Investigational Ygalo Shows Promise for Relapsed or Refractory Multiple Myeloma, Interim Data Show

Ana Pena, PhD avatar

by Ana Pena, PhD |

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Ygalo (melflufen), a novel compound under investigation for relapsed and refractory multiple myeloma, was well-tolerated and demonstrated promising signs of high efficacy in two global clinical trials conducted by Oncopeptides.

The data was presented April 1–2 at this year’s American Association for Cancer Research Annual Meeting, held in Atlanta, Georgia.

The interim clinical data was communicated in two posters, titled “Melflufen in patients (pts) with relapsed/refractory multiple myeloma (RRMM) refractory to daratumumab (dara) and/or pomalidomide (pom)” and “Melflufen and dexamethasone (dex) plus bortezomib (BTZ) or daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).”

Ygalo belongs to a novel class of agents called peptidase-enhanced compounds that work through a new mechanism of actionIt contains a chemotherapy agent — an alkylating peptide — that is only activated when in contact with enzymes called aminopeptidases.

Aminopeptidases are found inside all cells but overexpressed in several cancers including multiple myeloma.

Ygalo is administered into the vein (intravenously). Once it gets inside cancer cells and comes into contact with aminopeptidases, the cancer-killing agent is released and becomes trapped. Due to its ability to bind DNA, it is toxic for cancer cells, stopping cancer growth and triggering cell death.

As more aminopeptidases exist in myeloma cells than other cells, Ygalo selectively targets cancers, sparing healthy tissues.

In the lab, Ygalo was seen to selectively target tumors up to 50 times more efficiently than the same cancer-fighting agent that cannot be activated by aminopeptidases. This novel mechanism of action also has the potential to overcome some forms of treatment resistance found in myelomas.

Ygalo received Orphan Drug Status in 2015 in the U.S. and Europe.

Oncopeptides has launched three clinical studies — HORIZON (NCT02963493), ANCHOR (NCT03481556) and OCEAN (NCT03151811) — testing Ygalo for the treatment of late-stage multiple myeloma that returned (relapsing) or did not respond (refractory) to prior therapies.

HORIZON is a Phase 2 trial evaluating Ygalo for patients who underwent at least two prior lines of therapy, including an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI), and who were unresponsive (refractory) to Pomalyst (pomalidomide; also sold as Imnovid) and/or Darzalex (daratumumab). Patients received an intravenous dose of Ygalo on day 1 of each 28-day cycle plus weekly dexamethasone.

At the time of data cut-off for the interim analysis, 82 patients were eligible to be measured for a response. Of those, 33% experienced a response to treatment, or a greater than 50% reduction in tumor burden.

High-risk patients also seemed to benefit from the treatment. Those with most advanced cancers (ISS stage 3) had a response rate of 24%. Those with high-risk cytogenetics (chromosomal abnormalities) had a response rate of 22%, and those who were unresponsive to both Pomalyst and Darzalex had a response rate of 19%.

Median progression-free survival — time to cancer worsening or death — was four months.

About 75% of the patients experienced serious or life-threatening adverse events, mostly blood disorders such as low white blood cell counts (61%), low platelet counts (59%), and anemia (25%).

Treatment was discontinued in a relatively low percentage (13%) of the patients due to side effects; no deaths related to treatment were reported.

Another study, ANCHOR, is a Phase 1/2 trial evaluating two triple combinations: Ygalo plus Velcade (bortezomib) and dexamethasone, or Ygalo plus Darzalex and dexamethasone. Eligible patients were refractory or intolerant to an IMiD and/or a proteasome inhibitor and have been exposed to at least one but no more than four prior lines of therapy.

There were encouraging signs of efficacy at the end of 17 cycles with the Velcade combination and 36 cycles with Darzalex therapy, the researchers said.

All three patients assigned the Velcade combo achieved a partial response. Among those given Darzalex, six of seven had a partial or a very good partial response (90% in tumor reduction).

Most patients experienced some sort of adverse event, mostly a deficiency in blood cells or platelets. Those effects were serious in one patient.

“We are extremely pleased that these data have been selected for poster presentation at AACR, following their initial presentation at the ASH 2018 Annual Meeting, and believe that this further validates the promise that melflufen holds for the treatment of patients with advanced multiple myeloma whose treatment options are limited,” Jakob Lindberg, CEO of Oncopeptides, said in a press release.

According to Oncopeptides, earlier Phase 2 results also showed that 48% of patients on Ygalo were free of cancer progression at six months and 13.7% at 12 months. Median survival time of these patients was 20.7 months, which was higher than the median 12.4 months reported for standard of care with Pomalyst.

Moreover, Yaglo resulted in fewer side effects that significantly impact on day-to-day quality of life.

Following approval of its detailed design under the U.S. Food and Drug Administration’s Special Protocol Assessment, Oncopeptides also started the pivotal Phase 3 clinical study OCEAN (NCT03151811).

Eligible patients have received with two to four prior lines of myeloma therapy and are refractory to Revlimid (lenalidomide). The effect of Ygalo will be compared directly against the current standard of care, Pomalyst plus dexamethasone, in patients with relapsed or refractory multiple myeloma.

Oncopeptides is currently recruiting patients for its three trials in the U.S. and Europe. For more information, visit their official registry at (or click on the links: HORIZON, ANCHOR, or OCEAN) or the company’s website.

Based on positive preclinical studies, Oncopeptides is also exploring the use of Ygalo for cancers other than myeloma.