[U] "Salmon, Rising" -- Sarepta's Exondys 51® [Eteplirsen]: For Duchenne MD

While we wait patiently for The mighty battleship rises(!), takes the fly and line, running free now -- on this crisp cool clear fall Sunday morning. I'll post the graphic I just finished -- which gives a sense of the scale of this molecular entity. [Recent backgrounder of mine, here.]

That is one honkin' big structure. Okay Salmon -- the graphics are loaded; the FDA's new meds science guy has weighed in on your side -- and so now we await post your take (Parts I and II).

. . . .Salmon rising:

First a correction. As you noted the press is claiming the advisory committee voted 7-6 against approval. Actually the vote was 7-3 with 3 abstentions. Abstentions are often the made when people want to vote no but are afraid of the political fallout to their careers such as denial of future grants. So the advisory committee vote was clearly lopsided against approval.

The documents the FDA has released about this are also fascinating with regards to the internal politics.

Although the press has made it out as this was Ron Farkas, the team leader, who was holding up the approval this is not the case. First the team leader takes his cue from the primary reviewer.

Then not only was the primary reviewer and the team leader against approval, but so was the Neurology Division Director who writes the recommendation. It then goes to the Office Director, Ellis Unger, who makes the final decision and he was also against approval. Above the Office Director is the Director of the Office of New Drugs, John Jenkins, who was also against approval. It was at this point that Janet Woodcock was clearly pushing for approval as indicated by her statement at the advisory committee meeting.

Ellis Unger then took this to the Scientific Review Board. The Scientific Review Board then sided with Dr. Unger and said it shouldn't be approved. As Dr. Woodcock was then going to abuse her authority and issue an approval anyway Dr. Unger then made an appeal to FDA Commissioner Califf who basically said you had your opportunity to be heard through channels but I'm leaving the decision up to Woodcock. (Since the FD&C Act actually gives the approval decision to the Secretary of HHS it's delegated down. So Califf, by giving the decision to Woodcock, in fact made the actual decision.)

There have also been op-ed articles in the press and blogs on the internet that are clearly misleading. One such post from a former FDA official who is now an industry consultant claimed that the AC vote was rigged because the AC members were asked whether the study was adequate and well controlled. Yet this is the legal standard in the Food Drug and Cosmetics Act which requires it be determined by experts in the field. Thus he criticizes the FDA for simply asking the AC members if the drug met the legal standard for approval which the AC members (who are experts in Neurology who the law specifically says must make such a determination) essentially said it didn't. Whereas (in actuality) the decision was made by a single non-expert Janet Woodcock.

In another post an industry front group claimed that an FDA insider told them that this was just people inside the FDA who were overly concerned about safety. Yet there were essentially no complaints about safety by anyone opposed to approval and it was all about that the drug simply hasn't been shown to work. I've noticed that this is a meme that has been recently been put forth by industry in a lot of complaints about the FDA in attempts to decrease approval standards. While I don't know who the FDA insider is we need to consider that it has to be someone who has knowledge of the review and has the connections to actually speak to this (small) industry front group and get their position out and who has a particular ax to grind. In my [Salmon's] opinion the most likely candidate for this FDA insider (as someone who actually has knowledge of the situation) is Janet Woodcock. Clearly not someone who is impartial and who is someone who likely to leave the agency soon and move on to be on boards of directors.

As for costs: It's being claimed that the costs will be $300,000 per year. However this will be after rebates of 50%. Now I don't know what private insurer will allow payments for something that clearly all the experts have said hasn't been shown to work. Thus it's likely that the costs will fall on Medicaid and since Medicaid can't negotiate prices I don't know what rebates will actually be offered. Secondly this $300,000 (actually $600,000 per year) is based on a dosages for a kid weighing 25 kg (i.e. and 8 year old) with doses going up based on weight. Now an average adult male is 75 kg and assuming a linear dose relationship we could be talking closer to $2 million per year per adult patient. Plus have you seen the photos of some of the kids who testified and can barely walk around. They're morbidly obese. So with a 1000 kids nationwide we could easily be talking a $1 Billion per year. Plus if the bill before the senate passes (which Obama has promised to sign) other indications can be approved based on anecdotal claims. So for the other 90% of people with other forms of Muscular Dystrophy we could be talking $10-$20 billion per year for a placebo. (Now the finances are not my forte so if rebates are bigger than I expect, it might not be this high.)

As for parents and anecdotal data: One mother who testified at the AC meeting has a blog and is claiming Exondys will allow her kid to function and hold a job and not be a financial drain on society. How? Even if it works as claimed were' talking about slowing down a progressive decline and the kids will still barely be able to walk. Do we really believe that they won't be so physically overwhelmed that they will be able to run around and hold a job and be independent. I don't think so. In truth I think it would be cheaper to simply pay for round the clock care for these kids than to waste money on something that as of right now we don't have any good evidence that it's anything other than a placebo.

As for the claims that it's safe: It's only been tested in 12 kids! Since it takes at least 3 times as many people as the incidence that something occurs at to make sure you see at least one case of something, this means the only thing we can say is that the rates of various serious adverse reactions such as death likely occur in less than 1 in 4 people.

It this the kind of decision-making we want? "Well there's no evidence it works -- but it turns out to kill 1 out of every 5 kids who take it. . . .?" I'm not saying this will be the case for this drug, but that's the standard we're putting in place and it (or something similar) will occur eventually.

While my comments may seem harsh as to the families -- I truly do want the best for their kids. But when you approve things that have not been shown to work but you believe it might no one is going to sign up for studies the confirmatory trials or for new drugs from a different company that might actually work and truly help their kids. So if they or others have kids in the future with this horrible disease they may very well be condemning them to not having any effective treatments when there might have been if they hadn't insisted on an approval for a drug such as this before it had been shown that it actually works. . . .

There you have it. We will keep an eye on the law of small numbers effect, here -- to see whether it dissipates, or worsens -- in the ongoing larger clinical post-marketing studies. But I agree -- up and down the line -- with Dr. Salmon. Thank you once again, man.

And now, in truth, I Can't. Stop. Smiling. My. Cubs. Are. Series-bound. [Sadly, I was in a box-seat, in the friendly confines, on the night of October 14, 2003 -- the unlucky thirteen years ago, when they were just five outs away from the Series -- and well. . . Bartman happened, to Moises Alou. The Marlins went on to win the NLCS series. And we waited. And waited.] But now, we have returned the doorstep of history, once more. . . smile. Onward, to Cleveland -- Tuesday evening.

नमस्ते