behavior was in accordance with the law, which is the rationale often claimed by those who would prefer to not consider the moral bankruptcy of their position. We do not know whether there are grounds for criminal prosecution here, and our suspicion is that, even if there are, such proceedings would simply punish those who executed the wishes of those who created the policies, who created a corporate culture wherein the human toll associated with opioid addiction was not seen as sufficient reason to compromise their revenue stream. This is the kind of sociopathy one would expect to see on The Wire, not from those controlling a pharma company in Connecticut. The Sackler family, who own Purdue Pharma and to whom the profits flowed, should bear responsibility for the immoral corporate culture Purdue has come to embody. Since they chose to operate on the basis of their pocketbooks, that is where the penalty should be exacted. The largest pharma company fine ever paid was GlaxoSmithKline’s $3 billion penalty, back in 2012, for off-label promotion of its antidepressants and the suppression of safety data for a diabetes drug. But the sheer scope of human suffering, death, and societal harm that can be traced back to Purdue Pharma’s negligence makes GSK’s behavior look philanthropic by comparison. What would be a meaningful penalty in Purdue’s case?
This is NIR’s suggestion: The $31 billion of Oxycontin revenue taken in by Purdue over time is close to what the National Institute for Drug Abuse (NIDA) has for their 2016 budget–if multiplied thirtyfold. The Sacklers should return the $31 billion received for Oxycontin, but rather than having that fine disappear into the maw of the federal budget, let it go to NIDA, which is tasked with addressing and correcting some of the damage done by Purdue. We would not be unreasonably draconian about this; let the penalty be paid over the next ten years. That would in essence quadruple the annual funding available to NIDA, even permitting the funding of late-stage clinical trials for addiction therapies, programs that at present receive virtually no support from the pharma industry or investment community. This would not ‘even the score’, because there is no getting back the lives lost and wasted, but it would be a step in the right direction, and send a clear message that there are rules about sacrificing lives in the pursuit of profit.

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NIR in Cerebrum

NeuroPerspective’s editor and publisher, Harry Tracy PhD, was invited to provide a current assessment of the funding environment for therapeutics programs in the areas of Neurology/Psychiatry by Cerebrum, published by the Dana Foundation. That article–The Neuro Funding Rollercoaster–was released in early June. The link to the online publication, and the associated podcast,is:

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Acadia Outsources Compassion and Math

On their quarterly call, Acadia Pharmaceuticals announced the pricing for Nuplazid, freshly approved by the FDA for the treatment of Parkinsonian psychosis (PDP). The price has been set at $1950 per month, about $23,400 per year. A quick scan of the atypical antipsychotic drugs that might be supplanted by Nuplazid in PDP indicates that they tend to be priced at about $900-1000 per month. The expectation had been that Acadia would exact a premium over the predecessors, but not to this degree: Acadia has roughly doubled the price of their competitors, figuring that, with Nuplazid the first drug to primarily target 5HT-2a receptors, and to be labeled for Parkinsonian psychosis, they can do as they please. Which they can. But this does bring us back to a topic discussed in NeuroPerspective and Neurogram+ in the not-too-distant past; “Why do they hate us?” (In this context, ‘us’ refers to the Pharma industry, ‘they’ refers to everyone else). This is why.
Sure, compared to the $84,000 per year originally cited for Solvadi, this does not trigger the same kind of sticker shock, though it should be noted that Sovaldi is curative for Hepatitis C, whereas Nuplazid provides relief of a specific symptom-cluster within a chronic neurodegenerative illness, and its use for many patients might be stretched out over years. Even if one considers full remission of psychosis to be the psychiatric version of ‘curative’, that only applies to 14% of Nuplazid users.
Semi-attuned to the spate of recent negative publicity around drug pricing, Acadia hastened to add that they would take steps to ameliorate the financial burden, reminiscent of other companies who claim that with discounts and rebates, that the list price isn’t nearly as onerous as it sounds–no one pays ‘retail’. But Acadia’s actual behaviors are likely to fall short of their purported promise.
Rounding off Acadia’s own estimates, 1/3 of patients will have commercial insurance, and Acadia says that they will cover their co-pay, albeit based on “coverage and circumstances”, implying some kind of means-testing. But setting that minority aside for the moment, roughly two-thirds are expected to be on Medicare D, and here it gets more convoluted. Acadia indicates that the co-insurance obligation for Medicare D patients will be in the 25-30% range, which at the low end, is about $6000 per year. That would be a huge burden for many, if not most, elderly patients with Parkinson’s. With this population, the majority of Nuplazid patients, Acadia plans to make donations to “charitable foundations” in the expectation that they will in turn provide monetary relief to patients being impacted by this sizable co-pay obligation. In other words, for two-thirds of the Nuplazid population, Acadia intends to turn over the cost-amelioration task to charities, outsourcing the task of alleviating what might well be an untenable burden for many elderly patients and their families. This presumes that such charities have the infrastructure and skillsets to do so, which they do not.
Let’s see how this would play out. For the sake of simplicity, let us suppose that Nuplazid might eventually generate in the neighborhood of one billion dollars in revenue per year. If two-thirds of patients are on Medicare, that is $660 million per year of drug cost attributable to that population, and the 25% co-pay obligation associated with that total comes out to…$165 million. Based on what Acadia has cited as their plan, in order to actually offset that out-of-pocket burden, Acadia would have to donate something approaching $165 million per year to charities who would in turn somehow funnel it to those patients in need. To be clear, they did not cite this figure, since they are making no revenue projections at this time, but based on the model that they presented as their approach to ‘easing the burden’, that’s how it would pan out: $165 million in charitable donations, somehow passed through some intermediary ‘charities’ to PDP patients and their families. We look forward to hearing from anyone who thinks this is going to happen, and how it would work.*
This is of course part of a much larger-scale problem: The American approach to drug pricing, where a sky-high list price is cited along with vague reassurances that the ‘real’ cost won’t be nearly so bad, turns the pharma industry into a giant used car lot. Recalling that CarMax’s corporate model did away with the smoke and mirrors, instead simply stating the no-haggle price for a car, we almost yearn for a DrugMax that would provide the same clarity in the pharma world. Like most of its peers, Acadia will exploit the lack of industry transparency, and it is this kind of gamesmanship, in the context of escalating prices and societal costs, that makes the American public skeptical that anything we say can be taken at face value, and buttresses the perception that the pharma industry operates primarily on the basis of greed. That is ‘why they hate us’, and turns this into one more step on the slow creep towards price controls. Acadia management probably figures that, as was the case with Sovaldi, they can milk the system until a competitor comes along, like Axovant’s nelotanserin. But there is another potential ‘side effect’: Given the population size, the FDA is certain to be more demanding when Acadia files for Nuplazid’s label-expansion into the huge Alzheimer’s market, and if the atmosphere around Nuplazid is tainted by media stories about the cost-reduction that wasn’t, and anecdotes of PDP patients financially strapped by the costs or doing without, that could come back to haunt Acadia.
Acadia can be semi-excused for buying into the double-speak and illogic, because they are on the receiving end as well. Case in point: Their European marketing application for Nuplazid will be delayed while they sort out what the EU wants in terms of a PIP for Nuplazid, because the PIP must be approved before the filing can be accepted. What is a PIP? It is the Pediatric Investigation Plan–the presentation of how pediatric testing would be done, or waivered. That’s right: Pediatric factors must be explicated to the satisfaction of European regulators before they will accept the filing for a drug for Parkinson’s, one of the least pediatric indications in all of creation. That kind of absurdity sets the tone, and the stage, for cynicism.
Unfortunately, Acadia took the bait, decided to push the pricing envelope as far as they can, and to make the problem of financial burden…someone else’s. Perhaps it is unfair to blame them for doing what everyone does, but at some point, somebody will have to break the mold, or else it will be broken and reshaped for us, and that outcome will not be to the taste or benefit of the pharma industry.
*Acadia was contacted with the questions of whether this correctly depicts their plan for Medicare D cost-offsets, and whether any charitable organizations had identified themselves as prepared to collaborate with them on this. No response was received.

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New Literacy Requirement for Physicians

“FDA has approved a brand name change for the antidepressant Brintellix (vortioxetine) to decrease the risk of prescribing and dispensing errors resulting from name confusion with the blood-thinning medicine Brilinta (ticagrelor). The new brand name of the drug will be Trintellix, and it is expected to be available starting in June 2016. No other changes will be made to the label or packaging, and the medicine is exactly the same.

Because of the lag time associated with manufacturing bottles with the new brand name, health care professionals and patients may continue to see bottles labeled with the brand name Brintellix during the transition period.

In a July 2015 MedWatch Alert, FDA warned that name confusion between Brintellix and Brilinta had resulted in prescribing and dispensing errors since Brintellix was approved in September 2013. Due to continued reports of name confusion between the two medicines used for very different purposes, FDA worked with Brintellix manufacturer Takeda Pharmaceuticals to change the drug’s brand name.”


(Albany, NY: May 3, 2016)
The New York State Board of Medicine has announced a new literacy test for physicians seeking to practice medicine in New York State

Multiple Choice Test for Medical Licensure in the State of New York:

Select the correct answer from the four choices:


1) These two drug names start with the same three letters, which means they can be substituted freely for each other, like herceptin and heroin
2) These two drugs start with the same three letters, but otherwise are different
3) These are names of towns in upstate New York; each has a Post Office, an Arby’s, and a gas station. They are indistinguishable, and can be substituted freely for each other, like Utica and Ithaca
4) These two drug names are indistinguishable, so Brintellix should be given a new name–something like Trintellix, or maybe Toronto

Correct answer: #2

Licensure candidates who chose #1: the DEA has some questions to ask you
Licensure candidates who chose #3: Your medical malpractice coverage has been terminated
Licensure candidates who chose #4: the FDA has a career opportunity for you

Ed. Note: Takeda/Lundbeck have already had a hard enough time establishing/differentiating Brintellix, no thanks to the FDA, which went against the recommendations of its own AC in rejecting the Brintellix label-expansion application.  Now they must, to some degree, start over. Isn’t it reasonable to expect physicians and pharmacists to be sufficiently attentive and literate that they can differentiate these two drug names? How dumbed-down does this system need to be?

Other Notes
Just as the May-June issue of NeuroPerspective was being released, the FDA granted approval to Acadia’s pimavanserin/Nuplazid, with the expected black box warning. While generally expected, it was still something of a relief to see the FDA follow through on its own stated willingness to grant approval based on one Phase III, and to see the Agency go along with the recommendation made by its own Advisory Committee. This interrupts a sequence of ill-considered and/or ill-communicated decisions announced over the past two months, vis-a-vis Newron’s Xadago, Takeda/Lundbeck’s Brintellix, and Catalyst Pharma’s Firdapse.

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A Fond Farewell to My Cali-Irish Lass

My Dearest Allergan:

The last few months have felt like a dream–you and I idling away the hours by the Irish Sea, picking out a spot for our new corporate cottage, singing the names of the staff we were going to keep, whispering the names of those to be laid off. Now we will have to comfort ourselves with what might have been. I particularly regret having left it to our corporate counsel to let you know the sad news–that it’s over. I should have had the courage to tell you myself. It probably felt terribly sudden and cold, it’s not how I wanted it to be, but I think you know it’s best for both of us.

You may be wondering–Was it all about the money? Is that why I am leaving you?  No, of course not. Well yes, that’s a big part of it, but not all. We come from different backgrounds, you and I, very different cultures. You being from Southern California, er I mean, Ireland, me from….well I’ve lost track at this point–it’s all very confusing. I’m not sure who I am now, and I don’t want to burden you with it all. To be honest, I’m not sure I ever really got over Astra, she still haunts me. I have a lot to think about, as does my Board–two failed engagements in two years, I just don’t seem to be good at the relationship thing.

As the Pfizer counsel probably mentioned, I am sending you some money–I know it’s not much, but at least it will help you with a fresh start.

There’s just one more thing. You deserve honesty, and you shall have it:  When you smile, your mouth kind of changes shape, but your eyes don’t move at all. Nothing. Nada.  It sort of creeps me out. You might want to dial back on the Botox, I think you may have overdone it.


Ian Read

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