Ygalo Continues to Show Positive Results in RRMM Patients, Oncopeptides Announces

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Combination treatment with Ygalo (melflufen) continues to be safe and effective in difficult-to-treat patients with relapsed or refractory multiple myeloma (RRMM), according to the latest results from clinical trials.

Data from the clinical program of Ygalo and multiple myeloma’s impact on quality of life will be presented at the American Society of Hematology (ASH) 2019 Annual Meeting, being held Dec. 7–10 in Orlando, Florida.

Oncopeptides‘ Ygalo is an investigational lipophilic peptide-conjugated alkylator that belongs to a new class of compounds known as peptidase enhanced cytotoxics (PEnC). It works by rapidly delivering a cancer-killing agent (an alkylating peptide) to malignant cancer cells.

The medication is intended for people with triple refractory multiple myeloma — those who received and failed to respond to treatment with at least one immunomodulatory drug (IMiD), one proteasome inhibitor, and one anti-CD38 monoclonal antibody.

Two of the posters will address Ygalo’s long-term efficacy and safety in people with RRMM, evaluated in the company’s ongoing Phase 2 HORIZON trial (NCT02963493). This study is still recruiting participants at several sites across the U.S. and Europe for a total of up to 150 patients.

Oncopeptides is planning to use data from HORIZON to support the submission of a new drug application to the U.S. Food and Drug Administration requesting accelerated approval of Ygalo for the treatment of triple refractory myeloma patients. The company expects to file the application in the first quarter of 2020.

In HORIZON, Ygalo is being tested in combination with dexamethasone in patients who had received at least two prior therapies, including one IMiD and one proteasome inhibitor, and failed to respond to treatment with Janssen‘s Darzalex (daratumumab) and/or Celgene‘s Pomalyst (pomalidomide).

All participants will receive Ygalo intravenously (into the vein) at a dose of 40 mg on the first day and 40 mg of dexamethasone on days eight, 15, and 22 in 28-day cycles, until disease progression or unacceptable toxicity.

The trial’s primary goal is to assess overall response rate, which refers to the percentage of patients who responded to treatment. Secondary goals include overall survival, progression-free survival (the period without disease progression), and duration of response.

The study, “Clinical Activity of Melflufen in Patients with Triple-Class Refractory Multiple Myeloma and Poor-Risk Features in an Updated Analysis of HORIZON (OP-106), a Phase 2 Study in Patients with Relapsed/Refractory Multiple Myeloma Refractory to Pomalidomide and/or Daratumumab,” addresses HORIZON’s latest efficacy and safety data from the 121 participants (median age 64 years, median follow-up 10.8 months) treated up to May 6. Almost three-quarters (74%) were refractory to three classes of therapies.

As of this cutoff date, 113 patients had treatment response data. As reported previously,  the proportion of patients responding partially or completely to treatment was 28%, with 40% achieving at least minor responses to treatment. One patient achieved a stringent complete response, meaning there were no signs or clinical markers of cancer.

Patients lived for a median of 11.2 months and remained without signs of disease worsening for four months. The median duration of response was 4.4 months.

Treatment was generally safe and well-tolerated. Severe (grade 3) treatment-related adverse events were reported in 24% of the patients. Life-threatening reactions (grade 4) occurred in 49%, the most common being reduced levels of platelets (36%) and neutrophils (31%).

Only 14% of the participants stopped treatment due to side effects. No deaths were reported.

Two posters will focus on the latest findings from two ongoing Phase 1/2 trials called O-12-M1 (NCT01897714) and ANCHOR (NCT03481556), which are assessing the safety and efficacy of Ygalo in combination with other agents for the treatment of RRMM patients.

In the poster, “Updated Progression-Free Survival (PFS) and Overall Survival (OS) with Melflufen and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Phase 2 Study O-12-M1,” Oncopeptides will show results of the combination of Ygalo and dexamethasone in 45 patients (median age of 66 years) taking part in O-12-M1.

The median time from initial diagnosis was five years, and patients had received a median of four prior lines of treatment.

After a median follow-up of 30.1 months, patients lived for a median of 20.7 months and remained without signs of disease worsening for 5.7 months. No new adverse events were reported.

The study, “ANCHOR (OP-104): Updated Efficacy and Safety from a Phase 1/2 Study of Melflufen and Dexamethasone Plus Bortezomib or Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Refractory to an IMiD or a Proteasome Inhibitor (PI),” explored the combination of Ygalo with dexamethasone and Darzalex or Velcade (bortezomib, by Takeda) in patients who had received up to four therapies and failed to respond to an IMiD, a proteasome inhibitor, or both.

At the time of data cutoff on May 8, five patients had been treated with Ygalo, dexamethasone, and Velcade (regimen A; three with Ygalo at 30 mg and two with Ygalo at 40 mg), while 24 had been treated with Ygalo, dexamethasone, and Darzalex (regimen B; six with Ygalo at 30 mg and 18 with Ygalo at 40 mg).

Among those who completed two or more treatment cycles, all participants in regimen A and 82% in regimen B responded to therapy. Treatment responses improved with continued therapy in both groups.

Progression-free survival had not been reached with regimen B, indicating sustained response.

Most patients (90%) enrolled in ANCHOR are still receiving treatment. The study is ongoing with the 40 mg dose of Ygalo.

“The update on ANCHOR data will be of high importance as this will be the first time that we present progression free survival (PFS) data with longer term follow up,” Jakob Lindberg, the company’s CEO, said in a press release.

The study, “The Burden of Relapsed/Refractory Multiple Myeloma: An Indirect Comparison of Health-Related Quality of Life Burden across Different Types of Advanced Cancers at Baseline and after Treatment Based on HORIZON (OP-106) Study of Melflufen Plus Dexamethasone,” compared quality of life data from 41 participants in HORIZON with six other studies including 2,068 RRMM patients who had received at least two prior therapies.

Results were similar across the studies, as RRMM has a high impact on patients’ health-related quality of life. In addition, after comparing the same measures with data from 534 patients with other types of advanced cancers — such as lymphoma and bladder or breast cancers — investigators found that RRMM has a similar or even higher impact on quality of life.

At the meeting, Oncopeptides will also present two posters on Ygalo as a potential treatment for light chain (AL) amyloidosis.

“The acceptance of six abstracts from our robust clinical development program evaluating melflufen in multiple myeloma and AL amyloidosis is a significant validation of Oncopeptides’ progress in advancing our pipeline and conducting thorough scientific exploration of the compound,” Lindberg said.