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New Miracle Drugs: What Would You Pay?

Levi Collazo, before and after Kalydeco treatment for cystic fibrosis.
Levi Collazo, before and after taking Kalydeco for CF.

Levi Collazo, a biology major at Southwestern Oklahoma State University, has cystic fibrosis (CF).

“In the first photo, I was making fun of my own weight. I’ve always used humor as a defense mechanism. I weighed 110 pounds. I’m 5’10”. After taking Kalydeco for 2 years, I’m up to 148 pounds,” he wrote on the Facebook page Kalydeco Miracles.

The success of Kalydeco for some people with CF – “K” to its fans – is astonishing. The drug corrects misfolding of the CFTR protein that certain mutations cause.

When the daily pill, developed by Vertex Pharmaceuticals, came on the market in 2012, only the 2,000 or so patients who have a specific mutation could use it. The drug cost $294,000 a year. Since then, further clinical trials have swelled the patient pool to about 3,100. The FDA approved the drug for a tenth mutation December 29, 2014.

Families still fight insurance companies for coverage, but the Cystic Fibrosis Foundation has funded development of Kalydeco and recently sold royalty rights, and is using the $3.3 billion to help patients and fund further research. With 75,000 people in North America, Europe and Australia having CF and trials on extension to other mutations continuing, the market may increase, and perhaps the price decrease.

Madi Vanstone, age 12, learned in June that the Ontario Drug Benefit formulary would cover the cost of her K and of everyone else’s in the province with a treatable mutation. Before that, insurance had been paying half of the $348,000 annual cost and Vertex 30%, leaving $60,000 for the family to cover. Without daily K, Madi would have needed a lung transplant in a few years and might not have survived her teens. Now, she has a future.

What would you pay to treat a debilitating and deadly disease?

Over the past few months, we’ve seen incredible price tags for groundbreaking new medical treatments.

Glybera is the first gene therapy approved in the western world. It treats lipoprotein lipase deficiency.
Glybera is the first gene therapy approved in the western world. It treats lipoprotein lipase deficiency.

Like Kalydeco, Glybera debuted in 2012. Amsterdam-based company UniQure with partner Chiesi make Glybera, the only approved gene therapy in the western world.

Glybera treats painful and lethal lipoprotein lipase deficiency (LPLD). The price in Germany, announced in late November, set a new record for a medicine to treat a rare disease: $1.4 million for the one-time series of 42 intramuscular injections that should banish the disease.

In LPLD triglycerides build up in the pancreas, liver, skin, and spleen. About 1,000 Europeans have LPLD, and it affects one in a million in the US – about 323 people. Prevalence is greater in Quebec due to a founder effect: French and Scottish settlers introduced two mutations three centuries ago. In the province 1 in about 6,000 people has the disease.

John Kastelein, Colin Ross, and Michael Hayden recall Glybera’s long developmental trajectory, which began in Hayden’s lab at the University of British Columbia, in a compelling article in Human Gene Therapy. In September 1986 they met a 19-year-old with sky-high triglycerides, painful pancreatitis, and skin lesions, and identified his LPLD mutation. A severely fat-restricted diet hadn’t helped.

Experiments using mice and cats followed, and eventually clinical trials tested several versions of a gene therapy delivered in adeno-associated virus. In severely affected patients, abdominal pain diminished, lipid levels fell, and they could eat more, including foods they couldn’t tolerate before. One patient even had a baby.

What would you pay to treat a painful and deadly disease?

Glybera costs so much because it is first-of-its-kind, was decades in development, and encountered an unusually thick regulatory morass. And the market is very small, so the monumental development costs must be divided by a small number of patients.

But Glybera is the test case for much wider application of the technology, which UniQure is exploring for several other indications. One is hemophilia B, the clotting disorder mentioned in the Talmud and seen in Queen Victoria and some of her descendants.

Doing the math for hemophilia B, it’s easy to see how gene therapy will earn out its development cost. This is the less common form of the clotting disorder, affecting 4,000 people in the US.

Traditional treatment is the missing protein, clotting factor IX (FIX). It came first from blood donations, then using recombinant DNA techniques after HIV in the blood supply infected 90% of people with hemophilia in the 1980s.

Giving FIX protein to treat hemophilia B is expensive, painful, frequent, and not entirely effective. It costs $100,000 a year if used only to treat “bleeds,” and up to $250,000 if given 2 or 3 times a week to prevent bleeding. That’s about $20 million over a lifetime.

But giving the FIX gene — the instructions for cells to make the protein — could last forever and costs about $30,000. The lower price may be because the gene is small and simpler to insert into the viruses that carry out gene therapy than others, and a tiny jump in FIX level makes a huge difference in clotting time and how a patient feels. The promise of hemophilia B gene therapy is why several teams are racing to get it to the clinic. (Spark Therapeutics recently partnered with Pfizer to develop the gene therapy). I predict it will be among the first gene therapy approvals here.

My #1 prediction for first-to-be-approved gene therapy in the US is for Leber congenital amaurosis type 2 (LCA2), chronicled in my book The Forever Fix (shameless book plug in honor of pub date anniversary, today.) The treatment for this form of hereditary blindness won’t cost much, for several reasons: delivery into the eye is well-established, the inventors have forsaken earning anything, and kits are ready to ship to ophthalmologists.

Another intriguing new drug is Cerdelga™, to treat type 1 Gaucher disease. The FDA approved it in 2014.

Bone loses cells in Gaucher disease.
Bone loses cells in Gaucher disease.

Gaucher disease type 1 causes an enlarged liver and spleen, anemia, poor clotting, collapsed hips, arthritis, impaired lung function, bone pain and fractures. Cells become packed with lipids, and symptoms may begin at any time. It’s autosomal recessive, but carriers may develop a Parkinson-like condition later in life.

An earlier treatment for Gaucher, Ceredase, came on the market in 1991. Developed at Genzyme Corporation, Ceredase was an infusion and the first enzyme replacement therapy. In 1994. Cerezyme replaced it, made using recombinant DNA technology and altered to target fat-engorged Gaucher cells. Globally 5,000 people take Cerezyme, including 1,500 in the US.

Cerezyme works, but delivery isn’t easy. Dose and schedule of IV administration must suit each patient.

”For people receiving Cerezyme for a long time, that adds up to a lot of infusions and having to be poked every few weeks limits one’s schedule,” Gerald Cox, MD, PhD, Vice President of Clinical Development for Rare Diseases at Genzyme told me. A pharmacist must provide the drug and a nurse administer it, at home or at a clinic. “When we asked patients what more they would like from a treatment, they all wanted a pill,” Dr. Cox said.


So Genzyme researchers sought another way to intervene in the biochemistry – alleviate the buildup of substrate that occurs when an enzyme is blocked, as it is in Gaucher. FDA approved the substrate reducer Cerdelga – a capsule! – last year. Clinical trials were complicated, requiring patient volunteers to give up Cerezyme to test its new cousin.

The price per patient? $310,250 a year, a little more than its predecessor. Dr. Cox explains why.

“Orphan diseases follow a little different set of ground rules. There’s a lot of investment. But we have to go through all the regulatory hurdles that all the other companies do for common diseases, and when they want to recoup that investment there are 10 million people who are going to use the drug. You can keep the cost low because so many people are going to use it. But for an orphan disease with 5,000 worldwide, if you invest and divide by the number of patients, it winds up being a high price.” Relaxing regulations and shift of drug development towards academia might help for the ultrarare diseases, he adds, or foundations or governments stepping in, like for Kalydeco.

What would you pay to treat a painful and highly disruptive disease?


Kalydeco for CF: 3,100 patients, ~$300,000/year each. For a 10-year-old who lives Logodollar2until 60, that’s about $15 million.
Glybera for LPLD: 323 patients, ~$1.4 million/lifetime
Cerdelga for Gaucher: 1,400 patients, ~$310,000/year each.

We’ve all heard the big pharma mantra, “R&D for a drug takes 10 to 15 years and more than $1 billion.” Add the costs of buying companies (like Sanofi bought Genzyme), and of discontinued clinical trials. Yet the treatments are justified when there isn’t anything else or existing approaches don’t work well or for everyone.

Now let’s look at hepatitis C.

Hepatitis C virus
Hepatitis C virus

Hepatitis C is hardly a rare disease. About 2% to 3% of the global population has it – that’s  130 to 170 million people, including 3.2 million in the US. It’s more prevalent than HIV infection, and many people are unaware that they have it and can spread it. You’d think that’s enough people to keep costs down.

For more than two decades, treatment for hepatitis C infection has been the cytokine interferon and the antiviral ribavirin, which only some patients can take and which can make people pretty miserable. Availability of new drugs, based on the success of HIV antivirals, was good news indeed.

Last April, the World Health Organization called for assessing all infected people for two new drugs, because more treated people can block transmission.

An editorial in the New England Journal of Medicine was unusually optimistic: “Collectively, these regimens promise to transform hepatitis C from a condition requiring complex, unsatisfactory therapies and specialist care to one that can be effectively treated and easily managed by a general physician with few contraindications and side effects.”

But consider the price.

My friend Fred took the 3-month course of interferon/ribavirin/Solvadi. “My insurer paid. I paid only $20 for the whole course. That’s the good news. The bad news is that I relapsed after 90 days and am now on a newer combination drug, Harvoni. It’s reported to cost even more ($1,124) per tablet and I’ll need to take it for 6 months.” Solvadi is about $1,000 a pill.

Fred hopes he doesn’t get any surprise bills. “Keep your fingers crossed for me, this time I’m going to win!”’ Success rates for the new drugs are in the mid 90% range.

800px-HepC_replicationThe drug combinations are confusing. Harvoni is Solvadi plus a viral inhibitor called ledipasvir. Both combinations are from Gilead Sciences.

Olysio, at $733 a day, is from Janssen Pharmaceuticals and is taken with Solvadi, interferon, and ribavirin.

Viekira Pak, developed by AbbVie and approved last month, for about $925 a pill, combines three new antivirals and one old one. Like the hugely successful HIV drugs, these newcomers target various steps in the choreography of viral entry into human cells and replication.

Why do the hepatitis C drugs cost so much? A New York Times article lists a few justifications: R&D expenses, superiority to older treatments, future savings from preventing complications. True, the drugs seem to cure, compared to the HIV drugs that lighten viral load (unless hepatitis C virus peeks out in a few years). And Gilead paid $11 billion to the company that originated Sovaldi. But I don’t get it.

Prices in Pakistan, Egypt, China and India will reportedly be much lower. And by one estimate, cost to manufacture is actually about $150 to $250 per patient. A medical economist posited that it will take treating about 150,000 patients to recoup development costs.

What would you pay to stop a deadly disease? And how long would you wait?

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