Targeting cancer

Gleevec was the first drug that targeted a cancer.  The way it was priced helped create a mindset.  

When I entered medical school, in 1958, aside from nitrogen mustard, chemotherapy for cancer, was virtually nonexistent.  In the subsequent decades a number of drugs that attacked rapidly growing cells, malignant or otherwise, were developed.  In the 1960s doctors started using combination of several of these drugs to cure some lymphomas and leukemias.  The drugs also commonly cured specific malignancies—like– some widespread testicular cancers and choriocarcinoma.   

They were toxic and often caused major side effects, but they worked.  When used in people with widespread cancers the medications caused tumors to shrink, and extended some lives. 

They were later used to destroy potential metastases. We knew that malignant cells from some of the surgically removed cancers had already seeded parts of the body. The “seeds” were not visible, not detectable; but we could identify the cancers that were at risk, the tumors that would statistically benefit from chemotherapy.  Our toxins eradicated some of these microscopic implants.

Then Gleevec (Imatinib), a drug conceived and fully developed over many years in the labs of big Pharma—was introduced, and our approach to fighting malignancies underwent a sea change. 

At $26,000 a year (in 2001) Gleevec’s introductory price was deemed “high but fair” by the Chairman and CEO of Novartis.  Then its price rose and kept rising. 

One of the first drugs that attacked cancer cells and left the rest of the body unharmed, Gleevec was the product of decades of research at the Ciba-Geigy labs in Basel Switzerland.  A research team funded by big Pharma spent millions of dollars chasing a dream, a theory, a hypothesis.  Alex Matter, a Swiss M.D. advocated looking for a small molecule that would get inside cancer cells and stop them from growing.

“Inspired by the likes of Louis Pasteur and Marie Curie.  Matter was only 12 years old when he began dreaming that he would one day be involved in the discovery of important new medicines.”  I don’t know if he ever practiced medicine, there’s not much written about his private life, but he became a Ciba researcher in Basel Switzerland in  1983.  At the time he was apparently wondering what happens when the offspring of a normal cell turns out to be cancerous.  Could it be that one of its numerous tyrosine kinase enzymes, proteins thatfunction as an “on” or “off” switches, gets stuck in the “on” position, and causes the cell to grow and grow”?

Each part of the body is made up of cells.  Within each of these small units, traffic is directed down various metabolic pathways by enzymes called kinases.  These enzymes establish the functions of cells.  At the appropriate time they cause them to “grow, shrink, and die.”  Malignant tumors are often created when one of the kinases gets stuck in the pro-growth position.  The cells don’t die when they are supposed to, and the collection of abnormal cells gets bigger and spreads.

What if we could block the corrupting kinase without harming a cell’s other 90 or so kinases?  Could we cure cancer?  That was the dream.

Kinases have inlets on their outer surfaces.  When these are filled–plugged by a small molecule that “fits,” the cell dies.  Locating the bad kinase and plugging it with the appropriate small molecule, is a little like finding a needle in a haystack.  But that’s what the Swiss Geigy team lead by Alex Matter and Nick Lydon set out to do.  They started with a small molecule that they knew would selectively inactivate one and only one of the 90 or so kinases found in each cell.  Repeatedly altering the protein, they fashioned and tested each of the new molecules they created.  A few seemed promising.  Gradually they made dozens of blockers, each of which inhibited the activity of one and only one kind of kinase.  The project took years and must have been quite costly.

In the 1980s Lydon went to Boston in search of a cancer that might be susceptible to one of his kinase inhibitors.  He met Bryan Drucker, a physician who was studying chronic myelocytic leukemia.  For technical and legal reasons it took a few years before Drucker, then in Oregon, was able to obtain and test the kinase inhibitors.  When he did, he found a blocker that caused chronic myelocytic leukemia (CML) cells to die.  (Chronic myelocytic anemia is an unusual kind of cancer.  It’s caused by two genes that switch locations and fuse.  The “hybrid” gene that is created causes these cells to keep reproducing themselves.)

The dream was realized.  A small molecule could selectively inhibit an enzyme and control or cure cancer.  Turning the chemical into a drug a human could use required proving its safety in animals, then people.  Several hundred million dollars needed to be spent before the company could market a medication that would only affect a few thousand people.

Novartis (the company created by the Ciba-Geigy—Sandoz merger) decided to give the chemical a shot, to see what it did to the cancer in question.  It proved to be amazingly effective.  Chronic myelocytic Leukemia wasn’t cured but it became a chronic disease, and an entirely new era of research was launched.

The first clinical trial of Imatinib mesylate (Gleevec), took place in 1998.  In 1991 the FDA approved the new medication and granted Novartis a 5 year monopoly.

Initially marketed for $26,000/year, its price was defended by the CEO of Novartis as being “high but fair”.  It then crept up by 10 to 20% each year.

When it first came out the company knew that CML patients who took a Gleevec pill each day were alive and well three years out.  But they worried.  Most cancers eventually become resistant to therapy.  They were pleasantly surprised.  Gleevec and a slightly altered later iteration “changed the natural course of chronic myeloid leukemia (CML).  In 2015 a study of people who had taken the drug for 10 years found that 82% of them are alive and progression-free.”  Leukemia. 2015 May;29(5):1123-32.)

Each year an additional group of people develop CML, and they, too, start taking a pill a day for the rest of their lives.

The annual cost of the drug reached $132,000 in 2014 and 146,000/year in 2016.  (The prices I’m quoting are estimates from one or another press report.)

In 2015 Novartis sold $4.65 billion of the drug. Medicare and American insurance companies were normally charged $101,000 a year.  The price in the U.K was “$31,867, France paid $28,675 and Russia spent $8,370.”  “from 2001 to 2011, sales of Gleevec world wide totaled $27.8 billion.

India started allowing companies to patent drugs when the country joined the World Trade Organization.   That year, 2005, Novartis filed a Gleevec patent.  It was challenged.  “India accused the company of evergreening, extending the life of the patent by making ever-so-slight adjustments to the compound, altering it just enough to warrant patent extensions without changing the underlying mechanism of the drug.”  The courts ruled the patent invalid on technical grounds.  Indian judges seem to be more in tune with the needs of their nation’s people than they are with the desire of the world’s wealthy to further enrich themselves.

It’s impossible to know how much Ciba Geigy spent creating the kinase inhibitors…  Geigy funded the studies “reluctantly;” at the time Matter’s was told to keep investigating other approaches to cancer; and the kinase program was supposed to be “very very small…hidden in plain sight. “

But the company, no doubt, spent millions, maybe more than a billion dollars over the years bringing a great drug to market.  “A year after its initial approval, in 2002, worldwide sales of Gleevec totaled more than $900 million.” Even if the initial price reflected their research and development costs, it clearly had little bearing on the subsequent annual increase in the price point.  (Jessica Wapner: 2013 The Philadelphia Chromosome)

In the years following Gleevec’s release the culture around drug pricing evolved.  Repeatedly challenging the market— the Swiss corporation (with a major U.S. presence) charged a little more each year or so.  They made as much money as they could—kept increasing stockholder value.   That’s what public corporations are supposed to do.

Hollywood tells us that charlatans used to sell snake oil from the back of their covered wagons for cash.  Visible money was exchanged.   Today doctors e-mail pharmacies and high priced medication/commodities are dispensed for a few buck co-pay.  Transactions for the highest prescription prices in the world are all completed out of sight and mind.  We aren’t bothered by the fact that the same drug for the same disease often costs more in the U.S. than it does in Europe or almost anywhere else in the world.   Our health insurance pays most of our drug costs, or if we’re on Medi-Cal or have Medicare D it comes out of our taxes.    

In the early years of the 21st century the Swiss company, Novartis (Gleevec) perhaps unknowingly, helped create the high priced U.S. market for cancer drugs.  Starting in 2001 at $2200 a month, $26,400 a year, Gleevec’s price increased annually.  Initially it rose in parallel with inflation; in 2005 yearly boosts started exceeding inflation by 5 percent.  In 2009 they took off.  Gleevec’s annual cost was “$3,757 a month ($45,000 a year) in 2007,” passed $60,000 in 2010,  and passed the $100,000 a year mark in 2013.   ( Carolyn Y. Johnson, Washington Post March 9, 2016.; http://ascopubs.org/doi/full/10.1200/JOP.2016.019737 )

The next few cancer fighting drugs were created and developed in the labs of pharmaceutical companies.  The skilled researchers had a general blue print, but their research involved a lot of trial and error.  The true costs, if they really matter, are a black hole.  But the market was established.  Competition based on price was not a serious option.  The cost of a successful drug was set at about $100,000 a year. 

The success of Imatinib-Gleevec showed researchers that it’s possible to develop small molecules that are highly specific to one of the hundreds of tyrosine kinase inhibitors…molecules that can inactivate a specific critical enzyme in chosen targeted cell.  There were a few known targets—so called low hanging fruit– and researchers in startups and in the labs of big Pharma started making thousands of molecules and testing them with their biologic assays.  Not that it was easy.  Developing a molecule that targeted a specific genetic alteration took time, luck, optimism, and money.

The two initial genetic alterations researchers around the world targeted were the ALK Fusion gene and EGFR:

The ALK fusion gene had been identified by Japanese researchers at the Division of Functional Genomics, Center for Molecular Medicine.  Jichi Medical University, Tochigi Japan.  The mutation is the cause of 5-7 percent of non small lung cancers.  The first tyrosine kinase inhibitor that targeted the gene was marketed by Pfizer.  It kept the cancer from progressing for an average of 4 months, but it didn’t make people live any longer.  Called crizotinib, (Xalkori) it was initially priced at $11,000 a month and its price didn’t rise much its first two years on the market.  But it was too much for the Canadians and Brits, and they decided it wasn’t cost effective.  (Do our politicians really want to negotiate with drug companies?  Can they take the political heat if government negotiators get tough and walk away from the table?)

The second tyrosine kinase inhibitor that targets this gene, alectinib was approved by the FDA in 2013.  Developed in Japan by Chugai (which is majority-owned by Roche) it “originated from the company’s screening program.”  It does, on average, make people with metastatic cancer live longer, and is often effective when criznotinib stops working.  It also crosses the blood brain barrier and can affect the growth of brain metastases.  Its current price is more than $13,000 a month.

The recently approved second generation Novartis ALK inhibitor ceritinib (Zykadia) was approved by the FDA in 2014, and, not surprisingly, costs $11,428 a month. ($8100 to $13,500 depending on dose.)

I have no reason to believe that pharmaceutical companies price fix.  But they all seem to know that charging less than $100,000 a year for a new cancer drug is foolish.  Politicians and the media have grown accustomed to the $100,000 plus a year price point.  Some may complain and wonder aloud how the price was set.  But in the end they must know.  New targeted cancer drugs always seem to cost about the same as the other similar drugs on the market.  And companies seem to choose a price that is the maximum they think they can (more or less hassle free) get away with. (The web says a month’s worth of alectinib costs $13,589.)

The other known cancer causing target…EGFR–(epidermal growth factor receptor) was discovered decades earlier and was known to cause uncontrolled cell division.  When it was found in some lung cancers, it too became a target for the right kinase inhibitor.

IRESSA™ (gefitinib), the first clinically available EGFR inhibitor, could slow the growth of lung cancer for months.  Developed in house by Astra Zeneca, it was the product of years of tedious expensive work.  It only helped 10% of afflicted Caucasians but 30 percent of Asians with lung cancer, especially non smokers, responded.   As a result Astra Zeneca did most of its marketing in Japan and China.  (The drug was available in 81 countries.)  By 2015 the medication was bringing in $500 million a year.  $23 million of the sales were in the U.S.  Chinese with lung cancer paid 7000 Yuan–11,430 a week for the medication.  After a decade the Chinese pharmaceutical company, Qilu, started making a generic version called Yiruike.

Cancer drugs outside the U.S. cost a lot and there are people, all over the world, who are willing to pay.  I suspect Astra Zeneca recovered its development cost..which must have been substantial.  I doubt that the drug made anyone rich.

Most of the targeted cancer drugs are made in the labs of big companies and we don’t know much about their research and development.  The Tarceva story provides a window.  An EGFR blocker, the medication was developed by OSI, a small pharmaceutical company located in Long Island, New York.  When Collen Goddard became its CEO in 1989, it employed 20 people and had a biology and a small molecule discovery group.  A Brit, its leader Goddard had previously been a researcher in Birmingham England and at the NCI (national cancer institute).

The startup was looking for a chemical that would modify EGFR.  They had a relationship with researchers at a nearby mega company, Pfizer, and people at OSI persuaded investigators at the big company to screen a number of their small molecules.  At the time Pfizer was evaluating molecules for a different cancer target: Her-2 neu, and they needed a “control.”  When they checked the compounds for OSI, Pfizer scientists identified Tarceva early on.   OSI subsequently kept the “lead rights” to the chemical and Pfizer had some ownership.

Pfizer agreed to give the drug to a few people with advanced cancer and see what happened.  They bailed when they learned the drug caused a rash.

About this time Pfizer was buying the company that owned Lipitor.  It was an expensive hostile takeover, and Pfizer gave their Tarceva ownership back to OSI—free.  (They later went on to acquire the company that owned Lipitor.)

OSI raised $440 million, ran clinical trials, and found out their drug, in fact, made some people with cancer live longer.

A few years back an athletic, non smoking friend had a nagging back ache that kept getting worse.  An MRI showed bony defects caused by metastatic lung cancer.  His brain was involved, and it was radiated.  The X-ray treatment caused terrible side effects–a month of no appetite or thirst.  When he recovered he knew he was not interested in conventional, toxic chemotherapy.  But he spoke of a dream– of sitting on a boat in the bay and fishing.  Would that be possible?  His tumor was positive for EGFR and he was given Tarceva.  His back pain improved, he got stronger, and he was able fish and enjoy life for about a year.  Then the tumors in his brain started growing. 

Genentech and Roche bought $35 million worth of OSI stock and commercialized Tarceva.

The internet says Tarceva costs Americans $2600 a month.  That’s more than the British National Health Service was willing to pay.  In 2007 the Swiss drug maker Roche negotiated and agreed to cut the U.K. price from $2766 a month to $2133 a month.  The Canadian online Northwest Pharmacy claims they get drugs from reputable factories in many parts of the world, then ship it directly to patients who mailed valid prescriptions.  Their price for brand name Tarceva 150 mg per month is $3174.  Their generic version goes for $1384 a month.  Approved by the FDA in 2004, it became a $94,000-a-year drug.  Genentech sold $564.2 million of Tarceva in 2011 and over a million dollars worth in 2016.  (An article in the LA times questioned its effectiveness) http://www.latimes.com/business/la-fi-fda-tarceva-approval-20170204-htmlstory.html

In India, in 2012, the Cipla pharmaceutical company produced a generic version of Tarceva, and lowered the price of the medicine from $459 dollars a month to $182 dollars a month.  The Delhi court ruled that the Swiss patent was valid, but that the generic product didn’t infringe. http://www.firstwordpharma.com/node/1031419?tsid=17#axzz4pCaI5OxA

http://www.medscape.com/viewarticle/830145 (peter Bach quote)