In less than a year, Graphite Bio has sped from series A to Wall Street welcome as it rustles up capital to fund gene-editing treatments for sickle cell disease, an immune system disorder and Gaucher disease.
In a move that’s starting to look like a formality in biotech, Graphite filed to raise up to $100 million in its Nasdaq debut in early June. On Monday, that goal was amended to as much as $213 million, according to an SEC filing, eventually snagging $238 million by offering 12% more shares than originally planned.
And, like its biotech brethren, Graphite is a preclinical-stage company going public without any human data—a choice once unheard of that has become commonplace in a sector buoyed by optimism and its role in fighting the COVID-19 pandemic.
Graphite’s gene-editing treatments are based on technology developed at Stanford University by Matt Proteus, M.D., the academic founder of CRISPR Therapeutics, and Maria Grazia Roncarolo, M.D. The technology is designed to repair a genetic defect or completely replace a malfunctioning gene with a normal one. It could also be used to treat non-genetic diseases such as cancer, neurodegenerative diseases and diseases that cause enzyme and metabolic deficiencies, by inserting a genetic sequence that directs cells to permanently produce certain enzymes or proteins.
This approach is different from first-generation CRISPR, which targets and cuts genes, then relies on the cell to repair that break—a process that can lead to errors. Graphite’s technology cuts genes in targeted spots and then “drives cells to use their own DNA repair mechanism very efficiently to take a template of DNA and copy it into the target gene after it’s been cut,” said Graphite CEO Josh Lehrer, M.D.
Put simply, if CRISPR is the “cut” function on a word processor, Graphite’s technology is “cut and paste,” Lehrer said.
This is particularly useful when it comes to sickle cell disease, which is caused by a single mutation in the gene that codes for beta-globin, a component of red blood cells. Graphite’s lead asset, GPH101, is designed to correct this mutation and restore normal hemoglobin.
“This approach actually lets you correct the point mutation and convert mutant sickle hemoglobin into wild-type normal hemoglobin and offer a definitive cure,” Lehrer said, referring to mutations where a single nucleotide base, or letter, is changed, inserted or deleted.
The company tagged about $90 million to bankroll the phase 1/2 study of GPH101, and about $40 million to get two more programs at least through IND-enabling studies, according to a securities filing. Another $80 million will go toward Graphite’s discovery programs targeting CCR5 and alpha globin.
Graphite will start the phase 1/2 study of GPH101 later this year, with hopes of proof-of-concept data by the end of 2022, Lehrer said. It plans to file INDs for its second and third programs by mid-2023, the filing said.
Following behind is GPH201, a treatment for X-linked severe combined immunodeficiency (XSCID), a rare, inherited disorder that leaves babies with little to no immune response. GPH201 works by replacing the entire defective gene behind XSCID, leading to the production of functional adaptive immune cells. Replacement is key, rather than correcting the genetic defect, because there isn’t just one, but hundreds of different mutations in the gene that can lead to XSCID.
Graphite’s third program is GPH301, a gene insertion treatment for Gaucher disease, which is caused by a genetic disorder that causes a deficiency in the glucocerebrosidase (GCase) enzyme and results in the harmful buildup of certain fats. People with Gaucher and similar diseases typically take lifelong infusions of the enzyme they are missing. The goal with GPH301 is to restore the production of the enzyme in a potentially one-and-done treatment.
All three of Graphite’s treatments are based on hematopoietic, or blood-forming, stem cells, which are edited outside the body. As these programs are advanced into and through the clinic, Graphite will keep building out its platform to eventually go into other cell types and maybe even gene-editing treatments that work inside the body, Lehrer said.