Navitoclax, being developed by AbbVie, is a BCL-XL/BCL-2 inhibitor being investigated to treat myelofibrosis, for both first and second-line treatment. Combination therapies are being explored to improve outcomes in myelofibrosis patients. TRANSFORM-1 Phase III trials showed adding navitoclax, a BCL2 inhibitor, to ruxolitinib significantly increased spleen volume reduction compared to ruxolitinib alone, leading to a doubling in patients achieving ≥35% spleen volume reduction at 24 weeks.

Previously, in July 2023, AbbVie announced top-line results from the Phase III TRANSFORM-1 clinical trial evaluating the safety and efficacy of navitoclax in combination with ruxolitinib in adult patients with primary or secondary myelofibrosis. The combination of navitoclax and ruxolitinib met the study’s primary endpoint; however, the study did not meet the first-ranked secondary endpoint of improvement in patients’ Total Symptom Score from baseline to Week 24. Thereafter, the company planned to engage with regulatory agencies regarding potential next steps.

At the EHA 2024 Congress, the updated findings from the Phase III TRANSFORM-1 were presented. A total 252 patients were enrolled, with a median follow-up of 20.3 months. Patients were randomized 1:1 to receive navitoclax + ruxolitinib (n = 125) or placebo + ruxolitinib (n = 127).

Get more insights of the report @ Myelofibrosis Market

The key outcomes reported were:

• Patients treated with navitoclax + ruxolitinib had a higher proportion achieving 35% or greater reduction in spleen volume (SVR35) compared to those receiving placebo + ruxolitinib. 

• Among patients with no Grade 1-related adverse effect (AEs), greater reductions in total symptom score (TSS) at Week 24 were observed with navitoclax + ruxolitinib compared to those experiencing Grade ≥1 Gastrointestinal (GI)-related AEs. A similar trend was observed across subgroups when looking at patients who achieved SVR35 at any time during study. 

• SVR35 was achieved at any time by 76.8% with navitoclax + ruxolitinib vs 43.4% with placebo + ruxolitinib.  

• Median duration of SVR35 was similar between navitoclax + ruxolitinib and placebo + ruxolitinib.  The median progression-free survival (PFS) was 25.2 months in patients who received navitoclax + ruxolitinib and 22.9 months in patients who received placebo + ruxolitinib. 

• 70% of patients in the navitoclax + ruxolitinib arm, and 63% of patients in the placebo + ruxolitinib arm had ≥50% variant allele frequency (VAF) at baseline. 

• Patients achieving ≥20% reduction in VAF, regardless of treatment, showed longer PFS. OS did not differ between treatment arms.  

• Common AEs included thrombocytopenia, anemia, diarrhea, and neutropenia, with serious AEs reported in 28% of navitoclax + ruxolitinib treated pool.

KOL insights

“This study marks a notable achievement in the field of myelofibrosis, as one of the first reported global phase III frontline randomized combination clinical trials in our field. This data set now opens the door for additional research and investigation into combination therapies to treat myelofibrosis and, importantly, highlights a potential new era of investigating disease modification for patients.” MD, United States.

Also, Read @ The Dynamic Landscape of Myelofibrosis Treatment: A 2024 Perspective

Conclusion 

Apart from the approved products, a few promising agents include those targeting BET proteins (pelabresib), BCL-XL/BCL-2 (navitoclax), and MDM2 (navtemadlin). The findings from the Phase III TRANSFORM-1 study showed that Navitoclax in combination with ruxolitinib in JAKi-naïve MF patients improved SVR35 at week 24 by 2-fold despite poor prognostic factors. Patients with HMR mutations showed longer PFS and DOR. Long-term safety revealed no new concerns, with fewer serious adverse events seen in this combination treated pool. 

As per AbbVie’s last pipeline update (February 2023), the company anticipated the regulatory approval of navitoclax in 2024 as first-line therapy for myelofibrosis. The company is also evaluating this combination for relapsed/refractory myelofibrosis in another Phase III TRANSFORM-2 trial, for which the company is expecting Phase III data readout in 2024.

Other Companies such as MorphoSys, Geron, Kartos Therapeutics, Karyopharm Therapeutics, Actuate Therapeutics, Telios Pharma, Bristol Myers Squibb, Incyte and others are also evaluating their assets in combination with JAKAFI for treating myelofibrosis. JAKAFI demand remains strong, and we expect continued future growth driven by maintaining its leadership as the standard of care in myelofibrosis. As per the Incyte, myelofibrosis will continue to be the largest portion of JAKAFI’s patient share until polycythemia vera patients ultimately take over. 

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