Medicine’s ‘orphans’: drugs for rare diseases

Medicine’s ‘orphans’: drugs for rare diseases

Egon Weck

Medicine’s ‘Orphans’: Drugs for Rare Diseases

The school grades of 18-year-old Katie (not her real name) had fallen precipitously. Six months earlier she had been getting a’s. Now she had an F and found the best she could manage was a C.

“I was depressed and lethargic. I found it hard to go to class and hard toconcentrate,” Katie recalls as she looks back on 1981 and her senior year at an academically demanding prep school. Friends noticed that Katie, whom they had known as a slim, attractive, outgoing overachiever, had become overweight, withdrawn and frumpy. She seemed to have a strange odor about her, and neither family nor friends could figure out what was causing the dramatic changes.

After counseling failed, her family doctor checked her physical condition and found she had a low white blood cell count and an enlarged spleen. The physician, deciding that Katie’s problem stemmed from the enlarged spleen, quickly hospitalized her for surgery. But in the coure of the operation to remove her spleen, doctors found that she had cirrhosis of the liver.

On the evening after Katie’s operation, a specialist in internal medicine who had atended her in the hospital puzzled over her condition. Gradually, the cirrhsis together with psychiatric and neurologic symptoms fell into place. “Of course,” he thought. “Katie has Wilson’s disease.” (Ironically, the enlarged spleen, which precipitated discovery of the cirrhosis, was totally unrelated to the Wilson’s disease.)

Doctors rarely see a case of Wilson’s disease because it afflicts only about 8,000 persons in the United States. “It’s so rare that doctors almost never think of the possibility, and so Wilson’s disease is often missed,” explains Dr. I. Herbert Scheinberg, a specialist in Wilson’s disease at New York’s Albert Einsteain College of Medicine.

Wilson’s disease afflicts people who have inherited two recessive genes–one from each parent–that prevent the body from ridding itself of excess amounts of copper. Minute amounts of copper are essential to normal body function, and the element is plentiful in foods such as broccoli, chocolate and mushrooms. With an overabundance of copper in the average American diet, however, it tends to build up to toxic levels in people who cannot eliminate it.

When Wilson’s disease is left untreated, copper deposits–which form in the red blood cells, kidney, liver, brain and eyes–irrversibly damage these tissues, leading to much suffering and ultimately death by the time the patient reaches 30.

Many patients who, like Katie, suffer from rare diseases had little hope in 1981 because far more prevalent diseases like cancer were winning medical research dollars. In the case of Wilson’s disease, however, much research had been done. And in 1983 President Reagan signed a new Orphan Drug Act, which ultimately helped people like Katie because it specifically targets hundreds of rare diseases such as Wilson’s.

Because Wilson’s disease is often overlooked or mistaken for other conditions, such as hepatitis, multiple sclerosis, Parkinson’s disease, or psychiatric problems, medical specialists estimate that only about 1,000 cases are under treatment.

Fortunately, a diagnostic test and the presence of certain physical signs enable the physician to differentiate these disorders from Wilson’s. First, a deficiency in ceruloplasmin–a blood protein that transports copper–can be detected in blood tests in 96 percent of patients with Wilson’s disease. Second, telltale golden-brown or green “Kayser-Fleischer” rings appear in the corneas (the protective covering over the lens) of the patients’ eyes.

Other signs of Wilson’s disease include a husky or barely audible voice; slurred or indistinct speech; stiff, distorted hands or feet; tremors such as head shaking, quivering legs, or flapping arms; loss of balance and difficulty walking; depression; impulsive emotional or sexual behaviour; excessive salivation or drooling; and hepatitis.

“When Katie first came in to see me,” Dr. Scheinberg recalls, “Kayser-Fleischer rings were visible around the entire circumference of her corneas, and they extended from the edge about a third of the way into the center of the pupils.” Often it takes an ophthalmologist using an instrument called a slit-lamp to identify the ring. In Katie’s case, however, it was easily visible to the naked eye.

Today, virtually all cases of Wilson’s disease can be treated effectively with one of two drugs. But what incentives are there for a pharmaceutical company to undertake the costly effort of developing a drug for such a rare disease–an effort that the pharmaceutical industry says now costs an average of $125 million for each genuinely new drug developed?

A rare disease has been defined as one that affects less than 200,000 Americans. There are an estimated 2,000 such diseases. Years ago, when the prospects of treating rare diseases were dimmer, the drug industry itself provided what companies called “public service products” for some of them.

In 1964, for example, a Pharmaceutical Manufacturers Association (PMA) survey of member companies found there were 35 public service products being made by member firms. By 1969 the list had grown to 92 products supplied by 26 firms in the association.

Hoffman-La Roche, for example, has developed about a half dozen drugs for rare disorders on its initiative; and the company continues to develop such drugs relying on its own resources.

For years, government health authorities had been aware of the plight of rare disease victims and have worked with medical researchers and companies to hel them. Then, in 1973, the Interagency Committee on Drugs of Limited Commercial Value was appointed to monitor needs and propose economic incentives that would encourage the development of drugs for rare diseases. Informal contacts between the federal government and the private sector gradually led to establishment of an office on orphan products in FDA and the Commission on Drugs for Rare Diseases in the private sector.

In 1981, the plight of children afflicted with another rare disease–Tourette’s syndrome–generated nationwide publicity. This disorder is characterized by bizarre, physical and vocal tics that wax and wane throughout childhood and adult life.

While a drug to treat Tourette’s–haloperidol–was available, it was not effective in all patients. A second drug–pimozide, produced by McNeil Pharmaceutical–was being used abroad and in Canada, but had not been approved by FDA foruse in the United States, largely because the necessary research would have been prohibitively expensive, considering the small patient population. (Pimozide was eventually approved under the incentives of the 1983 Orhan Drug Act.)

The publicity on Tourette’s syndrome had great impact. It focused public attention on rare diseases generally. And it galvanized voluntary health agencies that, in turn, appealed to Congress for help.

The term “orphan drugs,” first appeared in print in a 1968 editorial in the American Journal of Hospital Pharmacy titled “Homeless or Orphan Drugs.”

“The naming of drugs of rare diseases as ‘orphan drugs’ wass not done frivolously,” Congressman Henry Waxman, D-Calif., a cosponsor of the Orphan Drug Act, has observed. “They are very much like children who have no parents, and they require special effort.”

To increase recognition of the problem, the Food and Drug Administration in 1982 set up an Office of Orphan Products Development. Orphan products, according to FDA’s definition, include drugs, biologics such as vaccines, medical devices, and medicinal foods to treat uncommon diseases.

The office was assigned the task of identifying promising new therapies for rare diseases and commercial sponsors to develop the products. In Katie’s case, penicilamine, a drug that control Wilson’s disease, had been developed well before 1982. A prominent pharmaceutical company, Merck, Sharp & Dohme, was already manufacturing it.

Katie was put on penicillamine, but after nine months she developed proteinuria, a loss of protein in the urine that can lead to kidney failure. “Proteinuria,” Dr. Scheinberg explains, “is one of the commonest of several toxic effects of penicillamine therapy and occurs in a about 5 percent to 10 percent of patients.” So Katie had to be taken off the drug. as a consequence, in a few months her depression returned.

“Earlier, there would have been no hope for Katie,” Dr. Scheinberg explains, “and she would have been condemned to die as a young adult.”

But by the time Katie came to dr. Scheinberg, he had a new experimental drug for Wilson’s disease. Developed by Dr. John Walshe at the University of Cambridge in England, the drug, trientine, lacks the toxic effect of penicillamine. After a few months on trientine, Katie’s depression vanished. She continued to improve, and, in 1986, she graduated from Harvard University magna cum laude.

In 1982, FDA’s Office of Orphan Product Development, recognizing the apparent usefulness of trientine, began to look for a sponsor. FDA published the information about Wilson’s disease and the need for a drug sponsor in the Federal Register.

Merck, Sharp & Dohme was already making penicillamine available to doctors to trat 1,000 patients. Allerted by the notice in the Federal Register, the company agreed to develop trientine, even though the potential market for the lifesaving drug totaled only 100 patients.

To be sure, trientine had already been discovered by Dr. Walshe. But in 1982 it was still considered an experimental new drug. Under the regulations that guide FDA in enforcing the Federal food, Drug, and Cosmetic Act, the most costly and time-consuming research and development work is conducted after a drug is given investigational new drug (IND) status, meaning it can be tested in people. It is this work that eats up most of the research funds spent by the sponsor in order to obtain data demonstrating safety and effectiveness. Once approved by FDA as safe and effective, a drug can be made available for general use.

For orphan drugs, development costs are much lower than average since the patient population is so small. Nevertheless, by the early 1980s, there was growing recognition that the government had to assume more of the burden if patients suffering from many rare diseases were to be helped. FDS, acting on behalf of the Department of Health and Human Services, and Congress cooperated to make assistance from the federal government available.

The Orphan Drug Act consponsored by Senator Orrin Hatch, R-Utah, and Conressman Waxman and passed by both houses of Congress with bipartisan support, was signed into law by President Reagan on Jan. 4, 1983.

The act fostered the development of orphan drugs by several important means. Under its terms:

* The orpha drug developer has seven years of exclusive use or license, during which no one else may market the drug in the United States unless permitted by the sponsor.

* The developer of an orphan drug may claim up to 63 percent of the cost of clinical studies as a tax credit.

* FDA can assit sponsors of orphan drugs in developing the protocol, or guidelines, for conducting clinical studies.

* FDA can modify certain drug approval requirements for specific orphan drugs. For example, because orphan drugs are used by so few patients, FDA may permit an orphan drug to be tested in a relatively small group of persons. Or, in exceptional cases, FDA can waive the sponsor’s need to rule out a drug’s long-term potential to produce cancer, reasoning that if left untreated the rare disease victim would have died before cancer could hav been induced by the drug.

* FDA can put orphan drugs on a “fast tract,” giving them high priority for review.

* FDA can make grants of $20,000 to $70,000 in support of a sponsor’s clinical research of an orphan drug. In fiscal year 1987, FDA and $3.5 million available to make such grants, and for 1988, $4 million has been requested.

A 1984 amendment to the 1983 act extends the definition of a rare or orphan drug to products that may be needed by more than 200,000 persons, but have no reasonable prospect of recovering research and development costs from sales in the United States.

How successful has the Orphan Drug Act been? In November 1985, when trientine was approved by FDA, there were 72 designated orphan drugs either approved or under development. In April 1987, FDA’s Office of Orphan Products Development designated its 100th orphan drug, 24,24-dihydroxycholecalciferol (DHCC or 24, 25D), a compound to treat patients with kidney disease caused by complications from dialysis.

Examples of orphan drugs include:

* Pentimidine isethionate, to treat Pneumocystic carinii pneumonia, an opportunistic infectin that strikes may AIDS patients,

* Digoxin-specific antibody fragments, an antidote for life-threatening overdoses of digoxin–a commonly prescribed heart drug,

* Clofazimine, an agent to treat a drug-resistant form of Hansen’s disease (leprosy),

* Alpha fetoprotein, the first standardized diagnostic test to evaluate results of therapies for cancer of the testicles, and thereby help manage treatment,

* Naltrexone, to treat narcotic addiction,

* Cyclosporine, an immune suppressant to prevent organ transplant rejection,

* Desmopressin, a drug to treat moderate hemophilia, and

* Etoposide, to treat testicular cancer.

The list of drugs designated as orphans grows year by year. Persons seeking information on rare diseases and therapies to treat them can call the National Organization for Rare Disorders at (203) 746-6518.

COPYRIGHT 1988 U.S. Government Printing Office

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