On the third day of the J.P. Morgan Healthcare Conference, Arbor Biotechnologies and Vertex Pharmaceuticals announced that they would be expanding into reverse transcription-based in vivo genetic medicines. Vertex will now be able to use precision editing technology from Arbor for up to three diseases.
In 2018, the two companies started working together on gene-editing therapies. Vertex gave Arbor over $30 million up front, and Arbor gave Vertex its Cas13d RNA-changing enzyme for CRISPR gene editing to help Vertex’s treatments for cystic fibrosis (CF). The two businesses reunited in 2021 to work on developing new cell therapy methods for diseases like diabetes and hemoglobinopathies among others, at a completely new level—the billion-dollar level. Arbor received an undisclosed upfront cash payment with the potential for milestone payments totaling up to $1.2 billion over as many as seven programs.
“Today we announced an expansion of one of our collaborations with Vertex to expand into precision editing with reverse-transcriptase (RT)-based editing, which is fantastic for us as a company because it shows that over the last four years that we’ve been working with Vertex, they have recognized the hard work we’ve done and the science we’ve been able to generate,” Devyn Smith, CEO at Arbor, told GEN Edge.
“We continue to have a great relationship with them and a great partner. This one is exciting because it’s the first announced partnership in the precision editing space across the industry. It shows that the technology’s beginning to mature.”
Under the terms of the agreement, Arbor is eligible to get payments if certain research, development, regulatory, and commercial milestones are met. Vertex will also pay tiered royalties on the future net sales of any products from this partnership.
Some healthy competition (& controversy)
Arbor isn’t the only iron that Vertex has in the gene therapy fire. Before forming an alliance with Arbor, Vertex collaborated with CRISPR Therapeutics (cofounded by Nobel laureate Emmanuelle Charpentier) in 2015. The collaboration led to the creation of exagamglogene autotemcel (exa-cel), formerly called CTX001—an experimental, autologous, ex vivo CRISPR-Cas9 gene-edited therapy that is showing promising results in patients with sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT). (Vertex made an up-front commitment of $105 million to CRISPR, including $75 million in cash and a $30 million equity investment.)
In April 2021, Vertex increased its investment in CRISPR Therapeutics with an additional $900 million. The revised agreement indicated Vertex’s faith in exa-cel, which was backed by an announcement in September 2022 by Vertex that the FDA had given exa-cel a rolling review for the possible treatment of SCD and TDT. Last week on January 9, CRISPR Therapeutics tweeted that they had completed the regulatory submissions for exa-cel for SCD and TDT with Vertex in the EU and the U.K. in December 2022.
Almost a year before the exa-cel announcement, Vertex signed another CRISPR gene editing pact with Mammoth Biosciences, co-founded by Jennifer Doudna. In October 2021, Vertex announced it will dole out $41 million upfront and up to $650 million to Mammoth. The focus of the collaboration is on the diminutive Mammoth CRISPR systems, which are about one-third the size of the well-known CRISPR Cas9 enzymes.
Arbor has not disclosed much information about its RT editing technology. The best-known application of RT in precision genome editing is that of Prime Medicine, which licenses prime editing technology from David Liu’s lab at the Broad Institute. (Liu is a co-founder of Prime Medicine.) Prime editing boils down to just two components, a Cas9 nickase fused to a modified reverse-transcriptase and a multifunctional prime editing guide RNA (pegRNA), and Prime Medicine owns patents pertaining to both.
While Arbor has recently published papers on their nuclease technologies, notably a research article in Nature Communications (McGaw et al., 2022) describing an engineered Cas12i2 (called ABR-001) as a platform for genome editing, they do not appear to have published data on their precision RT editing technology.
When asked about Arbor’s RT technology, Smith played his cards close to his chest. “The RT editing is based, at least in part, on an Arbor proprietary nuclease fused to a reverse transcriptase and a guide RNA (gRNA) fused to a template sequence encoding a desired genetic modification,” he said. “Initial studies have shown that our proprietary RT editing system can incorporate the desired genetic modification into a genomic site of interest.”
This applies not only to Arbor but also to Tessera Therapeutics, which has also developed an RT editing system called RNA Gene Writing. Tessera’s technology appears to be rooted in a novel mechanism based on retrotransposons that encode RTs—specifically, bacterial group II intron-like RT—to function in host DNA repair. At the J.P. Morgan conference, Tessera reported some advanced data in this area with its RNA Gene Writing platform, notably clinically relevant levels of in vivo rewriting in the genome of liver cells in non-human primates following a single administration. “In genetic medicine, these non-human primate data are extraordinarily de-risking as that makes us very excited to move forward with a platform,” said Michael Severino, Tessera CEO and a CEO-Partner at Flagship Pioneering.
The RNA Gene Writing program also showed clinically relevant levels of in vitro rewriting in the genome of hematopoietic stem cells (HSCs) “We can rewrite to wild type, and when we put those [corrected HSCs] in culture and proliferate, they expand and have a survival advantage,” said Severino, who previously served as vice chairman and president responsible for research and development and the corporate strategy office at AbbVie and senior vice president of Global Development and Chief Medical Officer at Amgen. “We show data that we can have near complete normalization of hemoglobin production, going from a hundred percent sickle and untreated cells from donor patients with sickle cell disease to 98% of the hemoglobin being produced is normal. That’s in culture, but our goal ultimately is in vivo.”
Homegrown therapeutics
Arbor was co-founded by Feng Zhang, David Walt, David Scott, and Winston Yan primarily as a bioinformatics company developing its own therapeutic pipeline. “Our two lead programs are wholly owned by us, and we are planning to file our first IND at the end of this year,” said Smith. “[Our strategy is to] establish leadership and ownership in the liver and central nervous system (CNS) diseases, both of which have very different risk-return profiles and have severe, significant unmet needs in the genetic disease space that editing can help.”
For the liver, Arbor is utilizing lipid nanoparticles (LNPs), having previously announced a partnership with Acuitas to access some of their LNP technology for delivery. For the CNS, Smith said that much of the focus has been on the adeno-associated virus (AAV) space. Smith said that while Arbor builds its initial strategy around certain CNS diseases, they will partner to further expand that delivery capability in the CNS.
Beyond the liver and CNS, there are still many other promising targets for in vivo genetic medicines. Smith said Arbor has been very thoughtful about partnerships because there’s a lot of interest in editing.
“It’s a very exciting area that has a lot of potential, but we’re in the beginnings of the marathon—there is a long road to go here and a lot of new technology to be discovered,” said Smith. “There are no approved products yet. We are in a hurry to execute what we can do, but we’re not in a hurry to make a million partnerships. For us, it’s about being thoughtful and ensuring that the partner brings something that makes what we can do together much better.”
Planting genetic medicine seeds
Sitting at a table in a room at the Handlery Union Square Hotel, Smith grabs a piece of paper to draw out a circle representing the genetic medicine universe.
“With the traditional knockdown approach, you can hit some diseases,” he said while drawing a smaller, concentric circle. “And if you take a base-editing approach, there are some other diseases you can hit. It may be a bigger circle, but it depends on whether you think you need 200 products for cystic fibrosis or not.”
Smith is particularly excited about Arbor’s progress in the remaining areas: reverse transcriptase for precision editing, precise excisions, and large genetic insertions.
“Reverse transcriptase editing allows you to hit a good-sized circle,” said Smith. “And there are a lot of diseases that with [DNA] expansions that we fundamentally have been unable to hit with biologics or small molecules, and those are right for [precise excisions] because you can go in and just cut it. The rest of this circle is large insertions—being able to drop in exons or whole genes into the endogenous locus.”
Of those five segments, Smith said Arbor focuses on all but base editing.
Fruit to bear
According to Smith, researchers are just starting to understand the power of in vivo genetic medicines.
“We will begin to move beyond the Mendelian diseases, which are the low-hanging fruit, into these broader disease states,” said Smith. “Think about infectious disease and even these large diseases like Alzheimer’s, where fundamentally there’s some problem you can fix. [In vivo genetic medicine] is one of those technologies that will change the future of healthcare. I don’t think many of us have even imagined what it will do because you can now fundamentally change the underlying cause of disease rather than the approach we’ve taken of attempting to modulate disease in some way. Now, it’s like, just go fix it!”
