At Caribou Biosciences’ upcoming 10th birthday party celebration, the chardonnay will be flowing. That’s because the biotech is uncorking first-in-human data for its CAR-T cell therapy that CEO Rachel Haurwitz, Ph.D., believes are better than the three approved lymphoma treatments in the class.
The data set, to be presented next month at the European Hematology Association (EHA), will showcase Caribou’s CRISPR hybrid RNA-DNA guides, or chRDNAs (chardonnays), gene editing technology. Caribou will unveil results from an initial six patients who received CB-010 in a phase 1 trial called ANTLER, which features patients with relapsed or refractory B cell non-Hodgkin lymphoma who have failed on three or more prior treatments.
The five evaluable patients as of the data cutoff date of Feb. 23 showed a 100% overall response rate, while four of the patients experienced a combined 80% complete response rate. One patient had progressive disease as of the cutoff date. Of the patients who had a complete response, that was still the case at three months after treatment with the longest complete response recorded so far as six months.
“This is the first time that we get to share clinical data with the world and … it's a really significant milestone for us,” Haurwitz told Fierce Biotech in an interview.
To put these early—and yes, very limited—results into perspective, Haurwitz says that the approved CAR-Ts that focus on CD19-positive disease have achieved overall response rates of about 50% to 70% and overall response rates of 30% to 50%. These include Gilead’s Yescarta, Bristol Myers Squibb’s Breyanzi and Novartis’ Kymriah.
CB-010 boasts another difference from these meds: The therapy is administered at a much lower dose. This is key, according to Haurwitz, as these treatments are associated with neurologic effects that in some cases can be life-threatening.
Caribou’s med did cause some serious adverse events in half of the patients, even though Haurwitz characterized CB-010 as “generally well tolerated.” She said there were no cases of graft-versus-host disease reported, which is a known occurrence after allogenic CAR-T treatment. Caribou hopes its therapy will circumvent common limitations of CAR-T therapy with gene editing.
Most of the adverse events observed were grades 1 or 2, the CEO said. Grade 3 and 4 events, which are more severe, were observed in three of the six patients within the first 28 days of treatment. The company said the most common effects observed were related to low blood counts, including neutropenia, which means low white blood cell counts, and thrombocytopenia, which is low blood platelet count. The patient who experienced the grade 3 event received treatment and recovered within 39 hours, Caribou said.
Haurwitz said those events were in line with what is expected for allogeneic CAR-T therapies. To mitigate adverse events, Caribou is working with clinical sites with experience working of cell therapies to ensure staff can handle anything that might arise in the course of treatment.
With the initial data in hand, Caribou now intends to move into dose escalation, infusing 80 million cells instead of 40 million in the next cohort.
But Caribou has something else on the agenda: celebrating its 10th birthday, which will be in August. Haurwitz is pleased to have these first-in-human, proof-of-concept results in hand to toast to.
“As I look back over the past decade, it's really remarkable to have seen our team go from blank whiteboard to inventing the chRDNA technology to articulating and advancing a wholly owned pipeline of off-the-shelf CAR-Ts,” she said.
Good timing
At EHA, Caribou will have some new longer duration data to present in addition to the abstract being revealed today. More data from ANTLER are also expected by the end of the year, and the company is continuing enrollment for the second dose level. While these initial data are from patients with non-Hodgkin lymphoma, the trial is open to those with several different kinds of aggressive lymphoma.
Other priorities for the company include two off-the-shelf CAR-Ts for hematologic malignancies. A request for human testing is expected to be submitted for CB-011 in multiple myeloma in the second half of the year and for CB-012 in acute myeloid leukemia next year. At the same time, Caribou is in the discovery phase for a solid tumor natural killer cell therapy. A candidate for that program should be announced in the fourth quarter.
Meanwhile, Caribou is going full-steam ahead with AbbVie under a collaboration signed last year that brought $40 million upfront for the small CRISPR biotech plus $300 million in biobucks later on. Caribou is helping the Big Pharma develop two new CAR-Ts as well as some targets AbbVie brought into the fold.
“To the best of my knowledge, they were not in the off-the-shelf cell therapy setting prior to this collaboration, so I certainly see their selection of Caribou as a partner as an important external recognition of our technologies and capabilities,” Haurwitz said of the AbbVie partnership.
Caribou also has its antlers pointed at even more Big Pharma partnerships in the future. Haurwitz flags the hiring of Ruhi Khan as chief business officer at the end of 2021 as a sign that the biotech wants to make more deals.
“We certainly see partnerships as an important component of the company's future, whether that's partnering with larger companies in order to tap into areas we're not working on today or partnering with other smaller innovative companies in order to access technologies to unlock new therapeutic areas,” Haurwitz said.
This is all happening within a year of Caribou conducting a massive IPO and fundraising blitz in 2021. The company raised more than $500 million last year, between the $349.6 million IPO, $40 million in upfront cash and equity from AbbVie and a $115 million crossover round.
“That means that we have a pretty strong balance sheet,” Haurwitz said, noting $391 million in cash on hand. “And certainly, given the market conditions, I'm really pleased that we're as well capitalized as we are, because it gives us the ability to continue investing in our technologies and our pipeline programs.”
The conditions she speaks of are of course the brutal market correction that has sent biotech stocks tumbling. Haurwitz acknowledges that trying to pull off the funding Caribou managed in 2021 might not have been possible this year. That’s not to say that the biotech hasn’t been caught up in the mess: The company’s shares debuted at $16.32 in July 2021 and now sit at $6.63 as of close of markets Wednesday.
With the release of the EHA abstract, investors herded Caribou's shares up almost 20% to $7.93 apiece as the markets opened Thursday.
One thing that Caribou is not, however, tied up in, is an ongoing CRISPR patent dispute that some experts have said might impact the company's gene editing intellectual property. At issue are certain patents for CRISPR gene editing that could have wide implications for companies working on therapeutics using Cas9.
But Haurwitz said CB-010 is the only therapy Caribou has that uses CRISPR/Cas9 editing technology, and even that was developed in combination with the chRDNA platform. Further therapies developed by Caribou have used Cas12a with chRDNA guides.
“We have found that Cas12a yields a far better gene insertion efficiency, which is really important for these sophisticated armoring strategies that we're deploying across our cell therapy pipeline,” she said.