Precise repair of genes that cause sickness, starting with Sickle Cell Disease
Graphite Bio is an early-stage company developing gene therapies with a new technology, homology-directed repair (HDR), designed to achieve precise gene insertion, correction, and replacement. Its lead program, coded GPH101, is entering Phase 1 after FDA acceptance of its IND, aimed at directly correcting the ß-globin gene involved in sickle cell disease. Two other programs — GPH201, replacing the IL2RG gene in X-linked severe combined immunodeficiency syndrome (XSCID), and GPH301, a “targeted insertion” of the GBA gene in Gaucher disease types 1 and 3 — are in the “IND-enabling” stage. Other gene-insertion projects with undisclosed targets are still in discovery (validation).
WHAT’S AT STAKE
My primary question for Graphite Bio’s CEO, Josh Lehrer, is about its recent $238M IPO, an achievement all the more impressive for a company at such an early stage. The IPO came a mere nine months after Graphite’s founding in March 2020, which came with a hefty $45M Series A. Why would such a new company need funding at this scale? Lehrer’s answer carries some insight into the ways a gene-therapy company can stand out from the crowd of “conventional” biopharmas.
“The company is early, it’s fast-growing, and relatively unique,” Lehrer says. “We went from founding the company with no full-time employees to becoming a public company so quickly because we started from day one with a clinical- stage gene-editing development program. That means we needed to build a development organization and recruit some people who had experience in conducting clinical trials and others experienced in manufacturing cells to high standards. We also had a platform we wanted to develop in a lot of different areas. That required simultaneously building up a research organization, advancing programs in early-stage research and even new discovery efforts.”
Driving this early buildup was and is Graphite’s singular gene-editing platform, which demands dedicated, proprietary operations not only to discover and develop therapies but also even to produce them. Graphite had to hit the ground running quickly as a multi-integrated organization fully equipped with technology and managed by an expert team normally seen only in much more mature biopharma companies.
The situation reminds me of the early biotechnology built by typical startup companies, where the predominant manufacturing section contained big fermentation vats that gave the whole place a brewery-like smell. Before the CRO sector grew up to replace the in-house production of recombinant DNA proteins, “biotechnology” was chiefly a manufacturing-based industry, and Graphite’s early emphasis on production recalls the spirit of that era.
A word about what makes Graphite’s approach stand out in the gene-therapy space, not just in possible advantages, but in certain challenges: precision. Although CRISPR and other gene-related technologies have captured the public’s imagination with visions of flawless gene editing, their actual potential for genetic manipulation has been limited by their imprecise effects — imprecise, that is, at the infinitesimal scale of chromosomes and genes. Graphite’s roots extend back to many years of research by its founders, starting at Stanford, developing a gene-editing platform that can precisely “find” the mutated DNA in the defective gene and “replace” the new DNA to correct the defect or insert a new gene. “The ultimate goal is to repair and restore genes to normal,” says Lehrer.
If Graphite’s technology is precise, its precision also makes its application potentially broad. From sickle-cell anemia and other hematological conditions, it plans to move into wider areas such as cardiovascular and neurology. “We’re looking for areas where the technology brings something unique, where patients don’t have a lot of good options, and where we can make a big impact,” Lehrer says. Making its own challenges and opportunities, this company may keep to its fast-paced growth.
Employees: 60 Headquarters: South San Francisco, CA
$471.4M Total raised. Including $197.7M prior to going public and $273.7M from IPO in June 2021 (lead investors Versant Ventures, Samsara BioCapital, Fidelity, RA Capital)
Latest Updates June 2021: Exclusively licensed patent rights to high fidelity Cas9, an engineered version of Cas9 with significantly reduced off-target cleavage activity. Second Half 2021: Advanced Phase 1/2 clinical trial evaluating GPH101 for treatment of sickle cell disease towards enrolling the first patient.