There has been limited progress in the approval of novel agents in MDS. It has been a long wait since the last approval of lenalidomide (Revlimid) – only approved for 5–10% (del 5q) MDS patients – was granted 13 years back. Since then, only two other companies, Celgene and Astex Pharma; could succeed in getting approvals for this rare disease. In April 2020, the US FDA approved Reblozyl (luspatercept-aamt; Celgene Corporation) for the treatment of anemia failing an ESA and requiring two or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk Myelodysplastic Syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis. Reblozyl has already clocked considerable sales since its launch, and as per DelveInsight’s analysis, this drug is expected to be a blockbuster therapy at its peak considering the fact that BMS and Acceleron Pharma have also planned to launch the drug in the first-line setting for MDS after a final data readout in 2022/2023.

The second approval followed in July 2020 when the US FDA approved Inqovi (decitabine plus cedazuridine; Astex Pharmaceuticals) to treat adult patients with intermediate- or high-risk MDS chronic myelomonocytic leukemia (CMML). Until the approval of Inqovi, patients were highly dependent on intravenous decitabine, for which they had to visit nearby clinics to get the dose which incurred extra outpatient costs and reduced patient compliance.

DelveInsight highlighted a few of the most potential and late phase data readouts during the first and second day of the conference, including Takeda’s Breakthrough therapy, pevonedistat, Novartis’ sabatolimab, Aprea Therapeutics’ eprenetapopt (APR-246), Astex Pharmaceuticals’ venetoclax in combination with ASTX727, etc. Other displays include luspatercept (BMS), Apto-253 (Aptose Biosciences), evorpacept (ALX Oncology),and eltanexor (Karyopharm Therapeutics). These drugs are in development for different sub-types of Myelodysplastic Syndromes.

Pevonedistat + Azacitidine combination unable to meet primary endpoint in First-line Treatment for Patients with HR-MDS (Phase III Panther Study)

Pevonedistat is a NEDD8-activating enzyme inhibitor carrying the Breakthrough Therapy and Orphan Drug designations by the US FDA. Even though the study did not achieve predefined statistical significance for the primary endpoint of EFS, Takeda anticipated the potential approval of the drug in the US by 2022. At ASH 2021, the company reported that the combination did not appear to improve outcomes compared with azacitidine alone among patients with HR-MDS, CMML, or AML. In the intention-to-treat population, the ORR was 28% in the experimental group versus 32% in the azacitidine-only group. The median EFS with pevonedistat plus azacitidine was 17.7 months compared with 15.7 months in the azacitidine-only group; median OS was 20.3 months versus 16.8 months, respectively.

It is believed that pevonedistat + azacitidine versus azacitidine alone as a 1L treatment for patients with HR-Myelodysplastic Syndromes could have been the first successful Phase III study in this setting to demonstrate superior efficacy with the addition of a novel agent to azacitidine provided the trial had met its endpoints. Nevertheless, the company has hopes with the combination product, and we cannot wait to see the company’s plans in the development process for this combination.

 “While we are disappointed with this outcome, we are continuing to gain a greater understanding of the full data set and hope that findings from this Phase III study will provide information to help guide research and development for potential treatment options for these underserved patient populations.”

  • Head, Oncology Cell Therapy and Therapeutic Area Unit, Takeda (2020)

Initial data from ALX Oncology’s ASPEN-02 Phase I/II study in Previously untreated Relapsed/Refractory Higher-risk MDS

In its updated findings, ALX Oncology, announced that evorpacept in combination with azacitidine was well tolerated with no dose-limiting toxicities, no observed treatment-related serious AEs, and a maximum administered dose of 60 mg/kg Q4W. Industry Experts believe that Evorpacept’s favorable initial tolerability profile in combination with azacitidine suggests it may be safely added without worsening cytopenias, which is particularly notable for this patient population.

 “The initial tolerability and activity of evorpacept seen in ASPEN-02 further support CD47 as a relevant therapeutic target in patients with MDS.”

–Chief Medical Officer, ALX Oncology.

Phase Ib trial final presentation of Novartis’ Sabatolimab in Patients with vHR /HR-MDS and Acute Myeloid Leukemia (AML)

Sabatolimab, the Phase III candidate by Novartis, is a humanized anti-TIM-3 IgG4 antibody for treating MDS, AML, and other malignancies. The drug has received Fast Track and Orphan Drug designations for MDS with an IPSS-R risk category of high or very high risk combined with HMAs.

This year at ASH 2021, the company presented the final analysis from the trial. According to the results, in the 51 patients with vHR/HR-MDS who were considered evaluable for response, the ORR was 56.9%. Additionally, the median DOR in the vHR/HR-MDS group was 16 months, while the median DOR in patients with CR was 21.5 months. The estimated 12-month PFS was 51.9%. Interestingly, nearly 25% of patients with vHR/HR-MDS experienced a degree of improvement that allowed them to undergo hematopoietic cell transplantation.

Based on the datum that efficacy and safety of sabatolimab (MBG453) in combination with HMAs in patients with vHR/HR-MDS who underwent HCT, outcomes were generally favorable following the transplant procedure in patients, and no excess toxicities related to graft-versus-host disease were reported. DelveInsight believes that the drug holds a strong potential for the treatment of patients with this condition

Combined Phase II Results of Eprenetapopt in Patients with TP53 MDS and Oligoblastic AML

Eprenetapopt (APR-246) by Aprea Therapeutics is a small-molecule therapy that reactivates mutant and inactivated p53protein by restoring p53 conformation and function, thereby inducing programmed cell death in cancer cells. The asset has backed itself and has received Breakthrough Therapy, Orphan Drug, and Fast Track designations from the US FDA.

As per the results presented by Aprea Therapeutics at the ASH 2021 conference,eprenetapopt (APR-246) and azacitidine evaluated in HMA-naive TP53-mutant higher-risk MDS, MDS/MPN, and oligoblastic AML, showed an ORR of 69%, and CR/PR of 49% for MDS and 36% for AML. Overall, the combination came out to be well tolerated in mutantTP53 MDS and oligoblastic AML.

What can we further expect in the field of MDS?

Among the upcoming results on Day 3 of ASH 2021, Gilead Sciences is all set to present the updated findings from the trial investigating magrolimab (anti-CD47 Monoclonal Antibody) combined with azacitidine for treatment-naïve HR-Myelodysplastic Syndromes. The therapy has also backed itself with the Breakthrough Therapy Orphan Drug designations by the US FDA.

Results from the Phase Ib study demonstrated impressive outcomes compared to either single-agent azacitidine or decitabine, which have historically shown CR rates of approximately 6–17% and a median OS of only 18 months. Importantly, combination therapy did not result in significant neutropenia or thrombocytopenia, with the majority of patients improving their neutrophil and platelet counts while undergoing therapy. We eagerly await to see what the Phase III study holds for the treatment-naïve HR-MDS.

*overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS), overall survival (OS), Chronic Myelomonocytic Leukemia (CMML), Very high/high-risk myelodysplastic syndrome (vHR/HR-MDS), Acute myeloid leukemia (AML)Hypomethylating agents (HMAs), Immune-mediated adverse event (imAE), Adverse events (AE), Hematopoietic cell transplantation (HCT), Objective response (OR), Complete response (CR), Stable disease (SD), Granulocyte colony-stimulating factor (G-CSF), Event-free survival (EFS)