Rare Disease Treatments:
'Orphans' Saving Lives 
by Robert A. Hamilton 

  When Alison Ashcraft was 7, her family doctor called her parents in to
tell them she had a rare disease, severe combined immunodeficiency, a 
genetic disorder made famous by the movie " The Boy in the Plastic Bubble." 
For children like Alison with no compatible bone marrow donor, there was no 
cure. The only treatment was repeated transfusions of gamma globulin, which 
still left her exposed to a host of infectious diseases.
  After her diagnosis, her health worsened. "She would get a cold, it would 
turn into an infection, it would go to her lungs, and she would wind up in
bed for six weeks with pneumonia," said her father, Aaron E. Ashcraft. She
was fatigued, sleeping 20 hours a day, and unable to play more than five
minutes of tennis, her favorite sport. She could not attend school from 
December until March because of her susceptibility to normal childhood
infections and the possible dire consequences; even chicken pox could be
fatal for Alison. 
  Then she was enrolled in a study of a drug called PEG-ADA, in which she 
was given adenosine deaminase, an enzyme her body failed to produce on its
own. Last year, her sophomore year in high school, Alison was able to attend
school through the winter for the first time. And one recent weekend she and
her father played tennis 90 minutes without a break.
  As recently as 10 years ago, PEG-ADA might never have come to market. But 
under the Orphan Drug Act, the federal government provided a grant to 
support development costs, provided federal tax credits, and offered other
inducements, and PEG-ADA was approved by the Food and Drug Administration 
last March 23.

Other Rare Diseases 
  There are an estimated 5,000 known rare diseases that affect fewer than 
200,000 people each, but which collectively affect between 10 million and 20
million people, according to estimates by the Pharmaceutical Manufacturers
Association (PMA) and the National Organization for Rare Disorders (NORD).
  The Orphan Drug Act has helped in the development of products to treat
drug addiction, leprosy, hemophilia, and rare cancers, as well as diseases
most people have never heard of, such as cryptosporidiosis (an infection
caused by a protozoan parasite found in animals' intestines that causes 
diarrhea, fever, weight loss, and lymph node enlargement) and 
neurocysticercosis, a parasitic disease characterized by cysts in the brain 
and spinal cord.
  The Orphan Drug Act was one of the reasons the pharmaceutical community 
was able to rise to the challenge of acquired immune deficiency syndrome, or
AIDS. Pentamidine isethionate, used to treat a pneumonia that strikes many
people with AIDS, and zidovudine (commonly called AZT), which prolongs the
life of people with AIDS, were also developed under the Orphan Drug Act.
According to Marlene Haffner, M.D., FDA's director of orphan product
development, "Without the Orphan Drug Act, pentamidine may have been
developed much later, as may have AZT, and maybe some of the others would 
never have seen the light of day."

Just the Beginning
  The Orphan Drug Act has been in place more than seven years, but because
of the length of time required to bring a drug to market, it is only just 
beginning to yield results. There have been 41 orphan drugs approved, most
of them in the last few years, and, according to a recent trade publication,
Orphan Drugs in Development, 133 products for 96 rare disorders are in the
final stages of development.
  "The first couple of years the Orphan Drug Act was in place, there was a
lot of uncertainty about it, but the last four or five years it has really
blossomed," said Abbey S. Meyers, NORD director. "In fact, what we're seeing
now is a number of companies starting up specifically to pick up some of
these orphans. If you can pick up an orphan drug and it has a market of $5
million to $20 million a year, a little company is very happy with it." 
  One of the new companies is Medical Market Specialties Inc. of Boonton, 
N.J., which has an investigational new drug application for Elmiron, said 
company president Richard C. Lufkin. Elmiron (pentosan polysulphate sodium) 
has been around for years, but the company is studying it to determine
whether it can be used to treat a rare and painful bladder disorder,
interstitial cystitis, which affects about 45,000 people in the United
States, 90 percent of them women. 
  "Without the Orphan Drug Act, Elmiron would never have been pursued,
because there would have been no [marketing] protection," Lufkin said.
"After we got done with the [approval process], someone else could have made
it and sold it without the research and development expense." 

Recent Approvals
  In 1989, eight new orphan products were approved for marketing, including 
epoetin alfa for the treatment of anemia associated with chronic renal
failure, rifampin for anti-tuberculosis treatment, and cromolyn sodium for
mastocytosis, which can cause hives, itching, bone pain, diarrhea, and
chronic fatigue.
  Also in 1989, FDA awarded 21 new grants for research into conditions such 
as: graft-versus-host disease; sickle cell anemia; Wilson's disease, in 
which copper accumulations in the liver cause cirrhosis and ultimately
intellectual impairment; and neuroblastoma, a tumor of the adrenal glands or
sympathetic nervous system that affects about eight out of every 1 million
children. 
  Marketing exclusivity is one of the key features of the Orphan Drug Act 
because often a drug that has been around for years, and therefore cannot be
patented, is discovered to be effective against another disease. A
researcher might get approval to treat a few specific patients under an 
investigational protocol, but not have the time, money or expertise to guide
it through the regulatory process for market approval.
  "Some of these doctors were making these drugs by hand, and it occurred to
them that if they get run over by a truck their patients would die, so it 
became important to them to find a commercial sponsor," said Meyers.

Ucephan 
  That was the case with Ucephan, made by Saul Brusilow, M.D., at Johns 
Hopkins University until it was picked up by Kendall-McGraw. Ucephan is used
to treat three forms of urea-cycle disorder that, combined, affect perhaps
30,000 people.
   Each day Americans eat about 100 grams of protein, which contains
nitrogen that the body cannot incorporate. People with normal urea systems
excrete nitrogen in the urine in the form of urea, the end product of a 
complex biological process. But someone with urea-cycle disorder, a genetic 
defect, accumulates nitrogen in the blood as ammonia, causing lethargy, 
stupor, vomiting, brain swelling, seizures, and, ultimately, death. 
  Brusilow said he was talking with some colleagues about the disorder when 
someone suggested he try Ucephan, a drug made of sodium benzoate (a 
preservative in food and soft drinks) and another chemical, sodium phenyl 
acetate. The body converts both components to a nitrogen-containing compound
and then excretes it. 
  "Ucephan sponges up the nitrogen that the defective urea enzyme can't 
handle," Brusilow said. "The problem is that sodium phenyl acetate, which is
more effective, smells very bad. When I was the only source of sodium phenyl
acetate in the world, making it in my lab, I was stinking up the building." 
The sodium benzoate made the drug more palatable by reducing the smell. 
  Because Ucephan's patent had run out, without the seven years of marketing
exclusivity offered by the Orphan Drug Act, it would have been unlikely that
a manufacturer would have put millions of dollars into sponsoring Ucephan 
for urea-cycle disorder, because once FDA approval was granted any
manufacturer could have submitted an application to FDA to market a generic 
copy of the drug. But market exclusivity permitted an opportunity to recover
the development costs.
  Brusilow said handing production over to Kendall-McGraw has allowed him to
concentrate on second- and third-generation forms of the drug. He has 
obtained investigational new drug status for a new compound that replaces 
the phenyl acetate with sodium phenyl butyrate, which costs more but is 
odorless. 

Serendipity 
  Occasionally there have been serendipitous outcomes of orphan drug
development resulting in more possible uses for a drug than originally
expected. Penicillamine, for instance, was used to treat about 2,000 people 
for Wilson's disease, and, although it was not a money-maker, the 
manufacturer continued to make it available as a public service. Then a 
university in England discovered it was also effective as an arthritis
therapy.
  "If that manufacturer had stopped making that drug, we would not have one 
of the key treatments for severe rheumatoid arthritis today," Meyers said.
"That's really the lesson of orphan drug development."
  The same thing appears to be happening with Cytomegalovirus Immune
Globulin Intravenous, or CMV-IGIV, a biologic for treating kidney transplant
patients. The CMV-IGIV contains high concentrations of the cytomegalovirus
antibodies, which ward off the severe effects of the infection. Most adults 
in the United States have been exposed to cytomegalovirus, and it is usually
harmless to normal, healthy adults. In those whose immune response has been 
compromised, however, the virus can destroy the lungs, liver, eyes, and 
other critical organs. In kidney and other organ transplants, the immune
system is purposely suppressed to prevent organ rejection.
  On April 17, 1990, FDA granted Massachusetts Public Health Biologic 
Laboratories a license for CMV-IGIV, and the Red Cross began distributing it. 
  "Demand has been growing faster than expected and, unfortunately, 
production hasn't been able to keep up yet," said Lauren M. Foohey of the 
Red Cross product management unit.
  Although CMV-IGIV is licensed only for kidney transplants now, Foohey said
the Red Cross has been getting a lot of calls from physicians who are 
interested in its application in heart, liver, and other organ transplants, 
and there is some indication CMV-IGIV might be used for people with AIDS, 
whose immune systems are suppressed by the disease. 

PEG-ADA 
   One of the premier examples of how well the Orphan Drug Act can work came
this year with the approval of PEG-ADA. 
  "This was a breakthrough," FDA's Haffner said of PEGnology, the enzyme
replacement process developed by Enzon. "If it works the way it's thought it
will, this technology will change the way we can provide drugs to patients."
  The drug's roots date back to the 1970s, when Abraham Abuchowski was a
graduate student at Rutgers University and wanted to do his thesis on the 
enhancement of enzyme therapy.
  Direct enzyme therapy, to replace enzymes that the body cannot produce
because of a genetic defect, has several problems. Since enzymes are
proteins, they must be injected, rather than taken orally. Most enzymes 
remain in the blood only a short time, requiring frequent injections, which 
in turn can cause the development of antibodies that clear the enzyme from
the blood even more frequently. In time, serious allergic reactions can 
occur.
  Working with Frank Davis, Ph.D., Abuchowski developed a process called
PEGnology, in which strands of polyethylene glycol, a nontoxic polymer
already approved by FDA for use in food, cosmetics and other drugs, are 
attached to the surface of the enzyme, "camouflaging it from the immune 
system. As a result the body does not recognize the injected enzyme as
foreign and does not produce antibodies that would remove it from the 
blood," according to the company literature. "This reduces the number of
injections needed to achieve therapeutic blood levels in addition to
reducing allergic reactions." 
  "PEG-ADA, from a purely business and financial sense, might not have been 
the best product to select, but it really was done for other reasons," said 
Donna Chappina, a spokeswoman for Enzon, the company Abuchowski and Davis 
formed to develop the drug. "They felt it was the most difficult one to 
accomplish. It was purely a scientific venture, two scientists banging their
heads together."
  Severe combined immunodeficiency was also a disease that had received 
little attention, because its patient population was so small, perhaps 40 
cases known worldwide. When clinical testing began on the product, 14 
patients in the United States and Europe were included in the drug trial, 
patients who until that day had no hope of escaping frequent injections and 
the effects of the disease. All showed improvement within 6 to 12 months, 
according to Chappina.
  Although the cost of PEG-ADA therapy is almost $60,000 a year and the 
patients are responsible for the cost, Enzon has worked with the insurance
companies covering families of patients and believes in most cases the cost 
will be covered, Chappina said. "The cost of the drug really has to do with 
the very high cost of the native enzyme, bovine adenosine deaminase, and, 
because there are only 14 people receiving the drug, we can't spread the
cost out," Chappina said. 
  Enzon also has hopes for other PEGnology drugs, in various stages in the
development process, that might serve wider audiences, Chappina said. In the
meantime, there are other, nonfinancial rewards.
  The families of six patients were flown into New Jersey for a press 
conference when PEG-ADA's license approval was announced earlier this year. 
The morning after their arrival, they all went up to Abuchowski's table in
the hotel restaurant, many with tears in their eyes, to thank him for giving
their children a better life. 
  That is the promise that the Orphan Drug Act holds out to people
throughout the country who have a variety of rare diseases. No longer is a
disorder that might afflict only a dozen people ignored by medical product
manufacturers because the research is economically unfeasible. Now those
sufferers have a chance that somehow, somewhere, a cure or a treatment will 
be found. 

Robert A. Hamilton is a health and science reporter for New London Day and a
freelance writer in Franklin, Conn. 

History of the Orphan Drug Act

  FDA set up the Office of Orphan Product Development in 1982 to focus on 
drugs, medical devices, foods for medical purposes, and biologics such as 
immune globulin for rare disorders. President Reagan signed the Orphan Drug 
Act into law on Jan. 3, 1983. It guarantees the developer of an orphan drug 
seven years of market exclusivity and 50 percent tax credit for certain 
clinical research expenses. Initially, the act applied only to patient
populations when it could be shown there was little hope of recovering
development costs from sales in the United States. A later amendment to the 
act defined an orphan product as one with a potential patient population of 
fewer than 200,000 people.
  Under the Orphan Drug Act, FDA makes grants for drug development, assists 
the drug developer in designing the clinical studies required for marketing,
and can speed up the drug approval process. 
  "There are no real shortcuts," said Marlene Haffner, M.D., FDA's director 
of Orphan Product Development. "A lot of these drugs are for very serious 
and life-threatening disorders, in some cases affecting only a few hundred
people. You have the smaller NDA [new drug application] and a group of very 
needy people, and that's what expedites it. But the safety and efficacy 
requirements are the same." 
  Since enactment of the Orphan Drug Act, 41 drugs for rare diseases have 
been developed and brought onto the market. Activity in orphan
products--which, in addition to drugs, can include biologics, medical 
devices, and foods marketed for medical purposes--is reaching an all-time 
high. According to Haffner, FDA has designated as orphans 375 drugs, and at 
least 150 are being actively developed or are going through the approval
process. The federal monies available to fund orphan drug development have
increased steadily--from $500,000 in 1983 to $7.5 million in 1990.
  The term "orphan drug" refers to a drug that will serve so few patients 
that it will be commercially impractical for a manufacturer to sponsor it.
Orphan drug also refers to compounds in the public domain for which there 
can be no patent protection once a company goes through expensive efficacy
tests and gets FDA approval, so that a competitor could immediately begin 
producing a generic copy at a fraction of the cost. The phrase was coined in
a 1968 editorial in the American Journal of Hospital Pharmacy, "Homeless or 
Orphan Drugs."

--R.A.H.