Parsley, SAGE, Marathon, and Timing

–with apologies to Simon and Garfunkel, 1966

SIDE A

NIR has long been an admirer of how SAGE Therapeutics has been able to leverage predictive power from tiny pilot studies in Severe Status Epilepticus (SRSE) and Post-Partum Depression (PPD)—but today’s open-label depression results require much more sodium intake. In SRSE, the risk of a placebo response is essentially zero, and in PPD, there is compelling biology linking PPD and allopregnanolone, depletion of the latter heralding the utility of supplementing that hormone. But in Major Depression, if allosteric GABA-A activation truly offers such a rapid avenue to dramatic and immediate relief in MDD, that will require a rather drastic rethinking of how depression, and antidepressants, work. It is not as if we haven’t had GABAergic drugs fail to show benefit in depression before (e.g. benzodiazepines). We are curious about the gender makeup of the 13 patients, and the frequency of somnolence/sedation, not only as a side effect to consider, but as a driver of the placebo effect (’something is happening to me…’). If they can replicate this magnitude of change in the double-blinded, controlled Phase II, that will be very impressive. SAGE’s track record has earned them credibility, but here, science mandates considerable skepticism.

SIDE B

The January/February issue of NP included a satirical sidebar about ‘ToneDeaf
Therapeutics.
’ Unfortunately, Marathon Pharmaceuticals did not get the memo–or the hint. Marathon received FDA approval for deflazacort, a corticosteroid used in the treatment of Duchenne Muscular Dystrophy, but they then marched themselves into a public relations debacle.

1) Marathon announced that the drug will be priced at $89,000 per year. Previously, US families could obtain deflazacort from the UK for about $1600 per year. Marking up a drug more than 50-fold in an environment sensitized to such things by Turing,
Mylan
, and Valeant is like hanging a giant ‘kick me’ sign on one’s hindquarters. Do these companies not learn from the errors of their predecessors?

2) Marathon’s CFO, Babar Ghias, attempted to downplay the pricing issue by telling the WSJ that “Marathon estimates it will keep  only 61% of $89,000….or$54,000.” Most people are not going to see this as ethical or compassionate, it’s like reducing the price of a bottle of water at Coachella from $20 to $13.

3) Ghias stated that the other 39% would go to Medicaid rebates, copay coupons, and discounts, the kind of complicated shell game that makes the pharma industry seem more imbued with scam than science.

4) Ghias was also quoted by the WSJ as saying “more patients will have access to the drug because their health insurers will begin covering its cost now that it has FDA approval.” This is the insurance fallacy, the pretense that drugs covered by insurors have no cost to patients–they do, in terms of the premiums charged, as well as the out-of-pocket costs faced by those with high deductibles.

5) We do believe that a company that works to get US approval for a drug previously not available or validated here deserves to make a profit on the work done–such as Catalyst having to run Phase III trials for Firdapse in Lambert-Eaton Syndrome. But the magnitude of the profit margin has to pass some kind of smell test, and Marathon fails that test even as they claim: “the company showed restraint in how it priced the drug. Other new drugs for so-called orphan diseases, which by definition affect fewer than 200,000 people nationally, have carried price tags of $300,000 annually and higher.”

The $300K price tags the CFO referred to are attached to orphan drugs where there were significant R&D costs and risks borne by the developer, and where the drug often has a life-saving or changing component. Marathon took on limited clinical trial costs and very little risk, and while deflazacort is useful in DMD, it is purely symptomatic, providing some improvement in muscle strength. Referring to the ultra-priced drugs as a marker for ethical execution is a false equivalency, and does not make the case for this pricing.

With the current President having recently said “The (drug) pricing has been astronomical,” Marathon has now put itself in the crosshairs for whatever company-bashing will inevitably come next: They made a bad decision and are only digging themselves deeper in their clumsy attempts to justify it. Marie Antoinette said ‘let them
eat cake
’, and that did not work out so well. Pharma companies think coupons and the hope of insurance coverage provide them with sufficient cover from attack, but they do not: The mob is assembling, carrying torches and an assortment of sharp objects.

 

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One Response to Parsley, SAGE, Marathon, and Timing

  1. rogawski says:

    Harry, I completely agree with you on the issue of Sage. And, it is true that benzodiazepines do not have antidepressant activity. However, neurosteroids, such as allopregnanolone (active ingredient in SAGE-547) and the oral drug SAGE-217, are not benzodiazepines. Benzodiazepines are highly selective for certain GABA-A receptor isoforms and don’t touch other isoforms. Specifically, benzodiazepines only affect synaptic GABA-A receptors. Allopregnanolone has about equal activity on synaptic and and extrasynaptic GABA-A receptors and I (believe) SAGE-217 has about the same relative potencies. Having said this, I agree that it will be extremely surprising if the depression result holds up (other than in PPD). On the issue of pricing: Isn’t it the legal imperative in the U.S. for a company to maximize shareholder value? Since when do patients or the economy come into play? The people who are not “ethical or compassionate” are the people that (1) ruled in the court cases creating this legal imperative, and (2) the people who refuse to change the rules of the game. Demonizing Martin Shkreli or Heather Bresch or Marathon is wonderful theater for a Trumpian age of bullying but it is irresponsible because it deflects attention from the real villains — the hypocrites in Congress who blame the industry and refuse to buck up and make proper laws. Mike Michael A. Rogawski, M.D., Ph.D.Professor of Neurology and PharmacologySchool of MedicineUNIVERSITY OF CALIFORNIA, DAVISSacramento, CA 95817rogawski@yahoo.comrogawski@ucdavis.eduM 916-801-5714

    From: neurogram To: rogawski@yahoo.com Sent: Monday, February 13, 2017 9:09 AM Subject: [New post] Parsley, SAGE, Marathon, and Timing #yiv8788714629 a:hover {color:red;}#yiv8788714629 a {text-decoration:none;color:#0088cc;}#yiv8788714629 a.yiv8788714629primaryactionlink:link, #yiv8788714629 a.yiv8788714629primaryactionlink:visited {background-color:#2585B2;color:#fff;}#yiv8788714629 a.yiv8788714629primaryactionlink:hover, #yiv8788714629 a.yiv8788714629primaryactionlink:active {background-color:#11729E;color:#fff;}#yiv8788714629 WordPress.com | NeuroPerspective posted: “–with apologies to Simon and Garfunkel, 1966SIDE ANIR has long been an admirer of how SAGE Therapeutics has been able to leverage predictive power from tiny pilot studies in Severe Status Epilepticus (SRSE) and Post-Partum Depression (PPD)—but today’s” | |

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