Marizomib (previously called NPI-0052) is a natural, broad-spectrum proteasome inhibitor that is currently being investigated for the treatment of relapsed, or relapsed and refractory multiple myeloma (RRMM). It was originally developed by Triphase and later acquired by Celgene.

Marizomid, which is isolated from a marine organism, is administered by injection into the bloodstream. Preliminary studies have shown that marizomib is less toxic, more efficient, and structurally different from other proteasome inhibitors such as Velcade (bortezomib), Kyprolis (carfilzomib), and Ninlaro (ixazomib), all of which have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma.

How Marizomib works

Myeloma is a type of cancer that affects immune cells called B-cells. Normally, B-cells fight infections by producing specific antibodies. Myeloma cells grow uncontrollably and suppress the production and function of other normal immune cells by changing the bone marrow environment where all blood cells are made. Myeloma cells also produce excess proteins that can cause kidney problems.

Marizomib is a small molecule that inhibits a large protein complex called the proteasome whose role is to degrade abnormally folded or damaged proteins. The proteasome also regulates several proteins involved in cell growth, cell division, and cell survival. Myeloma cells are highly dependent on the proteasomes for their growth and survival. Hence, they are more sensitive than normal cells to proteasome inhibitors.

Marizomib in clinical trials

A Phase 1 clinical trial (NCT00629473) was conducted to determine the clinically safe and effective dose of marizomib in patients with multiple myeloma and other blood cancers. In this study, 44 patients were infused with doses of marizomib ranging from 0.075 to 0.6 mg/m2 over a period of one minute to two hours on days 1, 4, 8, 11, in three-week cycles, repeated eight times. Patients with multiple myeloma also received 20 mg of dexamethasone either orally or intravenously on the day of marizomib infusion and either the day before or the day after marizomib infusion.

The results of the study were published in the journal Clinical Cancer Research. They showed that the optimal dose of marizomib was 0.5 mg/m2 infused over two hours. The most common adverse event was fatigue. Among 27 RRMM patients who were eligible for treatment efficacy evaluation, one patient showed a very good partial response, three patients showed partial responses, four patients showed minimal responses, and 12 patients had stable disease.

Overall, marizomib was well-tolerated and did not lead to severe peripheral neuropathy or hematologic toxicity, which is observed with other proteasome inhibitors. It also demonstrated clinically relevant activity in RRMM patients who were previously treated with multiple medication regimens.

A Phase 2 open-label dose-escalation trial (NCT00461045) was conducted to determine the maximum tolerated dose of marizomib in RRMM patients. The study had two parts. In the first part, 32 patients received escalating doses (between 0.025 and 0.7 mg/m2 once weekly on days 1, 8, and 15) of marizomib. In the second part, 36 patients received escalating doses (between 0.15 and 0.6 mg/m2 twice weekly on days 1, 4, 8, and 11) of marizomib. In the second part, patients were infused with 20 mg per week of dexamethasone, if required.

The results were published in the journal Blood. They showed that the optimal dose of marizomib was 0.7 mg/m2 infused over 10 minutes in the first part and 0.5 mg/m2 infused over two hours in the second part. The most common adverse events were fatigue, headache, nausea, diarrhea, dizziness, and vomiting. Six patients showed clinically beneficial responses including five who showed partial responses. Marizomab was generally well-tolerated.

A Phase 1, multicenter, open-label, dose-escalation trial (NCT02103335) was conducted to estimate the relevant dose, safety, and tolerability of a combination of the FDA-approved immunomodulatory treatment Pomalyst (pomalidomide), marizomib, and low-dose dexamethasone (LODEX) in people with RRMM. This study enrolled 36 patients who had previously received between one and 10 different therapies, including current frontline therapies, Revlimid (lenalidomide), and Velcade.

Marizomib (at doses between 0.3 and 0.5 mg/m2) was infused into patients’ bloodstream over a period of two hours on days 1, 4, 8, and 11 of a 28‐day cycle. A dose of 5 or 10 mg of oral dexamethasone was administered on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, and 23. An oral dose of 3 to 4 mg of Pomalyst was administered once daily on days 1 to 21 of each cycle. Treatment was continued until disease progression or unacceptable toxicity.

The results were published in the British Journal of Hematology and showed that the combination of Pomalyst, LODEX, and marizomib was well-tolerated. Nineteen out of 36 patients showed a clinical response with a overall response rate of 53%. The clinical benefit rate was 64% with 23 out of 36 patients showing a complete or partial response. The most common adverse events were neutropenia (low neutrophil counts), anemia (low red blood cell counts), pneumonia, and thrombocytopenia (low platelet counts). The study demonstrated promising activity in heavily pre-treated and high-risk multiple myeloma patients.

Other information

The FDA and the European Medicines Agency granted orphan drug designation to marizomib for the treatment of multiple myeloma.

Marizomib can pass the blood-brain barrier and hence is also being investigated in a Phase 3 clinical trial (NCT03345095) as a potential treatment for a lethal brain cancer called glioblastoma.

 

Last updated: Nov. 14, 2019

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Özge has a MSc. in Molecular Genetics from the University of Leicester and a PhD in Developmental Biology from Queen Mary University of London. She worked as a Post-doctoral Research Associate at the University of Leicester for six years in the field of Behavioural Neurology before moving into science communication. She worked as the Research Communication Officer at a London based charity for almost two years.