Novartis’ Jeff Legos Discusses Progress and Potential in Oncology

Novartis EVP and Global Head of Oncology & Hematology Development Jeff Legos/Courtesy of Novartis

Novartis has more than 30 new molecular entities in clinical development across more than 80 programs, and the American-Swiss multinational presented new data on many of them at the American Society of Hematology (ASH) annual meeting, held December 11-14.

The company’s oncology pipeline is made up of four key therapeutic focus areas: targeted therapy, immunotherapy, radioligand therapy and cell and gene therapy. One hundred abstracts this past weekend touched on three of these and included programs such as the recently FDA-approved Scemblix, sabatolimab, a potentially first-in-class immuno-myeloid therapy and first-in-human data from its next-generation T-Charge CAR-T platform. To learn more, BioSpace sat down with Novartis EVP and Global Head of Oncology & Hematology Development Jeff Legos. 

Novartis presented 48-week data from the Phase III ASCEMBL trial of Scemblix (asciminib), a first-in-class STAMP Inhibitor that was approved by the U.S. Food and Drug Administration (FDA) in November for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML). Scemblix, the first FDA-approved CML treatment that works by binding to the ABL myristoyl pocket, demonstrated a 29.3% major molecular response rate compared to 13.2% for patients in the comparator Bosulif arm.

On the immunotherapy front, Legos highlighted sabatolimab, which is being studied across a range of hematologic malignancies, including myelodysplastic syndrome and acute lymphoblastic leukemia (AML). Novartis presented final data from a Phase Ib study of sabatolimab in combination with HMAs in patients with very high/high-risk MDS and AML. The data confirmed earlier Phase I findings, showing strong durability with a median duration of 16.1 months and an overall response rate (ORR) of 56.9%.

“This data is quite important because there's really been no material innovation over the last 15 years or so in this patient population, and unfortunately, because there have been no significant treatment advances, these patients are often dying anywhere from 12 to 15 months after their disease has progressed,” Legos said.

Making its ASH debut this year was Novartis’ T-Charge CAR-T platform. Novartis presented early data from two first-in-human dose-escalation trials: YTB323 and PHE885. In the first study, in diffuse large B-cell lymphoma (DLBCL), T-Charge demonstrated a 73% complete response (CR) rate at month three with dose level two. In the second study, where the platform is being studied in multiple myeloma, a 100% best overall response was achieved.

From a safety standpoint, Legos said Novartis “did not observe any significant or concerning acute cytokine release syndrome,” and that when it did occur, it was delayed and more modest compared to the first-generation CAR-T programs.

“We believe a lot of these product attributes are likely due to a much simpler, more robust, more reliable manufacturing process that not only allows for in vivo expansion instead of ex vivo expansion but also provides differentiated T cells for patients,” Legos shared. “We believe the T cells are healthier, more robust and maintain their stemness, meaning their ability to self-renew and proliferate.”

The overall manufacturing time for T-Charge is less than two days, and the “vein to door” time is about half the time of traditional CAR T therapies. The reason why this is so important, Legos said, is because “for most of the patients who ultimately will become candidates for CAR-T based therapy, their disease is often progressing rapidly. They may or may not have relapsed or been refractory to frontline chemoimmunotherapy, so time is of the essence to all patients.” Novartis’ goal, he added, is to make T-Charge a robust platform on which to base other CAR T therapies.

One area where Legos sees CAR-T making a big difference is in pediatric (ALL).

“I am incredibly proud of Novartis’ commitment to evaluate our medicines in the youngest possible patient population where the disease has clinical relevance,” Legos said.  He added that CAR-T therapies are a great example of this commitment, “especially in pediatric ALL where you can really provide a one-time infusion and provide that definitive therapy to really change outcomes for the pediatric patient community.”

Overall, Legos said of the platform, “I think this is truly the next generation of CAR-T therapy and believe it has the opportunity to revolutionize treatments for patients with heme-malignancies and really capitalize on the benefits of autologous cell therapies to provide deeper and more meaningful long-term clinical outcomes for patients.”

 In the non-malignant hematology space, Novartis highlighted 12-month data from the Phase II study of iptacopan, a first-in-class oral complement factor B inhibitor intended for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). Novartis shared data earlier this year at the European Hematologic Association (EHA) 2021 meeting showing iptacopan’s efficacy in patients who had previously received anti-C5 based therapies or were treatment-naive to these therapies. Data presented at ASH on Sunday reaffirmed these results, Legos said, in what Novartis believes is an important milestone for patients.

Legos also highlighted Novartis’ radioligand therapy that targets PSMA (Prostate-specific membrane antigen), which is expressed in more than 80% of prostate cancers. In June, Novartis presented the results of its Phase III VISION study where the treatment significantly reduced risk of death by 38% and risk of radiographic disease progression or death by 60%.

“What is really cool about the platform is that we can actually deliver high-dose radioactive beta-emitting particles precisely to a cancer cell on the basis of what antigen that cancer cell is expressing,” Legos shared. “It's kind of like having a GPS on the radiation that can bring it directly to the cancer. It gets internalized, it causes DNA damage and then ultimately triggers cell death.” He added that because the radiation is very discreet, covering only 1 to 3 millimeters in total direction, it has the ability to spare the surrounding healthy cells. “So, this is a precise and potentially safer way of delivering high-dose radiation to cancer cells.”

Legos said Novartis has 12 additional clinical or near-clinical-stage radioligand assets, as well as another 20 projects in preclinical development (both predominantly in solid tumor cancers).

“It's a platform that I think has a lot of applicability for the field going forward, and we're looking at different radioisotopes in different clinical settings to bring this to patients in the adjuvant and neoadjuvant setting where we're really looking for curative intent or for cures,” he said.

Finally, he touched on one of the most prominent trends in oncology today – combination-based therapies. “How do we leverage the power of combinations across these four platforms to really be able to prevent, delay or intercept resistance before it actually occurs? When you block orthogonal mechanisms of cell proliferation, we believe that's probably the way to lead to the deepest clinical responses, and then ultimately try to push patients more towards a cure.”