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Preventing Migraines with a New Kind of Antibody

A biopharmaceutical company will know this year whether an antibody produced using a unique technique can prevent chronic migraines.

For many who suffer from chronic migraines, nothing can reliably prevent or dull the debilitating headaches that may strike as often as every other day.

Fungal factory: Liquid cultures of genetically engineered yeast could be an alternative source of therapeutic proteins such as antibodies.

A biopharmaceutical company in Bothell, Washington, may have a solution. It hopes that a monthly injection of an antibody that blocks a well-known migraine-triggering protein will prevent these headaches.

The company, called Alder Biopharmaceuticals, is testing the efficacy of the drug in a clinical study of 160 patients, each of whom has between four and 14 migraines per month; Alder expects the results of the study to be in this fall.

The company’s new antibody is also produced in a novel way. It is made in yeast, a relative outsider in the world of therapeutic protein manufacturing, which is dominated by bacteria and mammalian cell culture. By producing the antibody this way, the company hopes to prove the new manufacturing approach, which Alder says will be faster and potentially cheaper.

Around 10 percent of people worldwide suffer from migraines, according to the World Health Organization, and as many as 4 percent of people have these disabling headaches 15 days or more each month.

“The physiology of people who have these headaches is variable,” says Linda Porter, who oversees research efforts on migraine for the National Institute of Neurological Disorders and Stroke, a branch of the National Institutes of Health. “It’s a complex [condition], which is partly why it is so hard to treat and prevent.”

The genetic components that make a person susceptible to headaches can differ from case to case, as can an individual’s response to treatments, she says. Some people respond to over-the-counter painkillers or prescription anti-inflammatories, and others don’t.

The target of Alder’s antibody is a protein called CGRP that is thought to be at the root of migraines. CGRP has been intensely studied by multiple drug companies, says Porter, but so far without success. The protein is released during the processes that trigger pain, says Porter, “and if you can block the release of it, then it seems it would be pretty effective to stop headaches.” One company had a late-stage clinical trial with a drug that blocked CGRP but, while the treatment seemed to reduce headaches, the trial uncovered problems with liver toxicity, she says.

For Alder, that trial, conducted by Merck, firmly established that managing migraine through CGRP control was going to work. An antibody—which typically is more specific and has fewer off-target effects than small-molecule drugs—could offer a safer mode of attack.

John Latham and two other former employees of a large antibody-manufacturing company called Celltech founded Alder with the goal of developing a new way of producing antibodies. The team decided to try to “change the paradigm with the way you make an antibody, make it faster and more reliably,” says Latham.

Today, all antibody drugs are made in mammalian tissue culture cells. The compounds made this way include therapies such as Humira for rheumatoid arthritis and Herceptin for cancer. According to Alder, it takes an average of 12 months to generate a commercial antibody strain using mammalian cell cultures. Alder’s yeast-based cultures take about five weeks. “The great benefit of using yeast in general is to have a very fast turnaround time and genetic understanding of the organism,” says Huijuan Li, director of Glycofi Molecular Discovery, a subsidiary of Merck that is developing yeast-produced protein therapeutics. That genetic understanding has helped Glycofi and other yeast antibody companies to tweak the organism’s biology so that it can produce more human-like versions of proteins.

Alder also says that producing antibodies in yeast will also be cheaper compared to producing them in mammalian cells, which grow more slowly than yeast and require more costly culturing conditions. Producing a more cost-effective antibody will be important to break into the migraine-treatment market, says Latham. Current antibody therapies cost around $10,000 to $25,000 per year, says Latham. “The most expensive drug launched to date [for migraines] is about $5,500 per year,” he says. So for Alder’s antibody to be viable in the migraine market, it will have to be more affordable.

Some doubt that the approach will bring the costs down significantly. While the cost of manufacturing is much higher for protein-based therapies than for classic small-molecule drugs, the amount spent producing the therapy is still only a few percent of the total cost, says Tillman Gerngross, a bioengineer at Dartmouth University and cofounder of Glycofi, which began as an independent biotech before joining Merck.

Still, the popularity of producing antibodies and other therapeutic proteins in yeast is likely to grow in coming years as the technology develops and more yeast-produced drugs are approved by the government, says David Bramhill, a biotechnology consultant and senior director of technology and business development at BioSavita, a yeast antibody company. “Very big gains in productivity should be possible.” One challenge will be overcoming a hesitation by some in the industry to make novel antibody medications in yeast rather than in mammalian cells, even though many yeast-produced proteins have already been approved by the FDA, says Bramhill.

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