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JP Morgan Healthcare Conference Day 2: Bluebird Bio, Ideaya, Revolution, Relay, and More 

NEW YORK – On the second day of the 42nd annual JP Morgan Healthcare Conference in San Francisco, Bluebird Bio discussed its commercialization strategy for its sickle cell gene therapy Lyfgenia; Ideaya talked about the precision cancer drugs it plans to advance in 2024; and Adaptive Biotechnologies mulled the strategic options for its minimal residual disease and immune medicine businesses. 

Below are brief reports on individual presentations from the conference. A recap of news from the first day is available here

Bluebird Bio 

Bluebird Bio's existing infrastructure that it used to commercialize the company's other gene therapies gives it a competitive advantage in the sickle cell gene therapy space, CEO Andrew Obenshain said at the meeting. 

"We're deploying a validated commercial strategy," he said. 

In December, the US Food and Drug Administration simultaneously approved Bluebird Bio's Lyfgenia (lovotibeglogene autotemcel) and Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) as the first two gene therapies for sickle cell with permission to be marketed in the US. Bluebird Bio has priced Lyfgenia at $3.1 million, while Vertex has priced Casgevy at $2.2 million. 

Bluebird Bio expects to treat the first patient with Lyfgenia in Q1 2024 and follow a commercial strategy informed by its other products, Obenshain said. Lyfgenia is the Somerville, Massachusetts-based gene therapy developer's third approved product, after Zynteglo (betibeglogene autotemcel) for beta thalassemia and Skysona (elivaldogene autotemcel) for cerebral adrenoleukodystrophy. 

Bluebird Bio has already established 48 treatment centers in the US with clinicians trained to administer Zynteglo, which the firm is building on as it launches Lyfgenia. So far, 35 of those treatment centers are also authorized to administer Lyfgenia, and the company plans to have all 48 of the centers equipped to administer the sickle cell treatment by the end of this quarter, with additional sites added throughout the year. 

Lyfgenia genetically modifies patients' own hematopoietic stem and progenitor cells ex vivo with a functional copy of a modified beta-globin gene. That gene is designed to produce a form of anti-sickling hemoglobin that the company says functions similarly to normal adult hemoglobin, which is deficient in patients with sickle cell. 

Bluebird Bio has used outcomes-based contracting for insurers offering Zynteglo — which was approved by the FDA in 2022 — and has said it will do the same for Lyfgenia, with risk-sharing tied to hospitalizations from vaso-occlusive crises. Bluebird Bio has signed two such agreements for Lyfgenia with unnamed payors that it says cumulatively covers 200 million lives. 

"This is what an 18-month commercial head-start looks like," Obenshain said. He added that in the future, Bluebird Bio could provide its manufacturing and commercialization infrastructure as a platform to other cell and gene therapy developers. "Alternatively, you could imagine that a larger player would want this platform," he suggested. 

Obenshain declined to share specifics on how the outcomes-based agreements for Lyfgenia are structured, but said Bluebird Bio is in "advanced discussions" with other commercial payors and more than 15 Medicaid agencies. "We feel that we're leading the way with this type of outcomes-based agreement, and obviously we want to protect the competitive landscape," he said. 

The company is on a "solid path to profitability in the near future," Obenshain said. However, as a "bridge to near-term profitability," the firm is evaluating other non-dilutive funding options, such as debt, royalty, or business development deals. 

Bluebird Bio's cash, cash equivalents, and marketable securities as of the end of 2023 were about $275 million, according to preliminary and unaudited financial results. This, excluding roughly $53 million in restricted cash, is expected to fund its operations into Q1 2025. 

Bluebird Bio had expected to be awarded a rare pediatric disease priority review voucher in conjunction with Lyfgenia's approval — even entering into an advance agreement to sell it for $103 million — but the FDA denied the voucher request, determining that the product didn't qualify since it has an active ingredient in a previously approved product, specifically Zynteglo. 

Bluebird Bio is planning to discuss the decision with the FDA to see if the agency would revisit its decision, "but we have to plan our business as if we're not going to get that," Obenshain said. 

Ideaya Biosciences 

Ideaya Biosciences is expecting to advance several precision oncology treatments in its pipeline this year. 

According to the company, enrollment is proceeding as planned in a Phase II/III trial of its PKC inhibitor darovasertib in first-line metastatic uveal melanoma. In that potentially registrational trial, Ideaya is evaluating darovasertib plus Pfizer's ALK inhibitor Xalkori (crizotinib) in patients with HLA-A*02:01-negative metastatic uveal melanoma. 

Ideaya also plans to work with Amgen on jointly publishing data this year from a Phase I/II study of its MAT2A inhibitor IDE397 and Amgen's PRMT5 inhibitor AMG193 in solid tumors harboring MTAP deletions. 

Then, in mid-2024, Ideaya will begin enrolling patients into another trial of IDE397. This time, Ideaya is working with Gilead Sciences to evaluate the MAT2A inhibitor with Gilead's antibody-drug conjugate Trodelvy (sacituzumab govitecan) in MTAP-null bladder cancer patients. 

Additionally, Ideaya CEO Yujiro Hata said the firm expects to share updates on its PARG inhibitor IDE161. Ideaya is initially focusing on developing this agent in key tumor types such as endometrial cancer, colorectal cancer, prostate cancer, and hormone-receptor positive, HER2-negative breast cancer. The drug is currently under evaluation in a Phase I/II trial in homologous recombination repair-deficient cancers, and Ideaya is aiming to put together a strategy for testing IDE161 in combination with other drugs, too. In the meantime, Hata said the firm has observed encouraging early responses, including in a prostate cancer patient who had a greater than 50 percent prostate-specific antigen reduction. 

Finally, Ideaya and collaborator GlaxoSmithKline will file an investigational new drug application this year for a Werner helicase inhibitor, seeking permission from the US Food and Drug Administration to begin clinical studies in microsatellite instability-high gastrointestinal cancers. If the FDA clears this IND, Ideaya stands to receive a $7 million milestone payment from GSK

"2024, we believe, is set up to be a truly transformational year for Ideaya with four first-in-class programs in the clinic, soon to be five," Hata said, noting that the firm has a cash runway that currently extends into 2028. 

Revolution Medicines 

Revolution Medicines is focused in 2024 on moving its lead candidate, the RAS-multi inhibitor RMC-6236, into pivotal trials in RAS-mutant non-small cell lung cancer and pancreatic cancer. 

Revolution CEO Mark Goldsmith said that the firm expects to begin two pivotal Phase III trials of RMC-6236 in 2024. One study will evaluate the drug against docetaxel in previously treated NSCLC patients harboring a RAS G12, G13, or Q61 mutation. The second Phase III trial will explore RMC-6236 versus physician's choice of chemotherapy in an all-comer population of previously treated pancreatic cancer patients, but investigators will stratify patients based on biomarker testing for RAS G12, G13, and Q61 mutations. Goldsmith noted that Revolution is talking with health authorities about the design of these trials. 

The firm is also looking ahead to data readouts that will inform future late-stage study designs for two other KRAS inhibitors, the G12C inhibitor RMC-6291 and the G12D inhibitor RMC-9805. Both drugs are currently in Phase I studies in solid tumors, and data from these trials will not only inform future development of these assets but also elucidate how their activity differs from RMC-6236, which has activity against both G12C- and G12D-mutant cancers, Goldsmith said. 

For the G12D-targeted drug, RMC-9805, Goldsmith said the research hasn't yet shown how it differs from or is similar to RMC-6236. The latter agent "is pretty compelling, so it does set a pretty high bar for what RMC-9805 has to do to either complement it or to displace it," he said. "Ultimately, we're probably going to combine [the two candidates]. So, as long as there's not overlapping toxicity, we may be able to get away with taking the benefits of both of those." 

Revolution's top priority, according to Goldsmith, is advancing the RAS-multi inhibitor RMC-6326, but the firm will keep exploring the more specific drugs like RMC-9805 and RMC-6291 for different or additive activity. 

Wei Lin, Revolution's chief medical officer, underscored the firm's interest in exploring potential combination opportunities for its pipeline candidates. "We're focused on RAS-addicted cancers and [we've found] that hitting it hard produces efficacy, [and] so, hitting it harder may produce even better efficacy," Lin said. "Having the combination of the RAS-multi [inhibitor] with the mutant selective G12D [inhibitor] allows us, through combination, to hit it harder." 

Relay Therapeutics 

In 2024, Relay Therapeutics will focus on developing its most advanced pipeline candidates while pausing work on earlier-stage programs. 

In breast cancer, the firm will keep advancing its lead PI3Kα inhibitor RLY-2608 but is pausing development of less mature PI3Kα inhibitors, a CDK2 inhibitor, and an estrogen receptorα degrader, Relay CEO Sanjiv Patel said. 

Phase I trial results presented in December showed that RLY-2608 plus fulvestrant was well tolerated and had activity in patients with hormone receptor (HR)-positive, HER2-negative locally advanced or metastatic breast cancer harboring a PIK3CA mutation. He added that RLY-2608 caused no grade 3 hyperglycemia events, which are often associated with PI3Kα inhibitors such as Novartis' Piqray (alpelisib). 

The firm is continuing to explore combination therapies with RLY-2608 in this Phase I trial. In Q4 2023, Relay added an arm, in which patients will receive a triplet combination regimen comprising RLY-2608, fulvestrant, and Novartis' CDK4/6 inhibitor Kisqali (ribociclib), Patel said. 

Relay sees an opportunity in the breast cancer market to improve the efficacy of standard-of-care CDK4/6 inhibitors and chemo combinations with its RLY-2608. "To do this, you need to have two things: First, you need to be able to demonstrate efficacy on top of the standard-of-care [treatments], and second, you have to have a tolerability profile of the third agent that is able to be stacked on the first two," he added. "We believe RLY-2608 has that exact profile." 

Relay will also focus on advancing the FGFR2 inhibitor RLY-4008, or lirafugratinib, in FGFR2-altered metastatic cholangiocarcinoma and other solid tumors. However, the firm is putting a hold on development and commercial activities in cholangiocarcinoma while it waits for data on RLY-4008's activity in the tumor-agnostic setting, which is expected in the second half of 2024. So far, in a Phase I trial, the drug has also shown efficacy in breast, gastric, and lung cancers and in tumors harboring different FGFR2 alterations, including fusions, amplifications, and mutations. 

"Our plan for [RLY-4008] is to enroll the pivotal cholangiocarcinoma cohort, allow the data to mature, and continue to collect data in tumor types outside of cholangiocarcinoma," Patel said. "[We will] look at the totality of the data in the second half of this year and determine a go-forward regulatory pathway." 

Adaptive Biotechnologies 

Adaptive Biotechnologies CEO Chad Robins said the company plans to reach a decision regarding reorganization of its minimal residual disease (MRD) and immune medicine businesses by the end of Q1 2024. 

The company announced in November that it had hired Goldman Sachs to review "strategic alternatives" for the two businesses, which Robins noted are at different stages of maturity and have different natural investor bases. 

He said on Tuesday that a variety of options are on the table, including operating the two business independently. He indicated, however, that the company will almost certainly not maintain the status quo. 

Meanwhile, Robins pointed to a number of priorities for 2024 and beyond as it aims to grow both businesses. Regarding the company's MRD business, he said Adaptive aims to increase the percentage of heme MRD testing done in blood from 39 percent to 50 percent; to expand into new indications, particularly in non-Hodgkin lymphoma; to expand patient use cases, both currently marketed indications and upcoming ones; and to continue to integrate its tests into clinical workflows. With regard to the last priority, Robins said the company is in the middle of an EMR integration with Epic with five installations completed and another 15 to 20 scheduled for 2024. 

Robins said that the company believes that between its efforts to increase MRD test volume and average selling price, while reducing costs, the business will become profitable by the second half of 2025. 

On the immune medicine side, Robins said Adaptive and its collaborator, Roche's Genentech, plan this year to enter the clinic with their T-cell receptor (TCR) based T-cell therapy. He also highlighted the company's work in the autoimmune space noting that it has identified an antigenic target in multiple sclerosis that it believes could be an effective drug target for multiple sclerosis as well as other autoimmune disorders, including type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease. 

"We are doing in vitro and in vivo models to essentially further validate the target," he said. 

Cabaletta Bio 

Cabaletta Bio expects to report initial clinical data on its autologous CAR T-cell therapy CABA-201 in myositis and systemic lupus erythematosus during the first half of 2024 and report initial data from the therapy's use in systemic sclerosis and generalized myasthenia gravis during the second half of the year. 

The firm recently began enrolling patients into its clinical program for the CD19-directed cell therapy, and Cabaletta President, CEO, and Cofounder Steven Nichtberger said that the firm's cash runway extends into the first half of 2026. 

Cabaletta purposefully designed a clinical program that it believes could accelerate the therapy's path to regulatory approval. The Phase I/II trials include multiple independent patient cohorts, each including six patients. "This allows us to enroll patients in parallel in each study, rather than sequentially as is typically the case in the initial CAR-T experience," Nichtberger said, adding that the clinical trial design allows Cabaletta multiple "shots on goal" when it comes to regulatory approval. Any of these simultaneous trial cohorts, he said, could be extended and expanded to fulfill what he believes would be the Phase III requirements for approval. 

The firm also plans to set up the commercial manufacturing process for its cell therapies during 2024 and expand its portfolio of investigational new drug application-cleared indications. On the commercial manufacturing side, Nichtberger said Cabaletta hopes to expand its existing relationships with contract development and manufacturing organizations; move into or assume ownership of its own facility; or strategically partner with other firms where cell therapy manufacturing "could be part of the relationship, either regionally or locally," he said. 

The firm announced this week that CABA-201 has garnered fast-track designation from the US Food and Drug Administration for its development as a treatment for autoimmune diseases with unmet need including dermatomyositis, systemic lupus erythematosus, lupus nephritis, and systemic sclerosis. 

Editas Medicine 

Editas Medicine this year will begin enrolling adolescents into its Phase I/II clinical trial of renizgamglogene autogedtemcel (reni-cel), the investigational gene-editing candidate for severe sickle cell disease and transfusion-dependent beta thalassemia (TDT). 

Reni-cel, previously known as EDIT-301, involves editing the gamma globin genes HBG1 and HBG2 promoters ex vivo in patients' autologous CD34-positive hematopoietic stem and progenitor cells in an effort to increase production of fetal hemoglobin, the adult version of which is lacking in patients with sickle cell disease and TDT. 

Editas is prioritizing filing a biologics license application (BLA) with the US Food and Drug Administration for reni-cel, the company's first clinical-stage investigational therapy, and building up its pipeline of in vivo gene-editing treatments, including demonstrating preclinical proof of concept in an undisclosed indication. 

Reni-cel's safety and efficacy in sickle cell disease and TDT is currently under investigation in two single-arm, open-label Phase I/II trials, dubbed RUBY and EdiTHAL, respectively. In 2024, Editas plans to initiate an adolescent cohort in the RUBY trial, as well as complete adult enrollment in the study, which so far involves 19 treated patients. 

Editas expects to be able to present a "substantiative clinical dataset" on reni-cel in sickle cell disease in mid-2024, based on data from about 20 patients with at least three to five months of follow-up, Editas President and CEO Gilmore O'Neill said. That's the time frame in which the firm has seen "robust fetal hemoglobin expression and correction of anemia," so far. 

He noted that the FDA accepted the BLA for Vertex Pharmaceuticals and CRISPR Therapeutics' gene-editing treatment for sickle cell disease, Casgevy (exagamglogene autotemcel), based on interim clinical trial data on nearly 20 patients. Casgevy edits the BCL11A gene ex vivo with CRISPR-Cas9 to increase production of fetal hemoglobin. 

Investigators in the RUBY trial expect to dose the 20th patient this month, suggesting Editas may be able to file a BLA by late 2025, O'Neill said. 

Editas in 2024 is also looking to monetize its intellectual property, namely its exclusive licenses to certain patents for using CRISPR to make human medicines. That includes a Cas9 patent estate owned and co-owned by Harvard University, the Broad Institute, the Massachusetts Institute of Technology, and the Rockefeller University. 

In December, Editas announced a deal giving Vertex a nonexclusive license to use Editas' Cas9 gene-editing technology for Casgevy, which recently garnered approval from the FDA for use in sickle cell. 

That means that while Editas and Vertex could be competitors in the gene-editing treatment space, they're also partners. 

"There are a lot of companies that are engaged in Cas9 [and] Cas12 programs," said Erick Lucera, Editas executive VP and CFO. "We want to be an enabler of this, we want to be collaborative and work with these companies, but we also want to make sure that we can strike a deal to get the value of the patents that we have. … We believe everyone that's working in this area is going to have to have a conversation with us." 


CEO Steve Chapman expanded on Natera's preliminary Q4 and FY 2023 financial results, released Tuesday morning, noting that revenue growth was driven largely by the Signatera minimal residual disease test, which has reached "near-peak levels" of growth, as well as significant momentum in the average selling price (ASP) of its tests. 

The firm is also on track to hit cash flow breakeven in 2024, he noted, and it reduced its annual cash burn by about $200 million in 2023. 

Improving reimbursement has been a key focus for Natera, and the company has taken strides to boost test payments. It has improved its billing operations to further raise its ASP, Chapman said. "Just in the core business, without new guidelines coming in, without new Medicare coverage, without going and getting new commercial coverage, we're getting paid a higher percent of the time because we're operating better." 

The firm has also made multiple submissions to Medicare's MolDx program to expand Signatera into further cancer indications that will hopefully boost reimbursement, said Solomon Moshkevich, the firm's president of clinical diagnostics. "These are areas where we're already doing a decent amount of testing commercially and just not collecting as much as we will after getting the approval," he said. 

Chapman also discussed upcoming clinical trial results in 2024, noting that its randomized trial ALTAIR — the circulating tumor DNA-guided treatment escalation arm of the CIRCULATE-Japan trial evaluating Signatera's utility in colorectal cancer patients — is expected to read out in the first half of the year and will potentially be a catalyst for growth. If the readout is positive, it may also positively impact reimbursement, Moshkevich added. 

State biomarker laws will also likely have an effect on payments and reimbursement. Multiple states have enacted mandates for commercial payors to cover biomarker testing if it is covered by Medicare. About 60 percent of Signatera's volume is provided to beneficiaries covered by commercial payors, but much of that testing is not getting reimbursed, which would change under the biomarker laws. Those changes could lead to Signatera's ASP doubling, although Natera's model is conservative because "we haven't seen this play out before," Chapman said. 

Other potential catalysts include commercial payor coverage for the Prospera test for kidney transplant assessment; guideline inclusion of its women's health tests, possibly for 22q11.2 deletion or carrier screening; and product launches across its core business and new areas. 

Chapman emphasized the innovation of its noninvasive prenatal test (NIPT) Panorama to screen for 22q11.2 deletion syndrome, which is an area of focus for the company. Panorama uses SNP-based technology to target a very small region of the genome in cell-free DNA, which Chapman said makes it able to get more than 25 times the read count at the particular region of interest than tests that use massively paralleled sequencing. 

In the firm's Microdeletion and Aneuploidy Registry (SMART) trial, Panorama NIPT was performed on more than 20,000 patients, 12 of whom had a fetus with confirmed 22q11.2 deletion syndrome, and Panorama detected 10 of these cases (83.3 percent sensitivity) with a positive predictive value of nearly 53 percent. Results were published in the American Journal of Obstetrics and Gynecology in 2022, and at the end of 2022, the American College of Medical Genetics and Genomics conditionally recommended that noninvasive prenatal screening for 22q11.2 deletions be offered to all patients. 

The company is also expecting the initial readout of performance data for its early cancer detection test in 2024 and, depending on the results, it will consider starting a clinical trial in 2025 or 2026 to support a US Food and Drug Administration submission, Chapman said. 

Chapman also briefly addressed Natera's patent infringement victories in 2023, including a permanent injunction against Invitae and ArcherDx and a preliminary injunction against NeoGenomics. Chapman said that it is challenging to get injunctions and that they speak to the strength of Natera's intellectual property. 

Olema Oncology 

Olema Oncology is looking ahead to starting a pivotal clinical trial near the end of 2024 of its selective estrogen receptor degrader (SERD) palazestrant, also known as OP-1250, in combination with Novartis' CDK4/6 inhibitor Kisqali (ribociclib) as a first-line therapy for advanced estrogen receptor-positive, HER2-negative breast cancer. 

Olema CEO Sean Bohen said the company's goal is to replace treatment with an aromatase inhibitor or fulvestrant and a CDK4/6 inhibitor with a combination of palazestrant and Kisqali in the first-line setting. 

"This is where we can really prolong disease-free survival and potentially overall survival," Bohen said. "The challenge has been that agents in this class have a lot of trouble combining with CDK4/6 inhibitors." 

In addition to being a SERD, palazestrant is also an estrogen receptor antagonist. Olema believes that these combined mechanisms may allow the drug to overcome resistance caused by mutations in ESR1. 

In results presented at the San Antonio Breast Cancer Symposium in December, treatment with combinations of palazestrant with Kisqali and Pfizer's CDK4/6 inhibitor Ibrance (palbociclib) in patients with advanced or metastatic ER-positive, HER2-negative breast cancer were well tolerated. In a Phase Ib/II study of palazestrant with Kisqali, investigators found that palazestrant did not affect ribociclib exposure in patients and vice versa, and there were no dose-limiting toxicities. In another Phase Ib/II study of palazestrant with Ibrance in the same setting, there were no observed drug-drug interactions and no induced metabolism of either drug or increased exposure. Treatment-related adverse events were mostly grade 1 or 2, and the incidence of neutropenia was similar to that observed in previous studies. Seven patients out of 46 had partial responses, and the clinical benefit rate was 46 percent in all patients and 60 percent in patients with an ESR1 mutation at baseline. Patients who were naïve to prior CDK4/6 inhibition had a clinical benefit rate of 71 percent. 

Bohen said the ability to combine palazestrant with the two CDK4/6 inhibitors is "unique in this field and really opens up that opportunity toward the end of the year to initiate a first-line pivotal trial." That trial will be an expansion of the ongoing combination trial with Kisqali that Olema is carrying out with Novartis. Bohen said Olema expects to update clinical results from the Phase I/II portion of the trial in the second quarter of 2024. 

Olema is also conducting a Phase III trial, dubbed OPERA-01, of palazestrant as a monotherapy compared to standard of care treatment in second- and third-line advanced or metastatic ER-positive, HER2-negative breast cancer.