Submitted photoLily Perkins smiles with her fiance, Silas Davis, and his daughter, Chloe. Perkins was able to avoid terminating her own pregnancy thanks to the drug Soliris, which treats PNH, a rare blood disorder.

Lily Perkins believes her unborn baby may have saved her life. Now, she’s returning the favor. Doctors advised Perkins to terminate the pregnancy to save her own life after she was diagnosed with a rare blood disorder. If she continued, they told her, she had a one in five chance of dying.

Perkins was diagnosed with paroxysmal nocturnal hemoglobinuria, or PNH, a condition in which the body’s immune system destroys its red blood cells. A rare disease, it affects only 1 or 2 out of every million people, often with debilitating symptoms.

Faced with an agonizing decision, Perkins, 27, and her fiance, Silas Davis, felt they owed a debt to their unborn child. Had she not become pregnant, Perkins’ first sign of the disease could have been a fatal blood clot.

“My baby is the only reason we caught this and I’m still alive,” she said. “I felt like for the rest of my life, if I got better, I would never forgive myself.”

Perkins, who lived in Bend for seven years before moving to Portland a year ago, sought a second opinion at Oregon Health & Science University, where hematologists see a new PNH case, on average, every other year. It was only then that the couple learned they had been given outdated medical advice.

Soliris, a drug approved in 2007, has drastically changed the outlook for patients with PNH, and doctors no longer recommend terminating pregnancies.

The drug has improved quality of life for PNH patients so dramatically that insurance companies are willing to pay $440,000 a year for the drug, the single most expensive medication in the U.S.

While critics bemoan the high cost and the barrier it poses for patients worldwide, the success of Soliris — clinical and financial — has changed the landscape for PNH patients and the prospects of developing viable therapies for dozens of other rare diseases.

Bone marrow disease

PNH is a somewhat misnamed disease dating back to its discovery in the early 20th century. Patients would sometimes have dark urine in the morning, and when doctors tested it, they found high levels of hemoglobin. They correctly surmised that something must be destroying the patient’s red blood cells, dumping hemoglobin into the blood. But they mistakenly believed this happened only at night (nocturnal) and only from time to time (paroxysmal). Even the term hemoglobinuria, (hemoglobin in the urine) was not an accurate descriptor of the disease.

Only a third of patients will have hemoglobin in their urine, it’s not happening only at night, and it’s not happening sporadically, said Dr. Jack Goldberg, a University of Pennsylvania hematologist, during a seminar for PNH patients last year.

“We now know that term for this disease is really false, but we continue to have that name because it’s historic,” he said.

PNH occurs when the bone marrow is damaged and a mutated stem cell able to survive that damage begins to produce defective copies. The resulting red blood cell lacks the protein on its surface needed to fend off a part of the immune system known as complement.

With the protection missing, complement bores holes into the red blood cells, which then fill with water and eventually explode, dumping their contents into the blood stream. The resulting detritus causes most of the problems associated with the disease. The released hemoglobin binds up nitric oxide, which is needed for smooth muscle contraction and for constriction of blood vessels. That leads to problems such as difficulty swallowing, abdominal pain and erectile dysfunction. The lack of nitric oxide causes pulmonary hypertension, or high blood pressure, in the blood vessels of the lungs, which leads to shortness of breath and fatigue.

“These patients would have disabling fatigue, and I really emphasize disabling,” said Dr. Robert Brodsky, a hematologist at Johns Hopkins University and one of the leading PNH experts in the U.S.

He had one patient who described having to decide each morning whether to go downstairs to eat breakfast or take a shower. He had energy for one, but not both.

Meanwhile, defects in platelets increase the risk for blood clots, particular in the liver and abdomen. Patients often experience abdominal pain and are at high risk for strokes or other complications. And the kidneys can be damaged as they work overtime to filter the hemoglobin and other red blood cell contents from the blood stream.

Before Soliris, two-thirds of PNH patients would experience moderate or severe kidney failure, and 20 percent would die of kidney failure.

“It was bad for these patients,” Brodsky said “About 50 percent would get into real trouble, and the biggest trouble they would get into would be blood clots.”

Doctors tried to prevent blood clots by placing patients on blood thinners, with limited success. And because patients were often short of platelets, it was harder to regulate the blood thinners. Many patients were at high risk for fatal bleeding.

Frequently patients could be managed with blood transfusions, restoring their supply of red blood cells and platelets, but it was a less than ideal solution. Doctors treated the symptoms, but could do little to intervene with the progression of the disease.

Surviving PNH

“What did patients do before Soliris? I have to say many died,” said Melanie Marquez, 47, a PNH patient from West Chicago, Ill. “Most that I know of passed away between five to 10 years after diagnosis. I am in a rare group of PNH patients in that I have survived over 20 years without Soliris. There aren’t many of us.”

Indeed, data from a PNH registry shows that more than a third of patients die within five years of diagnosis, generally due to a fatal blood clot. Another third will die within 20 years.

Marquez was diagnosed in 1990, also as a result of a routine blood test when she wanted to start a family. Six months after the blood test, she received a call from her doctor.

“They told me, ‘We finally figured out what you have. I hope you’re not planning on starting a family soon,’” she recalls. “I told them, ‘I just found out today I was pregnant.’”

Marquez lost that baby due to blood clots, but went on to have two children even without Soliris.

Other than a yellowing of her eyes, a sign of potential liver damage, Marquez had no other symptoms when she was diagnosed. But problems began to emerge soon thereafter and got progressively worse.

“If I walked to the mall, I would have to stop and rest often,” she said. “People would look at me and say, ‘What’s the matter with you?’ because I’m not overweight at all.”

If she pushed onward she would develop terrible chest pains and eventually migraines. She learned to pace herself so she could go to the store, but a field trip to the zoo with her children was out of the question.

For years, doctors treated her symptoms — mainly with migraine or pain medications — but could do little for her underlying condition. Then several years ago she learned about Soliris from a PNH patient chat site. She said her HMO doctor saw the price tag and balked.

“You’re not that bad. You get some headaches,” she recalls him telling her.

A specialist disagreed. The repeated migraines meant she was at greater risk for a stroke.

“That first treatment, that first night, I knew it worked,” Marquez said. “Instead of feeling like I had sludge in my head, it felt like water. A lot of people say they don’t realize how bad they were until they started Soliris.”

Marquez can now comfortably walk a mile and has cut down her migraines from 10 a month to one every three months. A legal secretary, she helps manage the PNH Foundation and has seen the impact Soliris has had on other patients.

“For some of us, it was a game changer, a new life,” she said. “For others, it was just another treatment.”

Soliris so specifically targets the destruction of red blood cells by complement in the blood stream, that it has less impact on patients whose red blood cells are being destroyed elsewhere, such as in the spleen. Other patients have run into financial difficulties, particularly with annual caps on medical benefits, now outlawed by the Affordable Care Act. The effect can be varied even for a single patient, depending on factors such as stress, illness or exertion. Some patients need the treatment more frequently than every two weeks. Sometimes Marquez can feel the effects waning in the days before she returns for the next infusion.

“You just hope it’s going to be a good two weeks,” she said.

Often misdiagnosed

PNH is so rare that many non-hematologists have never heard of it. Patients are often misdiagnosed, swallowing difficulties attributed to acid reflux, chest pains to angina, dark urine to urinary tract infections. That results in unnecessary medications, useless tests and a delayed diagnosis.

But once diagnosed, few will have to endure what Marquez experienced.

“When the first patients started going on the medication, they were even more grateful for how they felt than the patients are today. The reason being is they often suffered through years and years of transfusion, fatigue, concerns about and complications from blood clots,” Brodsky said. “Whereas today’s patients are more rapidly diagnosed. They’re symptomatic for two weeks, three weeks, but they don’t know what it was like to have bad PNH.”

Previously, doctors could try to cure PNH with a bone marrow transplant, but that carried high risks and was generally done only in cases that couldn’t be managed with transfusions and blood thinners.

Soliris has all but eliminated that approach.

“We seldom pick patients for bone marrow transplant any more,” Brodsky said. “Before Soliris, I lost a lot of patients to the disease. It’s really changed the life of these patients. Since this drug has become available I almost never have a PNH patient in the hospital. This is a game changer.”

Its impact has been even more dramatic for pregnant PNH patients, as pregnancy itself is a risk factor for blood clots. Without Soliris, both mother and child face an increased risk of death during pregnancy, said Dr. Jamie Lo, a high-risk pregnancy specialist at OHSU treating Perkins.

“It can be as high as 10 to 20 percent, and babies can have pre-term deliveries in as much as half of the pregnancies,” she said.

Because PNH is so rare and Soliris relatively new, doctors have very little hard data for how the drug works during pregnancy. Brodsky and his colleagues have tracked about 20 cases. Lo said a similar number of cases have been described in medical literature.

“It’s a difficult thing because you have this new drug but we don’t know what the long term effects on her or the baby are,” she said. “But yet it can really reduce significantly mortality and morbidity for her and her baby. That’s one of the hardest things for (Perkins), I think, deciding that.”

Doctors do not believe Soliris can cross the placenta easily, and tests of umbilical cord blood and breast milk have found only trivial amounts of the drug.

The game changer

Perkins now receives infusions every two weeks, alongside many of the hospital’s sickest cancer patients. “You sit there for an hour while it slowly drips away,” she said. “It’s hard not to look around and feel like you’re dying.”

The liquid that drips into her arm contains one of the few medications on the market today that was designed rationally based on biological knowledge, rather than the trial-and-error approach used to find most drugs. In the 1990s, researchers at the biotech company Alexion Pharamaceuticals specifically set out to find a way to block the effects of complement. They screened 30,000 different antibodies before finding one that would target the precise link in the chain reaction that produces complement. Any further upstream, and they would have eliminated much of the body’s ability to fight off disease and infection.

By targeting the second-to-last step in the process, they block the destruction of red blood cells and sacrifice protection from just one common risk, meningitis. All Soliris patients are given a meningococcal vaccine prior to starting the drug.

Alexion nearly went broke before bringing its drug to market and stunning the world by charging $400,000 or more per year for the drug. Soliris is so effective at reducing the damage caused by PNH, however, that U.S. insurance companies will pay for the drug. Alexion banked $1.5 billion in revenues in 2013 selling a single drug.

Insurance plans are unlikely to have more than one or two patients on Soliris at a time, and even the staggering cost pales in comparison to the billions spent on medications for cholesterol, blood pressure or diabetes.

The high cost has proven a barrier in other countries. In Canada, the drug was approved by Health Canada, but is not being covered by some of the provincial drug plans. Patients have been fighting for access to Soliris in Australia, New Zealand and other countries.

The company does provide assistance to patients who don’t have insurance coverage for the drug, and the National Organization for Rare Disorders has helped patients with their copays.

“It actually is a success story, when viewed in the broader context of all rare diseases,” said Mary Dunkle, vice president for communications for the advocacy group. “According to the National Institutes of Health, there are nearly 7,000 such diseases affecting 25 to 30 million Americans. Of all those diseases, only a few hundred have treatments approved specifically for that disease.”

The Orphan Drug Act enacted in 1983 provides extra incentives for companies to pursue drugs for rare diseases, and it’s been effective in bringing new drugs to market. But the high price tags that have proven palatable for breakthrough drugs have created new markets for a burgeoning biotech industry.

While doctors have recently begun to push back against the high cost of drugs in the cancer field, oncologists can often substitute a less-expensive treatment. For many of the rare diseases, there is no other viable treatment, and patients and their insurance plans have little choice but to pay.

Perkins has health insurance that is paying for the medication, although her friends have started an online effort to raise money for non-covered expenses (See “How to help”).

Dr. Thomas DeLoughery, an OHSU hematologist, said Soliris is working well for Perkins and has brought down her levels of red blood cell and platelet destruction.

“There’s always an issue of whether this is reflecting an underlying bone marrow disease, so that’s something we need to keep an eye out for, but so far, it seems pretty stable,” he said. “I tend to be the eternal optimist, but so far I think we’re doing good.”

Perkins has chosen the optimistic route as well.

“You’re so grateful in weird ways when you’re sick,” she said. “Now it’s like all I think about is being positive. If I do think of something negative, I don’t want the baby to feel that, so I don’t let myself go there.”

Doctors will continue to monitor Perkins, now four months into her pregnancy, and the development of her baby. Pre-term birth and slowed growth remain a concern. Until a cure for PNH is found, she will likely have to continue taking Soliris for the rest of her life. PNH is not an inheritable disease, so it is unlikely her baby will be affected.

A graduate of Oregon State University-Cascades Campus with a degree in psychology, Perkins had launched a children’s day care before she was diagnosed but had to close it soon after. She said she has wanted to have a child of her own all her life.

“If I didn’t keep the baby, I would have felt like I had nothing to fight for,” she said. “When I found out I may not be able to keep the baby, I didn’t eat for three days and I wasn’t taking care of myself. I know I would have not cared. I don’t want to sound terribly morbid, but that would not have been a great outlook to have when you’re trying to survive something.”

—Reporter: 541-617-7814, mhawryluk@bendbulletin.com