About seven years ago, 4-month-old Annabelle Bozarth had something going on in her back. Her mother, Stephanie, couldn’t figure out what it was, nor could the pediatrician. But the X-rays told a story nobody wanted to hear. There were certain abnormalities in the little hip bones, in the tiny fingers and in the lower vertebrae—indications of a disease so rare that, when Stephanie got the call announcing the diagnosis, only 300 cases were known worldwide.Mucopolysaccharidoses IV, or MPS IV, is one of a group of genetic diseases characterized by a lack of or deficiency in the lysosomal enzymes, whose job it is to break down and recycle the metabolic waste material that occurs normally in cells. Without the enzymes, the cells can’t get rid of the waste. The result is progressive developmental damage throughout the body and sometimes the brain. Depending on the severity of the case, the patient’s future is one of damage in every body organ (including the bones), pain and shortened life expectancy.
Because her baby’s symptoms showed up so early, Stephanie Bozarth was warned that her daughter’s case was probably severe, and that, for Annabelle, as with everyone with the disease at the time, there was no treatment and no hope. Says Bozarth, “It was a parent’s worst nightmare.”
Changing the fates
This is the type of nightmare the scientists at BioMarin have turned into a thriving business. Founded in 1997 to develop and commercialize pharmaceuticals aimed at the world’s rarest diseases, BioMarin, a pharmaceutical company with manufacturing facilities in Novato and Shanbally, Ireland, is dedicated to changing the lives of a small number of people all around the world in a very big way. Its efforts are paying off. According to CEO Jean-Jacques Bienaimé, who’s been leading the company for eight years, the company has revenues “north of” $500 million, and, as other products are brought to market in the coming months and years, expects to see revenues grow.
BioMarin, which employs approximately 1,200 people in Marin County and throughout 30 countries and commercial operations in more than 40 countries worldwide, is a global company solidly based in the North Bay. “We have manufacturing facilities in Novato and Ireland,” says Bienaimé, recalling recent growth. “We have research labs in Novato, and we have probably 400 to 500 people in Novato. So the vast majority of our employees are in Marin County. And the balance are in the rest of the United States and the world.” He says the company plans to continue to expand its operations in Marin County in the future.
Right for Marin
Usually, “industry” and “Marin” aren’t two words one tends to link, but this industry is providing hope where before there was none. Also, says Bienaimé, this is a relatively clean industry. “We’re a low environmental footprint industry. We’re a relatively clean industry, overall—no smokestacks,” he laughs. “We’re very valuable for the community in the sense that we generate a lot of high-paying jobs and a lot of value for the county—and we have a lot of room for growth.
BioMarin currently has four approved products on the market and a number of products in the development stage pipeline. The diseases it targets are known as “orphan” diseases, because they’re so rare and affect so few individuals—but have such devastating consequences—and treatments are so difficult to develop and manufacture that there hasn’t been a rush of companies eager to adopt them.
Orphan diseases are good business
Thanks to the Orphan Drug Act of 1983, there’s hope for people like Annabelle Bozarth and her family. The law encourages research into cures and treatments for extremely rare diseases, which companies would otherwise avoid since the market is small and the production expense is large. The law provides tax breaks to offset the expense of research and development, and protection from competition for seven years after a drug has been approved.
According to Bienaimé, with the incentives in place, developing and manufacturing treatments for rare diseases has actually proved to be good business. “The development times are short,” he says. “When you’re addressing a world population of 2,000 patients, it’s difficult for the regulatory authorities to ask for a very big trial. So the costs of development are generally lower; the time of development is lower; and you have the ability to price the drug appropriately depending on your strategy.” Like a precious metal, rarity creates its own value, and treatments for diseases where there are no other existing therapies, are, as he says, “generally very valuable.” So the competition is somewhat rarified, too. “We have no direct competition at this time,” says Bienaimé. “The only competition is not finding the patients.”
Correcting an internal recycling problem
BioMarin originally formed its mission around lysosomal storage diseases, treating them by creating enzymes to do the work of the defective or absent enzymes in the patient. Bienaimé explains that, because each enzyme is specific, and their entry method into cells is very complex, creating drugs that replicate the exact enzymes involved in the particular disease is difficult.
Without the federal incentives, companies such as BioMarin may be less likely to tackle diseases that require such intensive and high-tech research and development. “A lot of the inventions came out of UCSF and Genentech,” says Bienaimé. “So we’re using recombinant DNA technology to create a replacement that’s as close as possible to the human enzyme.” He says the enzyme replacement must be injected into the patient every one or two weeks—for life. So far, Bienaimé says, the drugs have affected thousands of lives, with about 1,000 patients in the developed world having MPS VI, and about 3,000 in the world having MPS 1.
“There are degrees and variations in severity between patients,” says Bienaimé, “but the differences aren’t geographic; it varies between patients.” He says the United States isn’t proportionally the biggest market, and there may be fewer patients here than there are in other areas like South America, the Middle East and Eastern Europe. For one of its products, Naglazyme, which treats MPS I, 85 percent of sales are to patients outside the United States. Thus, BioMarin’s need for an international presence. Says Bienaimé, “We have a direct commercial presence in all Western European countries, in Southeastern European countries, in some Middle Eastern countries and in Turkey. In 70 percent of South American countries, we have a direct presence.” It also has a presence in Hong Kong.
The products
BioMarin has approved drugs for two MPS diseases, Naglazyme for MPS 1, and Aldurazyme for treating MPS VI, and is in the testing phase of a third, for MPS IVA, which is the one Annabelle Bozarth is currently taking as part of the testing process.
Kuvan, which is its third drug now approved and on the market, is used for treating phenylketonuria (PKU), a condition found in one in 15,000 in the United States (or around 15,000 to 25,000 people), in which the body can’t break down the amino acid phenylaline, which builds up and leads to multiple health problems if not treated with drugs and special diet. “The life expectancy for people with PKU is close to normal,” says Bienaimé, “but it’s a very serious disease. Before PKU screening was established in the mid-1960s, PKU was the number one cause of mental retardation in the world. So it’s serious.”
A fourth drug, Firdapse, has been approved in Europe for the treatment of Lambert Eaton Myasthenic Syndrome (LEMS), which is an autoimmune disease associated with muscular weakness.
Competition
“Aldurazane was approved in the United States 10 years ago and has been open to competition for three years. But I doubt you’re going to see any competitor for a while,” Bienaimé laughs. “Because it’s a very complex protein. The enzymes are very large, and the three-dimensional structure of the protein is very complex. So despite or beyond the Orphan Drug Protection Act, a lot of protection comes form the fact that it’s an extremely complex, difficult and expensive product to make. And if one should try to copy it—it would be a different product.”
The testing process can be a boon for parents desperate to find help for their child, and so it was for Stephanie and Austin Bozarth, who learned in 2011 that BioMarin was testing a new drug for MPS IV. At the time, there seemed to be no progress on the horizon for patients suffering from this disease whose damaging agenda pressed on unchecked. “Nothing was happening,” says Stephanie.
For Annabelle, who’d been enduring multiple surgeries to keep the symptoms under control, life was getting progressively more difficult. The simplest things other children could do—going to the store with mom—exhausted her. She’d go to sleep crying because of the pain in her joints. When offered experimental treatment (paid for by BioMarin as part of the testing process), the Bozarths jumped at the chance. “We probably were one of the first of 10 in that clinical trial,” says Bozarth. “It’s given us hope.” More than that, it seems to be giving Annabelle a [better] life.
“I remember back when she was on the playground, at two-and-a-half and three years old,” says Stephanie Bozarth, “and she’d come up and say, ‘Please, take me home.’ And the reason would be that she couldn’t keep up with anybody.” Now, thanks to her participation in BioMarin’s testing program for an MPS IV enzyme replacement drug, she stays and plays until everyone is ready to go home. “That, to me,” says Bozarth, “is a huge difference.”
A ray of hope
The company employees thrive on the knowledge that their products are transforming lives. “We’re very patient-focused, because we have such a small patient population,” says Bienaimé. “We have wonderful relationships with the patients and physicians. Our medical affairs people know all our patients.”
In addition to creating the drugs, they also work with doctors explaining to them what each disease is about, helping doctors and diagnostic lab properly diagnose the patients, and also helping patients work with their insurance companies to get access to the drugs. Bienaimé says BioMarin products are helping thousands of people all around the world. The company shows its appreciation to the families and patients, who struggle for health, on Rare Disease Day (February 28, 2013).
“On Rare Disease Day, we had probably 10 patients at our headquarters,” says Bienaimé, “and we had a meet-and-greet so they could talk to our employees. That’s the kind of thing that gets people at BioMarin excited. It’s amazing what they’ve overcome.”
What’s next?
BioMarin is a company centered around genetics, and today’s cancer research is moving more into the genetic or molecular level. So much, in fact, that genetically based cancer research is becoming an orphan business. “So one day soon,” says Bienaimé, “instead of treating all breast cancer patients with one drug, you’ll be trying to target the patients according to the genetic profile of the tumor and design drugs that will be very effective in a subset of patients.”
The pipeline is full of hope, both for patients and investors, and many products are in development. “We have one product in pre-registration—we filed for approval in April—with the potential to double the company’s sales to bring us more than $1 billion in revenue,” says Bienaimé. This is Vimizm, for treating MPS IVA, and aimed at a population twice the size of its biggest current market base.
It has another product in development for PKU, says Bienaimé, which is likely to be significantly more effective than the first one; and it has two other products about to start testing by the end of the year, one for Pompe’s disease, another inherited lysosomal storage disorder affecting the heart and other muscles, which is aimed at a $1 billion market. Another study is for a treatment for Achondroplasia, or dwarfism. They are also moving into the field of genetically defined cancers. Having licensed a gene testing program from University College London and St. Jude Children’s Research Hospital, BioMarin will be looking for a treatment for hemophilia A in the future.
Patients hope for company’s health
For people like Annabelle Bozarth and her parents, all of this is hopeful news. “This enzyme replacement therapy is definitely going to change her outcome,” says Stephanie. “I feel she’s going to have a great life.”
BioMarin Pioneers the Orphans 
Orphan diseases—so called because no one wants to take on developing treatments for them—require intense and highly specialized research. Key events along the BioMarin evolutionary path:
1997 BioMarin founded. In March, with a $1.5 million investment from Glyko Biomedical Ltd., BioMarin was open for business. The company’s mission was to leverage its proprietary enzyme technology to develop therapies for the treatment of numerous diseases and conditions including genetic diseases and burn and wound care. By the close of the year, the company had raised an additional $11.3 million from private investors
1999 Initial Public Offering (IPO) completed . In July, BioMarin completed an IPO raising $67.3 million. Since a large number of the early investors were based in Europe, the company was listed on the Swiss SWX Exchange in addition to the Nasdaq National Market.
2003 Aldurazyme approved. In April and June, respectively, the FDA and European Commission (EC) granted marketing authorization for Aldurazyme, the first approved enzyme replacement therapy for the treatment of MPS I. Aldurazyme received FDA approval just five and a half years after the investigational new drug application (IND) was filed.
2005 Naglazymeapproved . In May, BioMarin’s first independently developed and commercialized drug and the first FDA-approved treatment for MPS VI was granted the orphan drug designation in the United States, which confers seven years of market exclusivity.
2006 Commercial operations opened in Europe . In January, in anticipation of the pending European marketing approval for Naglazyme, commercial operations were established in Europe. BioMarin Europe Ltd., headquartered in London, with branch offices located in Spain, Switzerland and Italy, became responsible for overseeing the sales and distribution of Naglazyme to the 25 member states of the European Union, Iceland and Norway.
2007 Kuvan approved . In December, approximately three years after filing the IND, BioMarin received FDA approval for Kuvan(sapropterin dihydrochloride) tablets, the first specific drug therapy for the treatment of phenylketonuria (PKU). The product was launched in the United States immediately following the FDA approval.
2011 Phase 1/2 trial for BMN 673. In January, BioMarin initiated a Phase 1/2 trial for BMN 673 for the treatment of genetically defined cancers.
2011 Novato facility expansion approved. In November, BioMarin announced it had received approval from the U.S. Food and Drug Administration (FDA) for its manufacturing facility expansion in Novato.
2012 PEG-PAL results announced . In September, BioMarin announced preliminary results from the Phase 2 program of PEG-PAL (PEGylated recombinant Phenylalanine Ammonia Lyase) for the treatment of phenylketonuria (PKU) demonstrating long-term retention, tolerability and providing evidence of efficacy. Based on these results, the company expects to start a pivotal Phase 3 study in the second quarter of 2013, following an anticipated end of Phase 2 meeting with the FDA in the first quarter of 2013.
2012 GALNS study advanced . In November, BioMarin announced the success of the pivotal Phase 3 study of GALNS for the treament of MPS IVA, Morquio A syndrome.
