Orphan Radiopharmaceuticals And Other Libations

It has been a few years since I've made it to the Society of Nuclear Medicine annual meeting, so long actually that the Society has since changed its name, and is now called the Society of Nuclear Medicine and Molecular Imaging, I personally think this was prompted by the unfortunate amusement among the puerile (like yours truly) related to the original title's initials. SNMMI just doesn't have the same ring to it, but they don't ask me about these things. 

The exhibit hall is about 1/50th the size of the massive trade show at the RSNA, but most of the big players have a presence.

Herr Großkopf, the huge animated head, graced the Siemens booth, touting Amyvid. My new Intevo SPECT/CT was perpetually scanning a rather eerie half of a patient, also created by the geniuses of Legacy Effects. (By the way, if you want to see more on the production of Herr Großkopf, try this YouTube video:  http://youtu.be/L3gE1Zp9Vt8

It is a humbling experience to sit in the educational sessions presented by those quite a bit smarter than I am, and realize just how much I don't know. But somehow, we average rads/NM physicians do manage to muddle through. We can't all be the best of the best, but I'm grateful to those who are the best for their willingness to share their expertise with the rest of us.

I'm often asked how Nuclear Medicine differs from Radiology. The simple answer is that with the latter, we somehow externally energize the body, or pass energy through it; an X-ray is taken by passing the beam of radiation through the body and detecting what is blocked and what is transmitted. With MRI we spin your molecules, and with Ultrasound, we bounce sound waves off your tissue interfaces. You get the idea. 

Nuclear Medicine is different. Here, we inject some radioactive stuff (in the case of PET, we use honest-to-God antimatter) into your body, or make you drink or eat it, breathe it in, or in some cases instill it into places God did not intend us to instill things. We then use very sensitive detectors to see where the stuff went, how long it takes to go away, and so on. In the proper doses, some of the agents can be used for therapy as well. The stuff we give you is called colloquially a radiopharmaceutical, basically a drug with a radioactive atom attached to it, or in the case of radioiodine, the radioactive isotope of the element itself, delivered as sodium iodide, is given to scan, treat, or even ablate the thyroid, which gobbles up iodine, radioactive or not. 

The bottle of wine above isn't really a radiopharmaceutical, but I found it amusing as the term MUGA refers to a Nuclear Medicine heart scan, generically known as a Multiple Gated Acquisition. There were dozens and dozens of new scanning agents being discussed at this meeting, and at least some of them will be approved eventually for general use. Hopefully. That process takes a long, long time, and I'm told new drugs require a $4 BILLION investment each. Given this, you would think that a successful product would be celebrated and propagated.  You would be wrong.

One of the big areas of research in diagnosis and therapy involves labelled monoclonal antibodies, basically a radioactive atom attached to a natural molecule that targets some particular tissue. These so-called magic bullets have been somewhat disappointing overall, not quite magic after all. But some have worked, and in particular, a couple of these compounds, Zevalin and Bexxar, directed at treatments of some forms of lymphoma have really performed quite well. The antibody seeks out the tumor (actually a particular protein on the tumor surface) and the radioactive atom blasts away. For once, the term "cure" can be tossed around for patients who had failed other regimens. Zevalin uses yttrium-90, while Bexxar uses iodine-131 as its nuclear bomb, so to speak. 

I've administered both of these therapies. They are horrendously expensive, with pricetag of the pharmaceutical alone exceeding $26,000. Medicare paid us perhaps $15-17k, so there is a potential loss on every dose which much be made up by charging those with other coverage upwards of $100,000.  I've had more experience with Bexxar, and that experience has been good. We've achieved a number of complete remissions and we had no deaths that could be attributed directly to Bexxar. Our one Zevalin patient did not survive, but that is most likely due to the fact that this therapy wasn't applied until that particular patient was at death's door. Another shop in town did quite a few of these therapies, ending several years ago; some of the patients are now coming back with white cell depletion, a known complication when you are placing radioactive stuff right in the marrow. It's a problem, but one that they wouldn't have had without this therapy because they would most likely be dead.

One of the lectures this week at SNMMI touted the virtues of Bexxar, noting that as compared to Zevalin, its administration offers at least an attempt at radiation dosimetry. We give tiny doses to see where it goes and how fast it is eliminated, and base the final dose on that data. It's not complete, but it takes an army of physicists to do better, and out in the field, this is pretty advanced stuff.

Sadly, Bexxar, a very good treatment, is being pulled off the market. Why? Because the $100,000 per dose radiopharmaceutical couldn't turn a profit.

Jamie Reno, a Bexxar patient himself, writing in The International Business Times, bemoans the loss:

The discontinuation of Bexxar is an extreme example of a lifesaving drug being eliminated due to its relatively low profitability. In most cases, when a pharmaceutical company concludes that a niche drug is not making enough money, the product is sold to another, smaller company which continues to make it available. But continued availability is left to the discretion of the company (or companies) that owns the rights to the drug, which is how pharmaceutical companies can withhold potentially lifesaving experimental drugs that have not yet been approved by the FDA -- often, due to concerns that a potential problem resulting from such use could jeopardize the drug's ultimate approval.

Luke Timmerman, on Xconomy.com, traces Bexxar's history:

Bexxar, developed in the late ‘90s by South San Francisco-based Coulter Pharmaceutical and acquired in 2000 by Seattle-based Corixa, had a lot going for it. The drug was aimed at a protein marker called CD20, which was already a validated molecular target for cancer, based on the success a couple years earlier of a so-called “naked” antibody from Genentech and Idec Pharmaceuticals, rituximab (Rituxan). Corixa had a well-respected CEO in Steve Gillis who attracted scientific talent, and raised lots of cash. It had a Big Pharma partner in Glaxo to help it manufacture and market the drug to the fullest.

{snip}

Corixa, unable to turn Bexxar into a profit center, ended up being acquired by GlaxoSmithKline in 2005.

Without boring you with reams of positive data, suffice it to say that Bexxar worked, and worked well. There was talk of using it as a secondary or even a primary therapeutic agent, rather than a last-ditch hail-Mary for those who had failed all other regimens. But it was not to be. Timmerman continues:

But there was a catch. Oncologists who saw these non-Hodgkin’s lymphoma patients could prescribe rituximab at an infusion center, along with chemotherapy. These doctors made money on every patient that went through their infusion center. Prescribing Bexxar meant they’d have to forgo that revenue stream, and refer the patient to a nuclear medicine pharmacy or radiation oncologist who could handle Bexxar or Zevalin.

“There were complicated logistics with having oncologists refer to another part of the healthcare system they normally didn’t interact with,” Rivera says. “We couldn’t get them to change their habits. The doctor would usually say ‘Oh, I’ll give the patient another course of R-CHOP’ (Rituxan plus a specific chemo regimen) instead.”

Younes, the chair of lymphoma at Memorial Sloan-Kettering, has heard the story about oncologists rejecting Bexxar because they didn’t want to refer patients to medical centers that might be seen as competitors. He says that point is “exaggerated” and notes that oncologists refer patients to other specialists all the time. He points to other problems with Bexxar’s commercialization. “It’s almost a comedy of errors,” he says.

Are we to believe that the very people who were supposed to be saving patients walked away from a cure over profit? I'm trying hard not to... There were other factors, though:

There was a muddled clinical trial strategy, Younes said. Multiple trials were opened up to expand Bexxar usage, which may have been well-intended, but the plan ended up confusing physicians about where the drug was most useful, Younes said. A lot of clinical trials were sponsored, making it possible for many patients who might have paid to get the drug to instead get it for free. Then at one point, Glaxo abruptly shut down all the trials, Younes said.

“They ended up pissing off a lot of people,” he said.

There were headaches in manufacturing an antibody that was linked to radiation. The radioactive piece of the drug came from a supplier in Canada, and the occasional snowstorm would throw the whole supply chain out of whack, causing patients infusions to be delayed, Rivera said. That was a big inconvenience for some patients who sometimes had to drive hours for a scheduled infusion at a big academic medical center, Rivera said.

So what constitutes bad sales? Reno gives us the numbers:

While Bexxar saved this writer’s life in a clinical trial in 1999 with virtually no side effects and has saved many other lives, sales of the drug did not meet GSK’s expectation. Catalina Loveman, GSK’s director of U.S. external communications, oncology, told IBTimes that total sales of Bexxar in 2012 in the U.S. and Canada were approximately $1 million; for comparison, the blockbuster drug Viagra earned Pfizer a reported $2.05 billion in sales in 2012.

Everything is relative.  I guess it didn't occur to GSK that those who survive lymphoma might eventually become Viagra customers. Oh, well. I guess a few thousand lives pale in comparison to a few million...well, need I say it?

Zevalin will remain on the market because its owner has a different outlook:

Like Bexxar, Zevalin has also struggled in the marketplace. In the third quarter 2013, Zevalin’s profits were $8 million. But unlike GSK, Spectrum Pharmaceuticals, makers of Zevalin, is committed to keeping this drug on the market.

“What is happening with Bexxar is virtually unprecedented,” said Spectrum’s chief operating officer, Ken Keller, who came to Spectrum a year and a half ago from California-based Amgen, the world's largest independent biotech company. “I do not know of a single example of a drug company that has walked away from a drug that is this effective. Typically, when a company gives up on a treatment that works this well, they will a find a smaller company to sell it.”

Keller acknowledged that neither Bexxar nor Zevalin has been able to break through and become the blockbuster drugs that he says they both should be.

“I’ll be honest: We don’t gain a lot of value from Zevalin,” he said. “We have the data that shows how well it works, but it has still not caught on with many doctors. However, Spectrum will continue to manufacture Zevalin because our CEO [Raj Shrotriya] is on a mission to make RIT the standard of care for lymphoma in the U.S.. If this were only about finances, it could lead to different decision. But this treatment saves lives, and we believe we have an obligation to cancer patients. They deserve to have access to it.”

Why was Bexxar quashed? Only GSK really knows for sure. Maybe their Board of Directors all own stock in Spectrum. Information from a friend of a friend of a friend of a cousin of a sister of a guy who knows something indicates that the move was deliberate and based purely on profit or the lack thereof. Maybe someone looked into the zillion pages of ObamaCare as currently morphed and decided GSK would NEVER see any profit, let a break-even point, on Bexxar.

It occurs to me that this whole episode (put very nicely) represents a complete disservice to our patients. We have in Bexxar a VERY good treatment, a lifesaving treatment, and it was scuttled because oncologists wouldn't use it, and they wouldn't use it because they couldn't make money on it, so neither could GSK. Does anyone else find this sickening?

But I'm prompted to think outside the box.

I've become mildly addicted to Kickstarter and Indiegogo, crowd-funding sites that promote anything from researching burritos to sending people on a one-way trip to Mars. (I've personally helped fund a couple of smart-watches that haven't come to fruition and probably won't, and a few other frivolous items.)

I don't know IF GSK would consider selling the rights to Bexxar, and if they would, I don't know how much they might want for something they buried in their corporate backyard. If the price was reasonable, I would buy the rights myself and find a way to get Bexxar back on the market. Assuming the price tag is a bit above my weekly allowance, the next step might be a Kickstarter campaign for interested parties to pick up the tab. This would include not only people like me who want Bexxar to be available, in my case as a physician, but also patients and their families as well. It would, of course, be critical to attract folks who have connections in the pharmaceutical industry who could actually put Bexxar back into production.

To my knowledge, this has not happened before. We've all heard of orphan drugs, but I can't think of any/many that were actually completely suppressed in this manner. Nor have I ever heard of a consortium of the type I propose above rescuing a valid treatment from oblivion. But this needs to be done, and I challenge you to join me to do it.

GSK? Docs? Patients? Family members? Are you listening?