During the recent BIO International Convention, Caribou Biosciences (CRBU) CEO Rachel Haurwitz, PhD, shared with GEN Edge her journey from graduate student in the lab of Jennifer Doudna, PhD, to co-founder, president, and CEO of a biotech startup—as well as Caribou’s pivot from platform company for biopharma partners applying genome editing in research or product development, to a developer of genome-edited therapies its own next-generation CRISPR technology, which uses hybrid RNA-DNA guides or “chardonnays” (chRDNAs) that direct precise genome editing.
Caribou’s pivot paid off for the company this week in two ways. First, no less of a biopharma than Pfizer gave Caribou a financial vote of confidence by taking a $25 million equity stake in Caribou. Pfizer (PFE) purchased 4,690,431 common shares of Caribou under a Securities Purchase Agreement that closed June 30.
The second payoff from Pfizer’s capital infusion came on Thursday after the company announced the Pfizer equity investment, as Caribou shares rocketed 66% from $4.08 to $6.77 in early trading as of 10:12 a.m. before settling for a 46% gain, closing at $5.94. That surge made a bargain out of the $5.33 share price that Pfizer paid for its Caribou stock on June 29. But it was no bargain at the time, since Pfizer paid 32% above the $4.04 closing price of Caribou shares that day.
Pfizer shares slid 2% on Thursday, from $36.46 to $35.64.
In connection with the equity investment Sriram Krishnaswami, PhD, Pfizer vice president and development head, multiple myeloma and a 19-year veteran of the company, has joined Caribou’s scientific advisory board.
“We are encouraged by Caribou’s chRDNA genome-editing technology and the potential of allogeneic cell therapies as a promising off-the-shelf approach to cancer treatment,” Krishnaswami said in a statement. “Pfizer has a long history of supporting early, innovative science in the biotech ecosystem.
Krishnaswami said Pfizer looked forward to supporting Caribou as it continued advancing two candidates through Phase I clinical trials, with dose escalation data for both to be released by year’s end.
Pfizer’s investment sparked some investor speculation that it was positioning itself to someday acquire Caribou, since the pharma giant acquired $350 million worth of shares in Biohaven Pharmaceuticals as part of an initial $500 million upfront investment in the migraine drug developer—part of an up-to-$1.24 billion agreement signed in November 2021 to commercialize outside the U.S. two migraine drugs, Rimegepant (now marketed as Nurtec® ODT) and zavegepant, which won FDA approval in March and is now sold as Zavzpret. Last year, Pfizer agreed to acquire Biohaven for $11.6 billion cash, in a deal completed last October.
In its press release announcing the Pfizer investment, Caribou said it will use proceeds from the Pfizer investment to advance one clinical candidate, CB-011, an allogeneic anti-BCMA CAR-T cell therapy that is under study in the CaMMouflage trial (NCT05722418) in patients with relapsed or refractory multiple myeloma. But its regulatory filing disclosing the deal included a potential additional use of proceeds: “any other single-targeted anti-BCMA CAR-T cell therapy using an anti-BCMA scFv [single-chain variable fragment] owned or controlled by the Company, during the 36-month period beginning on the date of the Securities Purchase Agreement.”
Right of first negotiation
The regulatory filing also revealed that Caribou has granted Pfizer a 30-calendar day right of first negotiation should Caribou and a third party engage about potentially granting rights to develop and/or commercialize one of its BCMA product candidates—a stipulation that applies to any talks over a license agreement, a co-promotion/co-commercialization agreement, a profit share agreement, joint venture agreement, or asset sale agreement. If the 30-day period ends with no program rights agreed upon with Pfizer, then Caribou can pursue talks with any other company.
CB-011 applies Cas12a chRDNA genome editing by knocking out the TRAC gene to remove the T cell receptor; site-specifically inserting a humanized anti-BCMA CAR into the TRAC gene; and site-specifically inserting a gene encoding a B2M–HLA-E-peptide fusion into the B2M gene, which knocks out the endogenous B2M gene. That approach, Caribou reasons, will eliminate endogenous HLA class I presentation on the surface of the CAR-T cells and expresses HLA-E, a minor HLA class I antigen, to blunt both T and NK cell-mediated rejection of the CAR-T cell therapy by the patient’s immune system.
Caribou’s other clinical candidate is CB-010, a first-line, CD19-targeting off-the-shelf cancer immunotherapy designed to treat non-Hodgkin lymphoma by deleting the PD-1 checkpoint through CRISPR genome editing. CB-010 is now under study in the ANTLER trial (NCT04637763) in patients with relapsed or refractory B cell non-Hodgkin lymphoma (B-NHL).
Also by year’s end, Caribou expects to submit an IND application for CB-012, an allogeneic anti-CLL-1 CAR-T cell therapy being developed to treat relapsed or refractory acute myeloid leukemia (r/r AML), now in IND-enabling studies. CB-012 uses Cas12a chRDNA to make five edits that entail: Knocking out the TRAC gene to remove the T cell receptor; site-specifically inserting a human anti-CLL-1 CAR into the TRAC gene; knocking out PD-1; and site-specifically inserting a gene encoding a B2M–HLA-E-peptide fusion into the B2M gene, which knocks out the endogenous B2M gene.
In April at the American Association for Cancer Research (AACR) Annual Meeting, Caribou presented preclinical data showing cells treated with CB-012 showed antigen-dependent cytotoxicity, cytokine secretion, and proliferation in vitro, protection from NK cell-mediated cytotoxicity in vitro, and enhanced survival in AML xenograft models.
“While this update is too early to drive changes to our model, these data highlight construct rationale ahead of expected IND submission in 2H23 and subsequent clinical data,” Mani Foroohar, MD, senior managing director, genetic medicines and a senior research analyst with Leerink Partners (formerly SVB Securities), wrote in a research note.
Stated Haurwitz: “We believe Pfizer’s investment in Caribou highlights the potential of our clinical programs and we are excited to establish this partnership with one of the world’s premier biopharmaceutical companies.”
“We are actively advancing our allogeneic CAR-T cell therapy pipeline and look forward to providing updates from all of our programs over the next six months,” Haurwitz added.
In addition to Haurwitz and Doudna, a co-winner of the 2020 Nobel Prize in Chemistry, co-founders of Caribou include Martin Jínek, PhD, a former postdoctoral fellow in Doudna’s lab, now at the University of Zurich, who led the seminal 2012 study leading to the Nobel Prize; and James Berger, PhD, Director, Institute for Basic Biomedical Sciences, and a professor in the department of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine.
Caribou went public in July 2021, through an initial public offering that raised $321 million in net proceeds.
Leaders & laggards
- BioXcel Therapeutics (BTAI) shares plunged 64% on June 29, from $17.67 to $6.39, after acknowledging that day in a regulatory filing that the principal investigator of its Phase III TRANQUILITY II trial (NCT05271552) fabricated email correspondence related to the timing of the reporting of a serious adverse event to BioXcel’s pharmacovigilance vendor to make it appear as though this SAE had been reported in a timely manner as required by the study’s protocol. TRANQUILITY II is designed to assess BXCL501, an orally dissolving film formulation of dexmedetomidine as a treatment for the acute treatment of Alzheimer’s disease-related agitation. BioXcel announced positive topline results from the trial showing the 60 mcg dose of BXCL501 met its primary efficacy endpoint, as a statistically significant and clinically meaningful 7.5 point reduction from baseline in Positive and Negative Syndrome Scale-Excitatory Component (PEC) total score was seen at two hours compared with 5.4 hours seen in placebo patients.
- VBI Vaccines (VBIV) shares tumbled 50% on Thursday, from $2.42 to $1.20 as of 3:19 p.m., after the company priced an $18 million underwritten public offering of 10,909,091 common shares and accompanying common warrants to purchase up to 10,909,091 common shares, as well as a $3 million concurrent registered direct offering of 1,818,182 common shares and accompanying common warrants to purchase up to 1,818,182 common shares, at a combined public offering price of $1.65 per share and accompanying common warrant. The offerings are expected to close on or about July 10. VBI’s shares have plummeted 63.5% since June 30 when they closed at $3.29.