I am apologizing in advance for the series of lengthy illegible disorganized slides that you are about to see. But I hope that I don't completely undermine the story that I am going to tell because it really is remarkable in many ways. I think I've been set up very well by the previous two talks both of which were excellent. And I can't say how refreshing it is to not be the only fire-breathing radical on a panel.

I was trained in genetics. I work at Duke in Genome Sciences and Policy. I've done some work on intellectual property and gene patenting and this case came to my attention and my colleague's attention when the plaintiff's attorney for a group of patiens suing Genzyme and wanted some information and advice. Fabryzme. The more I looked into it the more fascinated I got with what was going on. And decided that instead of doing research to produce generalizable knowledge as we say on the IRB, that I will just try to write a magazine article about and I have been working on this for the last several months.

"Forward-looking statements and flaming hypocrisy disclore slide". You are free to re-broadcast this and so on. But it's very important that you understand that this is a work in progress. I am filling in at the last minute and I am working on this story as a journalist and none of this has been fact checked or peer reviewed and I am going to do my best. The goal is to publish something that will get as many people's attention as possible.

What is Fabry disease? It's a recessive disease, it's an enzyme deficiency that leads to a progressive accumulation of metabolites in the cell. It effects 1/40,000. There are many mutations in the GLA gene on the X-chromosome. A patient told me, how do you feel, and he said like 1000 needles are jabbing my foot. It has various other clinical features I will show you pictures of those. And a lot of patients who live into their 50s and 60s wind up with end-stage renal disease and various heart problems and susceptibility to stroke.

Females unlike what yuo were taught in highschool biology, they are not merely unaffected carriers, so there's this phenomnon called x-inactivation where one of the two female x-chromosomes are turned off, randomly during embryogenesis and depending on this how this goes, females can be quite severely affected as well and their lives tend to be reduced 15 years. Male life expectancy is reduced by 20 years. So that thing turned red is a lysosome. And when this enzyme can't do its business, the cell fills up with junk and this is a graphic depiction for those of you who are biochemically inclined.

They are visible. Coronal oppoacities.. some patients get diagnosed by dermatologists and opthamologists and kidney docs. There's a subtle sorta current characteristic. 

Like other diseases, in-born heirs of metabolism.. they are enzyme defects and there's this guy named Rosco Brady that still comes into work every day at NIH that showed in the early 70s that you could actually give people enzyme. Give people with lysosomal storage disorders an enzyme that would alleviate their symptoms. The problem was where would you get enzyme and initially, they had set up this kind of placenta processing factory where they would get placentas sent from around the world just to produce a few milligrams of enzyme. The recombinant version of the alpha-glucatose..-a gene was "invented" by Bob Desnick at Mt Sinai School of Medicine. He is one of the towering figure in lysosomal storage disease. There was a series of clinical trials and Fabrzyme, the recombinantally produced enzyme was approved in Europe in 2001 and in the US in 2003. And this is the 804 patent.. the main patent issue in the litigation.

This is a fairly remarkable document that has been filed actually by the defendants in the litigation and it's the licensing agreement between Genzyme and Mt Sinai School of Medicine conferring an exclusive license to make and sell. All of the numbers are blacked out, unfortunately. I assembled this figure from various public sources. SEC documents. Analyst reports. And Replical... and it's a similar enzyme made by Shire Pharmaceuticals based in Europe. They were neck-and-neck in the early 2000s and are co-exclusive in Europe. Replical was not approved in the US. It was then made by a small biotech called Transkaryotic Therapies. Fabrzyme was the 800 pound gorilla until 2008 and then its sales started to drop off. We will get into why that happened. And Replical was the beneficiary of that at least in Europe and the rest of the world.

As I mentioned, it was approved in the early 2000s. There were post marketing studies.. most of them small since there's so few patients. They manufacture it in Boston, MA. The thing that initiated this whole area was the fact that Fabre Disease and Goshay Disease and Pompay Disease.. if you've seen that movie with Harrison Ford and Brendon Frasier whose name escapes me.. that's about pompay disease. Genzyme makes pills for that too. These are diseases with less than 200,000 patients. So inventors are givne 7 years of exclusivity beyond the exclusivity of the license that Mt Sinai conferred to Genzyme. So as I said, things were going swimmingly, they raised the price from a 70kg man for a year's supply of Fabrzyme or Replical was on the order of $165,000. And the treatment for Goshay was in the range of $200k-$300k. By 2009 it was approved in 40 countries. Last year that 7 year period of exclusivity ended and in 2015 the 804 patent will expire. So what happened in 2008?

In 2008, the FDA inspected the Allston facility. It did not like what it saw. It issued a form FDA 483. That's not something you want to get in drug manufacturing compliance. Genzyme's account of this visit said that the FDA saw significant deviation in compliance but that the products in the Allston facility continue to meet the highest quality and safety standards. One of the curious things to me was that even before this inspection took place, Genzyme had initiated a study of what happens if you cut the dose of Fabrzyme to Fabray patients? So this was published in April 2009 after that inspection but before there was any official shortage. The conclusion said that nevertheless that there was variability in responsiveness.. and that dosing strategies that deviate from recommended doses be systematically monitored.

Why is this telling? This study was funded by Genzyme and it included six months on full dose. These were adult male patients, and 18 months on 1/3rd dose. This was launched, this study, in 2006. In 2009 lots of bad stuff started to happen. Viral contamination started to happen. The company updating the FDA on what was going on at the Allston facility. The FDA sent a warning letter and finally in June the shipments from Genzyme were suspended for the rest of the year and the FDA asked for an explanation. There was litigation about patent infringement. There was another inspection and 483. And in December, Replical came available to a small number of patients. Shire Pharmaceuticals, which owned Replical, was giving it away to 100-140 patients. At the end of the year, Genzyme subcontracted its fill and finish its last stage of drug preparation operations to Haspira.

Things just went from bad to worse. There was report of pieces of steel and rubber and other contaminants in Genzyme's manufacturing facilities. In 2010, in the early part of the year, the shipments were resumed and patients were on 1/3rd dose. Their sales were growing more slowly and by June the Replical access program ended very suddenly. The FDA said that this would cost you guys $175 million. This was the discourgement payment of $175 million. The FDA is presumably overseeing all Genzyme manufacturing.

Replical / Replagal. By 1999 it had fast-track status, it had orphan drug status, it submitted for approval both here and in Europe in 2000. Genzyme sued for patent infringement and Transkaryotic said "Oh yeah, two can play at that game". In 2001, the FDA requested additional data. It launched in Europe that year. And in 2003, said, the FDA said your endpoints don't demonstrate ethicacy and we want a head-to-head trial. There was various other legal proceedings. By 2004 it was available for sale in 28 countries. In 200x, Shire bought the company. It resubmitted in 2009, and then the FDA said that it needed more pharmacokinetic data. So Shire withdrew its application again. As you understand already, well into the Fabrzyme shortage. Meanwhile, Mt. Sinai sued Shire for patent infringement in the European Union. Replagal patents will begin to expire over the next couple of years.

This was the patient's petition to the FDA citing 11 instances where Genzymes said that it would have manufacturing back up by such-and-such date or that supplies will be normal at such-and-such date. Genzyme is banking on its new facility in Framingham, MA. It will include four 2000L reactors for Fabrazyme and Cerezyme. The latest news is that this new facility will be approved and that Fabrazyme supplies will be back up in the first half of 2012 and that patients are understandably skeptical.

This is from a recent sorto f supply update letter to patients and physicians and Genzyme says that, Allston is never going to deliver supplies. We're counting on this new facility. So, uh. It's relying on various things. Meanwhile earlier this year, Genzyme was sold to Sainafe, a French pharmaceutical company, the second biggest biotech deal ever (a little more than $20 billion). One of the things that Allen Black would discuss if he's here, this view that European Fabray patients are being treated differently than US patients.

This goes back to the original announcement of the shortage. Genzyme convened a group of so-called stakeholders. You can't see their names, but basically they were Genzyme employees, docs, patient representatives, who were funded by Genzyme in some way. There was nobody independent on this group. And they said, um, sorry, US patients, you are going to stay on reduced dose. Instead of getting your drug every other week, you'll get it once a month. And meanwhile, in Europe, physcians were told that if your patients are getting sicker - and inevitably they were - then you can restore them to full dose. And we see several examples of this in Dear Healthcare Provider letters.

And this became public. The European Medicines Agencies said that we want our patients on full dose. The FDA never said that. In the wake of the lawsuit, Genzyme says why are patients treated differently in different regions. Why are european patients treated with full dose? Genzyme says, well, we don't make treatment recommendations we're just a drug manufacturer. You'd have to talk to the doctors in Europe. Patients have petitioned Health and HUman Services, both NIH and FDA. NIH has denied this petition saying if we march in, if we liberate the 804 patent, it's not going to help because we're going to need years of clinical studies and regulatory studies. Anybody interested can still do clinical trials, and Genzyme seems to be trying to fix the shortage. So last year, and again this year, patients have initiated a class action suit.

So where are we now? It's still possible that FDA can hasten the approval of Replagal. I am mystified as to why that hasn't happened. Except for individual patients, everyone in this story has a conflict of interest. The court case is probably going to take years. It's not going to help this current group of adult patients whose kidneys and hearts are deteriorating. Genzyme took a risk in the 90s in developing this kind of therapy when nobody else was interested, it has improved thousands of lives, but somehow it went off the rails. And just because I'm a provacator, I leave you with this quote from this outgoing CEO of Genzmye. "We created a company worth minimally $20B+, I feel identified with some of that. I wasn't am anager. I created value. So I don't feel tremendously sensitive to receiving as much as $221 million after this sale. But I completely accept that these numbers are high. It's just the way that it worked out after 30 years."

Thanks.