Novartis keeps the leukemia innovation coming with FDA approval for Gleevec follow-on Scemblix as Tasigna patent cliff nears

About two decades ago, Novartis transformed leukemia treatment with the introduction of Gleevec. Now, the Swiss pharma has ushered a third-generation therapy targeted against the blood cancer across the regulatory finish line.

The FDA has approved Scemblix, or asciminib, for Philadelphia chromosome-positive chronic myeloid leukemia (CML) patients who’ve tried at least two prior tyrosine kinase inhibitors (TKIs), plus for those with the T315I mutation, Novartis said Friday.

The new go-ahead adds a third targeted therapy to Novartis’ blockbuster CML arsenal, and it comes as the company’s second-generation TKI, Tasigna, could follow Gleevec off the patent cliff in 2023.

Despite treatment with gold-standard Gleevec and Tasigna, about 15% of CML patients could progress to the third-line setting, where 75% patients would fail on existing therapies, according to Novartis. During a conference call last week, Novartis’ oncology chief Susanne Schaffert, Ph.D., said Scemblix has blockbuster potential in the third line alone.

Scemblix comes with a unique mechanism of action that could potentially overcome resistance to treatment, Jeff Legos, Ph.D., Novartis’ global head of oncology and hematology development, explained in an interview ahead of the approval. Unlike earlier-generation TKIs that bind to the ATP pocket of the BCR-ABL protein, Scemblix targets the ABL myristoyl part of the protein, which is associated with the production of leukemic cells.

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Scemblix proved its mettle in a head-to-head trial against Pfizer’s Bosulif. The Novartis drug triggered a major molecular response in 25% of patients at the 24-week mark, nearly twice the 13% seen with Bosulif. Scemblix also appears to be more tolerable; 7% of Scemblix takers stopped treatment because of side effects, while 25% of patients in the Bosulif group experienced that.

Major molecular response (MRR) is a good predictor of long-term clinical benefit such as patient survival, Legos said. The marker evaluates BCR-ABL1 in the blood and is much more sensitive than a bone marrow or a radiographic response as measured by the typical overall response rate endpoint.

“[MRR] would be the earliest point of detection that patients are stopping to receive benefit or starting to see their disease progress,” he said.

The MRR data have earned Scemblix a conditional nod for third-line CML. The drug also boasts a full nod for patients with the treatment-resistant T315I mutation, which, according to Legos, is the most common mutation that develops in patients receiving prior TKIs. The estimated rate of the mutation varies between 10% to 27% in CML cases.

In a small study, Scemblix recorded a response in 42% of 45 patients with CML with the T315I mutation at 24 weeks.

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Novartis is now also testing Scemblix in treatment-naïve patients in the phase 3 ASC4FIRST trial. The study will compare Scemblix with investigator’s choice of TKI. The hope is that Scemblix, with its novel mechanism, can prevent or delay the development of resistance in the front-line setting, Legos said.

Gleevec revolutionized CML treatment with an FDA nod in 2001 and opened the floodgates to targeted therapies for cancer. Before generics rolled out in the U.S. in 2016, Gleevec’s annual sales had been cruising at nearly $4.7 billion. In the first nine months of 2021, the drug brought in $791 million after a 12% decline over the same period last year.

Novartis is also experimenting on combining Gleevec with Scemblix in a phase 2 trial, trying to take advantage of their different mechanisms, Legos noted.

In 2007, Novartis introduced Tasigna for CML. Sales from that second-generation TKI reached $1.55 billion, up 7% year over year. Thanks to a label update in 2017, some leukemia patients may stop treatment with Tasigna after sustained response. The drug’s patent on compound will expire in 2023 in the U.S. and EU.

In addition, Bristol Myers Squibb has Sprycel, which recorded $1.56 billion sales this year by September, down 1%. Takeda’s Iclusig entered CML with an FDA green light for third-line treatment in late 2020.