IMMUNE INDUSTRIAL COMPLEX

In the last half of the 20th century two classes of drugs—each in their own way– altered the futures of huge swaths of the planet’s ill.  I call these medications “game changers.”  

THE IMMUNE INDUSTRIAL COMPLEX

The immune system (and our skin, and intestinal wall) protects us from micro creatures that live in and on our body.  It recognizes protein that doesn’t belong, tries to destroy cancerous cells, and it mounts a defense when we encounter the flu bug, a vibrio that causes cholera, or the tuberculosis bacillus.

B and T lymphocytes that are intolerant, that view our own tissue as foreign, are usually destroyed or inactivated before they mature.  At times some of them escape and attack.  When they do they can destroy vital organs, trigger painful joint swelling (rheumatoid arthritis), cause abdominal pain and bloody diarrhea (colitis), and attack the brain (multiple sclerosis) and kidney (lupus).

,We can temporarily control many of the body’s immunologic assaults with cortisone derivatives, but our body pays a price.  In recent decades a number of immune modulators have emerged.  Some have huge annual revenues:

When patients talk about high drug prices and major out-of-pocket costs they are often referring to one of the big three:  Humira (which in generated $19.9 billion in revenue; Enbrel/etanercept-$7.1 billion; Remicaid/infliximab-$5.9 billion.  Their companies recently got a tax break.)  The medicines act by blocking a pro-inflammatory molecule called TNF.

The story of their creation goes back to 1980 when a British researcher named Hilary Koprowski patented a process for making monoclonal antibodies.

(The technique he patented had been developed 6 years earlier in Cambridge England by George Kohler and Cesar Milstein: They injected purified protein into a mouse.  One of the lymphocytes floating in the creature’s blood realized the injected amino acid sequence was foreign and that it had to be destroyed.  The lymphocyte started cloning itself and making antibodies that would tag the protein for destruction.  Days went by.  Then Kohler drew blood from the animal’s spleen.  A large proportion of the mouse’s lymphocytes were clones of the original cell and their antibodies targeted the invader.  Kohler managed to fuse some of the lymphocytes to malignant plasma cells, cells that kept reproducing and didn’t die.  The fused entity, called a hybridoma, kept replicating and fabricating large quantities of the antibody to the original protein.  The investigators were awarded the Nobel Prize, but no one patented the technique until Koprowski came along.

With patent in hand Koprowski and an entrepreuneur named Michael Wall formed a company named Centacor and they tried to figure out how turn mouse monoclonal antibodies into gold.

At some point Michael re-met Jan Vilcek, a Czech researcher at NYU who studying one of the body’s immune regulators, a substance called Tumor Necrosis Factor.  It got its name because tumors sometimes got smaller following a bacterial infection, and an earlier researcher had wondered if the substance (that was made by white cells) could be used to fight cancer.

In 1984 Genentech scientists determined and published the complete amino acid substance of TNF and they gave some to NYU.    Vilcek and his colleagues tried to figure out what it did.  It had ‘a broad range of activities.’

In the 80s Centacor (still struggling) on a whim, a hope, produced a next generation monoclonal antibody to TNF.  It was “chimeric”, antigenically part human and part mouse.  The development took experts at Centacor 6 months and its patent was owned by NYU and Centacor.

The antibody didn’t (as Centacor had hoped) help people with sepsis.  But TNF turned out to be a significant immune modulator.  Blocking TNF, hypothetically, hindered the cascade of pro-inflammatory cytokines.

When London doctors (Feldman and Maini) injected the medication into the swollen inflamed joint of a person with Rheumatoid Arthritis it usually helped.  The effect lasted three months.  A repeat injection was also successful.  In 1993 a physician from Holland used the antibody to treat a desperately ill 12 year old girl with a severe case of Crohn’s disease, a chronic inflammation of the small and sometimes large bowel.  The infusion was very effective for 3 months and it helped 8 of 10 additional people with severe Crohn’s.

10 years after the original mouse antibody to TNF was generated in Jan Vilcek’s NYU lab, doctors had a tool that helped them treat a number of auto immune disorders.

Part of the cost was born by the taxpayer.  Part by Centacor. There was a lot of luck and serendipity along the way.

Both Centacor and NYU were rewarded.  The FDA approved the drug for use in inflammatory bowel disease (for Crohn’s they say has a positive effect 60 to 70 percent of the time),–and for ulcerative colitis, rheumatoid arthritis, ankylosying spondylitis and various manifestations of psoriasis.

In 1999 Johnson and Johnson bought Centacor for $4.9 billion.  Revenues from the drug (per J and J) rose annually between 2009 and 2016—from 4.3 in 2009 to $7 billion in 2016.

https://www.biopharma-reporter.com/Article/2017/05/31/Janssen-At-least-5-more-years-of-multi-billion-dollar-Remicade-sales

Humira—adalimumab,  another antibody that blocks TNF, was created in mice that were genetically modified in embryo.  It’s antibody to TNF is not destroyed by our immune system.

Some of the research on the drug was performed by researchers at the government funded Cambridge Antibody Technology, U.K.

The FDA licensed Humira at the end of 2002, and by 2005 the AbbVie, the company that owned it, was selling more than a billion dollars worth a year.  Its current revenue worldwide is close to $20 billion.  https://www.investors.com/news/technology/abbvie-stock-abbvie-earnings-humira-sales/

As a result of an amendment to the Affordable Care Act, AbbVie had the exclusive right to sell the drug in the U.S. for 12 years.  Then, as the result of a provision in the act, the company lawyers could keep biosimilars—competition–off the market by claiming one or several of the drug’s 126 patents were fundamental.  (All the patents were presumably novel, non-obvious, and useful).  The lawyers succeeded.  Biosimilars made by 4 manufacturers are now available elsewhere in the world.  AbbVie will not have competition in this country for five years.

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TRANSPLANTATION

On more than 34,000 occasions in 2017, foreign tissue from donors dead and alive —livers, kidneys, hearts and lungs–were implanted into the body of someone in the United States–and the immune system was challenged.

We learned organ transplant was possible in 1954 when an identical twin successfully gave his brother a kidney.  That’s as far as it went for decades because we weren’t very good at keeping a body from rejecting someone else’s organ.  Our original attempt to control the immune system, our “three drug anti rejection regimen”, according to Thomas Starzl, “wasn’t very effective or safe.” Starzl, a transplant pioneer, performed close to 200 dog transplants before he came to the University of Colorado.  “After surgery his dogs were normal for almost a week; then they began to reject their liver.”  As late as 1978 “Graft survival was unsatisfactory and patient mortality high.” (Starzl-the puzzle people. P.208)

Then Cyclosporine burst onto the scene and everything changed.  In the subsequent decades over 700,000 people in this country lived part of their lives with someone else’s liver, kidney or heart.  Kidneys, on average, last 12 to 15 years; livers had a shorter lifespan.  That’s going to change now that hepatitis C (a frequent cause of liver destruction) can almost always be cured.  (When a person with hepatitis C was transplanted, the new liver was always infected, and had a relatively brief lifespan.)

After a person receives a transplant, they (almost always) reject the intruder if they don’t take an immunosuppressant daily for life.  A few different anti rejection drugs are currently available.  There’s a marketplace and competition.

In 2012 Pharma spent $3 billion on consumer ads and “$24 billion marketing directly to health care professionals.” (John Oliver numbers) The promotion budget is almost always much higher than the amount spent on research.  The biggest spender in 2013, Johnson and Johnson, “shelled out $17.5 billion on sales and marketing, and half as much, $8.2 billion for research and development.”

Cyclosporine, the first truly effective anti rejection drug, was developed by Sandoz, a Swiss chemical company that, in the 1800s, manufactured dyes and saccharine.  In 1917 the company hired a chemistry professor, and created a pharmaceutical department.  His group isolated ergot from a corn fungus and turned it into a drug used to treat migraine and to induce labor.

In 1958, the company asked employees to take a plastic bag with them when they went on vacation or business trips, and to periodically collect “soil samples that might contain unique microorganisms.” (They were looking for the next great antibiotic.) A fungus in a sample of Norwegian dirt produced a metabolite (Cyclosporin) that lowered the immune response of lymphocytes.  It seemed to be relatively safe, and some, apparently, thought it could potentially become an anti rejection drug.

That’s as far as Sandoz was willing to go.  By 1973 the lab’s supply of fungus derived cyclosporine was largely depleted.  Large sums of money (around $250 million,) would be needed to create more, evaluate its anti-rejection potential, develop a drug, and obtain approval from the FDA.  There wasn’t much of an organ transplant market, and the investment didn’t make much sense.

In 1976, J.F. Borel, the Sandoz researcher who discovered the immune modulating effect of cyclosporine, presented his findings to the British Society of Immunologists.  A transplant surgeon in the crowd, Sir Roy Calne “asked Borel for samples”.  Calne used them to try to prevent the destruction of organs transplanted in rats and dogs.  The drug’s effect was dramatic.  With Borel’s help, Calne presented his findings to decision makers at Sandoz.  “The pharmaceutical company agreed that the drug looked more promising now that there was evidence of its effectiveness.”  In the early 1980s, an American transplant surgeon named Starzl used it successfully on liver transplant recipients.  With his results in hand the FDA fast tracked approval of the medication, and it became available for use in the U.S. in 1983.  (Currently made generically by a number of countries Cyclosporine’s (Wikipedia) wholesale price is not outrageous.  $106.50 a month in the developing world—GB £121.25 per month in the United Kingdom, and about $172.95 per month in the U.S. (if generic drugs are prescribed.)

Pharma scientists can produce great results.  But to create a truly innovative medication, in addition to money they need a modicum of serendipity, imagination, and stubborn determination.

http://www.sciencedirect.com/sdfe/pdf/download/eid/1-s2.0-S0269915X98801006/first-page-pdf

Read more: http://www.discoveriesinmedicine.com/Com-En/Cyclosporine.html#ixzz4ocaXJCDC

The second major, now widely used, anti rejection drug was Tacrolimus (Prograf).  Originally isolated from the fermented broth of a streptomyces bacteria”, it was discovered and developed in the 1980s by Japanese chemists working in a big Pharma lab. (At Fujisawa, a company that later merged and became Astellas, the world’s 14th largest).

English scientists tried Tacrolimus in dogs and “declared it too hazardous to test in humans.”  Dr Starzl’s group kept at it; they found the drug kept transplanted organs alive in some animals and “rescued some that, despite cyclosporine,, were being rejected.” Additional clinical trials “suggested that tacrolimus might be safer and better tolerated than cyclosporine”   https://www.nytimes.com/1994/04/13/us/government-approves-new-drug-to-assist-in-liver-transplants.html  

In renal transplant recipients Prograf led to improved graft and patient survival, and that lead to it’s routine use in U.S. renal and pancreas transplant recipients.  the FDA made it official in 1994.  The year before Prograf had a generic competitor, Astellas sold up to $2.1 billion dollars worth of the medication.

In 2011 an average transplant of one kidney had a price tag of $260,000.00.  Combined heart and lung transplants were costing $1.2 million dollars.   The first 180 days of post transplant medications was costing $18,000 to $30,000, and a number of generic immunosuppressive drugs had been marketed:  “(mycophenolate mofetil became available in 2008, Tacrolimus in 2009), and mycophenolic sodium and sirolimus in 2014”

It’s claimed that the annual cost of U.S. transplant immunosuppressive therapy averages $10,000 to $14,000.  If true then the 33,000 transplant recipients in 2016 are (directly or indirectly) paying $330 million to $462 million a year.  That becomes $3.3 billion to $4.6 billion over ten years if drug prices don’t rise or fall.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520417

In India (where the culture surrounding pharmaceutical prices is quite different from ours), the amount paid for Tacrolimus was slashed 65 percent in 2016.  The average recipient now pays $235 to $314 a month for anti rejection medications.

On October 30, 1972 President Nixon signed a bill that (apparently as an after thought) added chronic dialysis to Medicare.  Kidney failure wasn’t part of the bill the Senate debated during a rare Saturday morning session on September 30, 1972.  Nor was it part of the legislation passed earlier by the House of Representatives.  The amendment that added dialysis to the Medicare bill was introduced late that Saturday morning.  There was 30 minutes of debate before it was accepted by a 52 to 3 vote.  Weeks later a House, Senate Committee discussed the kidney amendment for 10 minutes, and left it in the bill.  Nixon, who was a pro health care president, signed the legislation with a flourish a week before he was re elected.

If someone on dialysis receives a kidney transplant (at a cost of hundreds of thousands of dollars) the operation and three years of anti rejection drugs are fully funded by the federal government.  At the end of those years the patient is removed from Medicare, and they have to pay for their own anti rejection drugs.  About 22 % of people on anti rejection medications stop them:  because of side effects, or they cost too much, or for other reasons.  When a kidney transplant recipient stops their immunosuppressive drugs they almost always reject their kidney, and they are forced to go back on dialysis or die. This is not theoretical.  It happens.  And it’s a problem.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991087/

http://timesofindia.indiatimes.com/life-style/health-fitness/health-news/Anti-rejection-drug-prices-cut-by-65/articleshow/52320897.cms

As newer anti-rejection compounds hit the market, and generic medications started competing, the cost of these drugs has waxed and waned.  The price seems to have little to do with the original research and development costs and much to do with current market forces.

Adjusted for inflation and expressed in 2012 dollars the U.S. cost to keep a kidney or liver alive was $9000 in 1993.  It climbed to more than $33,000 in 2007, and went down to $18,000 (twice the original price) in 2011.

http://www.renalandurologynews.com/american-transplant-congress/immunosuppressive-drug-costs-decline-but-still-expensive/article/293973/