A long wait, but worth it: Vonvendi’s Boston origins

blood vessel von willebrand factor Vonvendi
(ktsdesign/Shutterstock)

It’s no secret that it can take years, even decades, for a biological or medical discovery to move from the laboratory to the bedside. The Pharmaceutical Researchers and Manufacturers of America estimates that it takes on average at least 10 years (and $2.6 billion) to develop a new medicine from start to market.

But some wait times stand out. Take the story of Vonvendi, a recombinant form of von Willebrand factor (vWF), a clotting protein implicated in von Willebrand disease, a bleeding disorder.

Stuart Orkin, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and his then-research fellow David Ginsburg, MD, first cloned the gene for vWF in 1985. Pharmaceutical company Baxalta, which has been developing Vonvendi based on Orkin and Ginsburg’s original discovery, won FDA approval for the drug at the end of 2015.

But what makes this story unique isn’t the 30-year lag. Rather, it’s that — for reasons that aren’t entirely clear — the patent Orkin and Ginsburg filed for vWF in 1985 hung in limbo until 2013. But today, both men agree that while the wait was long, seeing their discovery emerge as a treatment is thrilling to no end.

Diving into unknown waters

vWF helps kick off blood clotting by stabilizing factor VIII — the clotting factor whose loss leads to hemophilia A — in the bloodstream. Different vWF mutations give rise to the different forms of Von Willebrand disease, a common bleeding disorder (affecting roughly 1 in 100 to 1,000 people) that’s usually so mild that it’s barely noticed.

But in the 1980s, no one knew how vWF mutations fueled forms of von Willebrand disease, because no one had the gene’s full sequence.

Stuart Orkin David Ginsburg von willebrand factor Vonvendi
Stuart Orkin, MD, and David Ginsburg, MD (Ginsburg photo: HHMI)

“There were a lot of interesting aspects of vWF’s biochemistry, and it was obviously important in coagulation and hematology,” explains Orkin, who is the associate chief of hematology/oncology at Boston Children’s Hospital and chair of pediatric oncology at Dana-Farber Cancer Institute. “And it was known that it was associated with factor VIII. But then, factor VIII was even more of a mystery than vWF.”

Fishing expedition

When Ginsburg and Orkin decided to tackle vWF, one of the biggest problems was figuring out where to start. Very little was known about the gene or its protein.

“What made it challenging at the time,” Orkin continues, “was that the vWF protein is enormous. We also had very little information upon which to go in and clone it. We had an antibody against von Willebrand factor and some small peptide sequences from the protein, but that was about all.”

Even using what was cutting-edge technology of the day, cobbling vWF’s sequence together was a painstaking, cumbersome process involving:

  1. taking messenger RNA (mRNA) from endothelial cells (which produce lots of vWF) and translating it into complementary DNA (cDNA; DNA that only has coding sequences)
  2. cutting the cDNA up into separate but slightly overlapping pieces and inserting the pieces into bacteriophage viruses
  3. infecting E. coli with the cDNA-loaded viruses to create a gene expression library
  4. using a vWF-binding antibody to fish for E. coli cells expressing bits of the vWF protein — which, therefore, must have been infected with bacteriophages containing fragments of the vWF gene
  5. isolating those vWF gene fragments and using them to screen the library for more coli cells holding other vWF gene fragments

and repeating step 5 over and over until they had a full-length copy of the von Willebrand factor gene ready for sequencing (manually, of course) and chromosome mapping.

Both researchers chuckle as they explain how different the process would be if they were to try this again now.

“Today you’d run whole exome or whole genome sequencing on a few patients with von Willebrand disease and go back to a reference genome map,” Orkin explains. “It took us a year to clone and locate vWF in the 1980s. Now, it would take minutes.”

“I tell my students that I started my career cloning a cDNA, and they look at me like, ‘Why would anyone do that? Did people really bother with that?'” laughs Ginsburg, who today holds professorships in human genetics and internal medicine at the University of Michigan. “But at the time it was a really big deal.”

von Willebrand factor Vonvendi
A portion of von Willebrand factor. (Nevit Dilmen/Wikimedia Commons)

First approval

Vonvendi’s approval marks a first for both Orkin and Ginsburg: the first FDA-approved drug to come out of their work. And the long delay in getting the patent issued was an unexpected boon. Had the U.S. Patent and Trademark Office issued it closer to the time that Orkin and Ginsburg filed it, the patent would have long since expired. As it stands, though, the patent will run until the 2030s.

“It’s all very unusual, but I think it’s great,” Orkin says. “There aren’t too many products that get FDA approval out of the hospital, and I’m glad that the work we did had a positive outcome.”

Even without the drug and the patent, though, Orkin and Ginsburg’s efforts have made an impact on von Willebrand disease.

“There are all these different mutations that relate to different forms of the disease, which all need to be treated a little bit differently, and which all taught us about how vWF works,” Ginsburg says. “This work was a great example of how much you can learn about a protein, how it functions, and how to decipher what you see in patients. But the first step for all that was having the cDNA sequence.”