Orphan Drugs

The Problem

It is estimated that 25 million people in the US alone live with some sort of rare or 'orphan disease.' Three more statistics emphasize the gravity of the situation: there are over 5000 rare diseases listed in the world today, with five new rare diseases described every week in the medical literature; 1 in every 10 Americans has a rare disease; and 85-90% of these rare diseases are serious or life-threatening.

These rare diseases are known as 'orphan diseases,' both because they have been neglected by doctors at times and due to the small numbers of people afflicted (they are 'health orphans'). Similarly, the drugs that treat them are called orphan drugs.

Another category of medication is included under the classification of 'orphan' as well. Sharma et al (2010) adds to the definition of orphan drugs those designed to treat "'a more common disease where manufacturers cannot expect to make profits.' For example, drugs and vaccine for tropical diseases are also defined as orphan drugs because patient sufferings from these diseases, although numbering tens of millions, are too poor to pay the price of medications."

Adding those afflicted with rare or orphan diseases to patients unable to pay for treatment for a more common illness resulted in large group of people in desperate need of help.

Throughout the 70's and 80's, the cost of drug research and development increased to the extent that pharmaceutical companies no longer wanted to invest in products that didn't promise large potential sales.

So treatments for high blood pressure and arthritis abounded, while drugs for untreatable and rare deadly diseases never made it to market.

In fact, drug makers' reluctance to develop orphan drugs didn't only arise in the development stages, as J K Aronson, Chairman of the Editorial Board, British Journal of Clinical Pharmacology, points out. Sometimes there were drugs whose efficacy was well-established in certain clinical situations, but there was no incentive to launch an actual efficacy trial of the drug for the rare condition.

For example, for one patient class, ibuprofen becomes an orphan drug: those children born with the rare disease of patent ductus arteriosus.  In this disorder the blood vessel called the ductus arteriosus fails to close when it is no longer needed, leading to abnormal blood flow between the aorta and pulmonary artery.

But ibuprofen's manufacturers never mounted an efficacy trial for the illness--it simply didn't pay.

Something had to be done to encourage drug makers to develop and test treatments for rare diseases, defined in the U.S. as illnesses that affect fewer than 200,000 Americans.

The Government's Solution: the Orphan Drug Act

So in 1983, Congress passed the Orphan Drug Act.

It reads, in part:

"The Congress finds that---

1. there are many diseases and conditions, such as Huntington's disease, myoclonus, ALS (Lou Gehrig's disease), Tourette syndrome, and muscular dystrophy which affect such small numbers of individuals residing in the United States that the diseases and conditions are considered rare in the United States;
2. adequate drugs for many of such diseases and conditions have not been developed;
3. drugs for these diseases and conditions are commonly referred to as "orphan drugs";
4. because so few individuals are affected by any one rare disease or condition, a pharmaceutical company which develops an orphan drug may reasonably expect the drug to generate relatively small sales in comparison to the cost of developing the drug and consequently to incur a financial loss;
5. there is reason to believe that some promising orphan drugs will not be developed unless changes are made in the applicable Federal laws to reduce the costs of developing such drugs and to provide financial incentives to develop such drugs; and
6. it is in the public interest to provide such changes and incentives for the development of orphan drugs."

So provide incentives it did.

The Orphan Drug Act:

• guarantees seven years of exclusive marketing rights to the drug maker;
• provides a tax credit for 50% of clinical testing costs;
• subsidizes through federal grants and contracts the clinical trials;
• absolves the pharmaceutical companies from paying FDA fees;
• and often ensures that the drugs get expedited reviews by the FDA, as well.

Some Real Success

The act made a difference.

From 1995-2005, over 160 orphan drugs were approved. Compare that with 108 from 1984 to 1994 and only 10 in the 10 years before the passage of the Orphan Drug Act.

Comparing the numbers year by year highlights the stark contrast. In 1983 16 orphan drugs were submitted for approval, and 2 were approved. Compare that to 2009 when 250 were submitted were approval (17 approved) and 2010 with 323 submitted (14 approved).

Those that do win approval change the lives of those suffering from rare diseases.

What Orphan Drugs Can Do

Just look at the some of the innovations for rare diseases--and consider the difference a Congressional Act, pharmaceutical commitment, and an infusion of cash in the research project can make:

1995: Rilutek (rulozole), by Sanofi-Aventis, is approved for ALS. Amyotrophic lateral sclerosis (ALS), commonly referred to as "Lou Gehrig's Disease," is a progressive degenerative disease that impacts nerve cells in the brain and the spinal cord. The degeneration of the nerve cells leads to their death, and when motor neurons die, the brain can no longer initiate and control muscle movement. Patients in the later stages are often completely paralyzed. It is a dread disease, and patients usually die within 5 years of their diagnosis.

Riluzole is the first drug to show any increase in survival for patients suffering from ALS. The increase is modest at best, extending life by an average of 3 months--but it is cause for hope.

Dr. Jeffrey Rothstein of Johns Hopkins University School of Medicine, believes so. This drug was developed, he said, “. . .against the background of decades when no drug ever did anything for the disease. Initial therapies for many diseases, like leukemia and other cancers, had the same kind of effect... a modest increase in survival. But they were followed by better therapies that, over time, increased patients’ survival…."

Hopes and prayers are that this one can, too.

1998: Forty years after thalidomide was taken off the market for inducing severe birth defects when used by by pregnant patients, it was approved by the FDA to treat an ancient 'incurable' disease. It treats the debilitating skin sores that result from erythema nodosum leprosum (ENL), a complication from leprosy that includes serious lesions, nerve pain, loss of nerve function, high fever, and joint swelling. Calgene distributes thalidomide under the name Thalomid for ENL.

2000: Certainly arsenic seems like the last substance you would give to somebody you hoped to heal. But the drug Trisenox (manufactured by Cell Therapeutics) contains a compound called arsenic trioxide. It was approved in 2000 to treat patients with acute promyelocytic leukemia, a subtype of acute myeloid leukemia (AML), a cancer that starts inside bone marrow, with the cancer growing from cells that would normally turn into white blood cells. In the promyelocytic kind, the patient has heavily granulated promyeloctyes, a type of white blood cell, which accumulate in the bone marrow and blood, replacing normal healthy blood cells.

Used for patients on whom other treatments have failed, the clinical trials showed the drug was effective enough to put 70% of patients into remission.

2003: Pegvisomant was approved to manage acromegala, a potentially fatal hormone disorder in which the pituitary gland manufactures excess growth hormone. Aside from abnormally large hands and feet, the illness can lead to diabetes, arthritis, and an increased risk of heart disease.

2008: The FDA granted approval to Arcalyst (rilonacept) for treatment of cryopyrin-associated periodic syndromes (CAPS) in adults and children 12 and older. Cryopyrin is a protein that triggers the inflammation and painful symptoms of CAPS, a group of rare genetic diseases that cause inflammatory symptoms like rashes, fevers, and joint pain. CAPS affects around 300 people in the U.S. The active substance in the drug attaches to chemical messengers that cause inflammation to block their activity.

When these orphan drugs have been approved and successful, the lives of the sufferers of the targeted disease are changed forever--for the better.

Developing Orphan Drugs Pay Off Big Time for Big Pharma

Government incentives aside, there finally seems to be some money in orphan drugs.

Forbes notes that spending on orphan drugs today makes up about 6% of pharmaceutical sales, but the annual growth rate of orphan drugs between 2001 and 2010 was 25.8% compared with 20.1% for non-orphan drugs.

Pharmacy Times found in its top 200 drugs of 2010 that a total of 44 new brand medications were launched in the U.S. in 2010, and 5 of those were orphan drugs--not a bad ratio.

A Thomson Reuters report, "The Economic Power of Orphan Drugs,” shows that, "while orphan drugs target much smaller populations than traditional mainstream drugs, the high cost of therapy and attractive developmental drivers, such as government incentives, smaller and shorter clinical trials, extended exclusivity and high rates of regulatory success, have made top orphan drugs as equally viable as their non-orphan peers."

The smaller market for the drugs is often offset by the high price the drugs can fetch, due to little competition and dire need. Additionally, 15% of the drugs analyzed by Thomson Reuters had second--or even third--launches for other rare illness.

In fact, in 2006 12 out of 19 leading orphan drugs started with just one approval for an orphan indication but became blockbusters by garnering approval for non-orphan diseases or through off-label usage.

The total worldwide market for orphan drugs was more than $28 billion in 2003, reached $58.7 billion in 2006, and generated over $50 billion in 2011. Predictions are that it will reach $112.1 billion by 2014.

Closer to home, the U.S. made up 51% of the market in 2009, revenue reached about $47.8 billion in 2011 and it is expected to reach $65.9 billion by 2014.

The revenues for individual treatments are sometimes staggering. In 2003 several orphan drugs had sales of over $1 billion.

Remicade (infliximab) for Crohn's disease; Neupogen (filgrastim), for the treatment of neutropenia (a dangerously low white blood count) associated with bone marrow transplant, and Avonex (interferon beta-1a), for multiple sclerosis were just some of the drugs in that billion dollar category.

In 2010, the most expensive drug was Soliris (eculizumab), at a price tag of over $409,000 annually, used to treat paroxysymal nocturnal hemoglobinuria, a highly-rare life-threatening blood disease. So far the drug has earned $541 million for Alexion Pharmaceuticals.

Surprisingly, after Lipitor, which earned over $197 for Pfizer, the second life-time revenue-winner is a drug called Rituxan (rituximab), with sales of  $154 billion, for the treatment of two orphan diseases (chronic lymphocytic leukemia and non-Hodgkin’s lymphoma), although it is also approved for the non-orphan illness of rheumatoid arthritis.

It should not be surprising, given the gains to be had, that there has been some fairly steep competition among drug companies for getting the right orphan drug approved first for a given illness.

Gaucher disease, named for the French physician who first described the symptoms in 1882, is an inborn metabolic disorder. Patients with the disease cannot produce an enzyme called glucocerebrosidase, which helps break down a specific complex lipid, glucocerebroside. If the body cannot break down this lipid, it builds up in body tissues, including the spleen, liver, bone marrow, lymphatic system, lungs, skin, eyes, kidneys, heart and the nervous system.

Big pharmaceutical companies want a piece of the orphan drug action. Shire pushed for FDA approval for its VPRIV (velaglucerase alfa) in 2010, useful as a long-term enzyme replacement therapy. Genzyme was at work on it is well with Cerezyme (imiglucerase), with its version of the drug, already marketed globally. Protalix and Pfizer worked to bring Elelyso (taliglucerase alfa) to market, and finally received approval this past May. Amicus was working hard, as well, to get theirs out, but was severely disappointed in 2009 when their treatment worked for only 1 of 18 patients in a clinical trial.

That's pretty steep competition for a disease that affects around 1 in 45,000-60,000 people worldwide.

Pfizer, GlaxoSmithKline, Novartis, Johnson and Johnson, Merck, Eli Lilly--these are just some of the big names involved in developing and promoting drugs for rare diseases.

There are even yearly conferences dedicated to the topic.  The next one to be held for North America is called--what else?--the World Orphan Drug Congress--and it is scheduled to meet on April 9-11, 2013 in Washington, D.C.  Its PR material calls it "North America's largest commercially-focused orphan drug event."

Coming up this November is the World Orphan Drug Congress: Europe.  Pfizer is one of the major sponsors, along with companies specializing in the development of orphan drugs.

Orphan drugs have reached the 'big time.'

Still A Ways To Go

But despite the growth--in drugs to market and in revenue-- and Thomson Reuters' rosy outlook, there is still a ways to go in developing treatments for rare diseases.

The Pacific Research Institute notes that, while rare diseases impact 6-8% of the world's population, drugs for these diseases make up less than 3% of the global market.

Clinical trials are difficult to organize, as it is hard to find enough patients to recruit.

The Institute also points out that, despite all the incentives, fewer than 4% of rare diseases have approved treatment.

Sharma et al (2010) write that "[p]rogress has increased, but the 300 orphan drugs and devices approved in the last 25 years are still only a drop in the bucket compared with the many thousands of orphan diseases."

Additionally, as Sharma points out, the philosophy of orphan drugs goes against the prevailing priorities of many societies. The primary focus in orphan drug development is on the individual, regardless of the cost to and effects on society at large. This is opposed to the way more socialized countries look at health care.

For essential medicines, the goal is to bring the drug to as many patients as possible, in the most cost-effective manner. For orphan drugs, the focus is on the individual patient--even a single person deserves all possible treatment and expense.

As the Brits put it, "treating 50 patients for a rare disease at perhaps £200,000 per annum would pay for a lot of hip replacements, or cataracts."

And then there's the cost to the individual, more applicable States-side. What is good for the drug-makers is not always equally good for the patient.

Prices of orphan drugs are often staggeringly high. To return to Gaucher disease, the  yearly cost of treatment can reach $400,000 per patient (Gross ML 2002). In 2004,  Genzyme had sales of  $840 million for its drug for Gaucher disease.  The company said that treating the average patient costs $200,000 annually, but, if the patient is on the higher of two recommended doses, costs can run as high as $600,000 a year.

Or take well-known orphan cancer drug Gleevec (imatinib mesylate), approved by the FDA in in 2002 as first-line treatment for chronic myeloid leukemia (CML), which affects around 40,000 people in the U.S.

In CML a blood enzyme is overactive, causing potentially life-threatening levels of white blood cells to be manufactured in the bone marrow and blood. Gleevac blocks the rapid growth of these cells.

In clinical trials and in clinical practice, Gleevac has turned the life-threatening illness into a manageable one. But. . .patients must stay on the drug for the rest of their lives, with treatment costing between $30,000-$100,000 a year. (Notably, in 2011, Gleevac earned $4.7 billion, and its patent is not due to expire until 2015.)

Congressional legislation subsidizes the drug companies to produce these drugs--but as yet there are no subsidies or legislation to help patients or obligate governments to pay for the treatments.

Insurance companies and employers are now excluding coverage of certain orphan drugs, due to their high prices, while others require employees to pay as much as half of the treatment.

"We have all of these new fantastic new drugs, but nobody -- not employers, not employees -- can pay for them," lobbyist Abbey Meyers, head of the National Organization for Rare Diseases, a nonprofit advocacy group, told the Wall Street Journal.

Which leaves us in a better place than we were pre-1983, as there are more medications available and for diseases that were considered untreatable before, but often, for the individual patient suffering from the rare disease, if she or he simply can't afford the overwhelming costs of these new and life-saving orphan drugs, there’s no benefit at all.

It is a serious problem--and one Congress has yet to tackle.