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The Science of Hope

Author: Judith M. Wilson
August, 2018 Issue

Rare diseases are one of medicine’s big challenges. The number of people that any one disease affects is small—fewer than 200,000 nationally—and patients are scattered across the country, so it’s unusual for most physicians to ever encounter a case. And when the few doctors who do see them are able to make a diagnosis, it can be difficult to find an effective treatment, since so few exist. The dearth of treatments is the result of a market that is too small to generate big profits, thus providing little incentive for large pharmaceutical companies to produce what are known as “orphan drugs.” Instead, hope often lies with smaller biotechnology companies that make the development of treatments for rare diseases a specific focus. Marin County is a hub for such companies, and their work is at the forefront of change for rare-disease patients.

Emil Kakkis, M.D., Ph.D., founded Ultragenyx Pharmaceuticals in Novato in 2010. He’s spent 22 years in the field of rare diseases and observed patients over the long term, seeing firsthand how their lives change when a drug that can help them gets approval. “As a physician, I was a medical genetics doctor. I was a specialist in diseases that are rare,” he says. He estimates that no remedies of any kind exist for 95 percent of rare-disease patients. As a result, the field for developing them is wide open and allows ample opportunity for finding first-ever treatments. “Our ability to change the future of patients is extremely high. You can do something profound for them,” he says. Kakkis worked at BioMarin Pharmaceuticals, the pioneering biotech company founded in 1997. In its early days, he was involved in developing some of the first treatments for rare diseases. When he branched out to start Ultragenyx, his goal was to find solutions for genetic diseases that are rare and ultra-rare, and he had his own vision. His experience allowed him to see what worked well and what didn’t. “Working from scratch, you get to define what the company is going to be,” he says. The development of drugs to treat rare diseases was the main purpose, but he wanted to go farther. In addition, he saw a chance for a new-generation pharmaceutical business to improve its ability to develop high-quality drugs.

The quest

Taking a drug from inception to the marketplace is a long and rigorous process that takes years. So far, Ultragenyx has received approval to sell two drugs. It started work on Mepsevii, which treats mucopolysaccharidosis VII, also known as MPSVII or Sly Syndrome—an inherited metabolic condition—in 2011 and received FDA approval in November 2017. Crysvita, a treatment for a disease that causes an unusual type of rickets, was approved in April 2018. Its development was in partnership with Kyowa Hakko Kirin Co., Ltd., a Japanese pharmaceutical and biology company. Kyowa Kirin did the research, and Ultragenyx then did the clinical testing and filing because it had experience in the area. “We’ve done the later part. We took their excellent knowledge and expertise and put them together in a development program,” Kakkis explains. He reports that the usual time frame for the entire process from the initial idea to sales, is usually 10 to 12 years, but can be shorter, sometimes taking as little as seven years.

Ultragenyx started with two people and two medicines in development early on, and has grown to a workforce of 570 with 2 approved medicines and 15 drugs in development. It has several drugs in its clinical pipeline—each at various phases of discovery and development—and the medicines in the lineup each fall into one of three distinct categories that define the approach to development. Biologics involves recombinant proteins that researchers make in large containers with engineered cells. “They’re proteins of a particular type,” says Kakkis. A second classification is small molecule, which involves substances, such as proteins, that inhibit or activate a process. And the third is gene therapy. “We can provide a copy of the gene to a tissue and let it make the missing protein inside the body,” says Kakkis. He gives the example of a patient with a UCD (urea cycle disorder) that prevents the body from detoxifying ammonia, which is usually a natural process. In some cases, one infusion might be enough. “If we could do that regularly in patients, that would be amazing,” he says, pointing out that a patient could stop taking medications and have a safer and more normal life. Gene therapy was popular 20 years ago, says Kakkis, but fell out of favor. Now, though, it’s back. “Gene therapy is exciting again. It’s working,” he says.

The first step is deciding on a disease to address, and for Ultragenyx to take on the development of a new treatment, a disease has to meet three criteria. A need must exist that isn’t already being met in any meaningful way; it must be without any approved therapies; and the science must be obvious. “We look for diseases where the genetics are clear,” says Kakkis. “The patient is missing something or has too much of something. Too much of something or not enough of something, and we can fix that,” he says. An enzyme that a person is lacking is one example. “We know exactly what is wrong,” he explains. Researchers can then set out to find a remedy, and when they have one with potential, they try different dosages to see how much it takes to make an improvement. For some patients, even a small amount of medication will have a positive effect, while others might need more.

Despite the seemingly simple explanation for the underlying cause of a disorder, the search for an effective treatment is time-consuming and complex. The process begins in a research lab, and once researchers have a drug they think will work, they make a small amount and test it on cells or animals. “If it works, then you go on to the next stage, which we call phase zero,” says Kakkis. The pharmacology in animals has to get good results, and researchers run a safety profile to show that the drug doesn’t cause any harm and also establish a range of safe doses. Throughout the process, their work meets exacting standards in accordance with Good Manufacturing Practice (GMP), and they compile all the information the Federal Drug Administration needs to review a treatment for approval. The next step is submitting an Investigation New Drug Application to the FDA, and approval allows a company to give the drug to humans in clinical trials.

A medication then goes through usually three phases of development before it’s eligible for final approval. Phase one is primarily about safety. “It’s first exploring the safety, then the dose,” Kakkis explains. Phase two goes on to establishing the dose by finding out how much it takes to get something meaningful to happen and whether it has any positive effect on a patient. “We usually do phase one and two together,” he adds. Combining safety and dosage is a departure from traditional drug development. Phase three-, clinical trials, are intended to confirm that a treatment shows efficacy that means something to patients and is also safe. Because patients aren’t concentrated in one area, clinical studies take place at multiple centers throughout the country, where physicians are treating people with a particular disease. Thomas Oliver Carpenter, M.D., for example, has been treating patients with X-Linked Hypophosphatemia, or XLH, at Yale University for 30 years. Carpenter agreed to test Crysvita on patients, but first, he had to get approval from Yale’s institutional review board, a body responsible for ensuring that a patient’s rights and welfare are protected. He also had to get patients to sign an informed consent form, a procedure that discloses what the risks and benefits of a treatment might be and makes sure patients understand them. At the conclusion of testing, assuming the results are satisfactory, the company submits an application to the FDA requesting approval to go to the marketplace and sell the product.

New-generation approach

As the rare-disease industry has matured, thinking has also evolved, resulting in new-generation practices. Thus, Ultragenyx differs from other more traditional companies in its approach to compassionate use, which is the practice of allowing a seriously ill patient to try an investigation drug —one that is still in the testing phase, and the FDA hasn’t approved—when they have no other options. “History has been against compassionate use,” says Kakkis, who points out that people could die before all phases reach completion. “We want to be more proactive on offering compassionate use,” he adds. According to Kakkis, that means giving patients access to treatments that are still in development, when there’s a clinically plausible benefit. “It allows engaging the crisis that exists in patients’ lives before you have final approval.”

In addition, Ultragenyx focuses on measuring the effect of a treatment in a more patient-focused and meaningful way. The team at Ultragenyx is composed of Ph.D.s and experts, and they talk to patients and find out what they want and what is meaningful to their lives. “It’s a new approach to measuring rare diseases. We’ve already created several new endpoints that haven’t been used before,” says Kakkis. In yet another innovation, the company has a disease-monitoring program instead of a registry. Kakkis explains that with a registry, a doctor submits reports, but doesn’t provide a lot of information to patients. A monitoring program, however, gives physicians and patient’s access to information so they can be knowledgeable about their progress. Ultragenyx plans to implement monitoring for all of its products for 20 years at least and will pay people to participate so follow-up can be more rigorous. “It’s a commitment into investing more in long-term follow-up,” says Kakkis.

The bottom line

The cost of getting a drug to market is high. “For many of the treatments in development in the industry, it’s more than $1 billion. We’ve raised about a billion dollars, but have only spent about $400 million,” Kakkis reports. Ultragenyx is a public company, so its funding comes mainly from sales of stock. It was primarily from venture investors initially, but now the company is part of many mutual fund portfolios, which have a large amount of money to invest. “It’s a lot of money,” says Kakkis. He points out that the high cost is one of the barriers to getting more treatments into development. “We could develop more drugs if we could speed up the process,” he says. He’s convinced it’s possible. He wrote a paper that analyzed costs and compared traditional methods with more efficient ones. Kakkis estimates that it’s possible to reduce costs by 70 percent. “We could develop three times as many drugs for the same money,” he says.

The high cost of development inevitably goes into the price of a drug, but Ultragenyx offers UltraCare, a support service to help patients access treatment. “We try to manage the cost per patient overall,” says Kakkis. The options include discounts, grants to nonprofits and assistance with getting health insurance. “If none of those works, then we would provide free drugs. Part of the responsibility is to not let financial issues stop someone from getting treated,” he says. “Usually in the end we’re able to negotiate a plan with an insurance company. It would be great if it wasn’t so difficult, but it is workable.”

For patients with rare diseases, simply knowing that someone is actively attempting to do something for them is meaningful. Kakkis describes their lives as akin to being in a dark, cold lake drowning, and no one is coming to save them. “It’s as if you’re able to throw them a rope and pull them in,” he says. “It’s a big win, regardless of what happens with the drug,” he says. “Finally, someone cares about them, when no one did.”

Rachael’s story

Ultragenyx’s recently approved drug Crysvita treats X-Linked Hypophosphatemia, a condition resulting from a genetic mutation that causes a rare type of rickets that results in symptoms such as bone pain, fractures and growth abnormalities. A more common form of rickets improves when an individual gets sufficient vitamin D, but XLH is resistant.

Rachael Jones, a Colorado resident, suffers from XLH, and while it’s a rare disease worldwide, with only one person in 20,000 affected, she reports that it’s common in her family. Her mother has it, and she and her brother inherited the defective gene and then passed it on to their children. “In all, it’s affected seven people in our family,” she reports, and because XLH isn’t well known, it’s been frustrating for them to find doctors who are familiar with the condition or aware of any remedies to alleviate the symptoms. After she found out about Crysvita, she began tracking its progress. “This has been such a wonderful thing to watch. The excitement has been building. I cried for the first hour after I found out about approval.”

Jones is working on getting Crysvita for herself and her children, who are 4 and 6 years old, and the children’s physician has gone through the process to meet with Ultragenyx and learn about protocols for treatment. She’s waiting for approval from her insurance company for her own treatment and hopes it will begin by the end of the summer. She notes that Ultragenyx did its part by working with insurance companies ahead of time, and people with different coverage have had an easier time getting approval. She has encouraged her brother and his daughters to consider using Crysvita. “I’m definitely working to be an advocate in my own family,” she says. She is also getting the word out to others suffering from XLH on online networks. When she thinks about what Ultragenyx is offering, “It’s hard to put into words. It’s truly wonderful, and it gives us all hope for the future,” she says. For the Jones children, it means a completely different childhood from their mother’s and will no doubt change their outlook for the future.

“When it works, it’s so compelling,” says Kakkis, who has treated some patients for 20 years and was present for their first infusion of a drug. “When you see it work, it becomes clear that’s what you want to do for the rest of your life. We want to do it over and over again.” For the North Bay to have a company that’s going to impact so many diseases for so many years is an exciting opportunity, he says. It’s an outlook that gives hope for the future, and Kakkis believes the rare-disease hub in the North Bay is poised to change the lives of patients around the world.

Orphan Drugs

The U.S. Food & Drug Administration’s Orphan Drug Designation program defines rare diseases as those that affect fewer than 200,000 people in the United States. The number of different rare diseases is approximately 7,000, and, cumulatively, the number of people suffering from them is about 10 percent of the country’s total population.

The United States Congress passed the Orphan Drug Act in 1983 to encourage the development of drugs for diseases that pharmaceutical companies had neglected or “orphaned” because such products would not reach enough people to be practical financially. Among the incentives, the act includes seven years of market exclusivity for an approved orphan product, the waiver of a prescription-drug user fee and some tax benefits.

To win FDA approval, developers of orphan drugs must do well-controlled studies to ensure they meet the criteria for safety and effectiveness.

Source: U.S. Food & Drug Administration


BioMarin Pharmaceuticals is a pioneering biotechnology company that has been at the forefront of developing drugs for rare diseases since 1997. It has a facility in Novato’s Bel Marin Keys, corporate offices in San Rafael and locations around the world. Its focus is on rare diseases that affect [approximately] one in 20,000 people. The company specializes in enzyme-replacement therapies and has seven products on the market and several more in its pipeline. Its revenues for 2017 totaled more than $1.3 million.

Among the notable people from BioMarin who went on to establish other companies are Emil Kakkis, M.D., of Ultragenyx Pharmaceuticals; John Klock, M.D., of QT Ultrasound and Christopher Starr of Raptor Pharmaceuticals, which Horizon Pharma of Dublin, Ireland, acquired in 2016. Starr was a co-founder of BioMarin.

Rare Disease Day

Rare Disease Day takes place in February each year around the world. It has a global theme, and in 2018, it was research. The National Organization for Rare Disorders—NORD—introduced it in the United States in 2009 as a way to raise awareness of rare diseases. It features academic and advocacy events throughout the country, and an online gallery, Handprints Across America, shares the stories of hundreds of people with a variety of disorders.




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