EMA REJECTS ANAMORELIN FOR CACHEXIA TREATMENT

When new data for anamorelin were presented at a large European meeting in 2014, oncology experts enthusiastically welcomed them, and hopes were raised that there may at last be a drug for cancer cachexia, the extreme wasting seen at the end stages of the disease.

But those hopes have now been dashed.

Having reviewed the clinical data, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) found only "marginal" effects and recommended that the product be refused marketing authorization in Europe.

Anamorelin, developed by Helsinn Birex Pharmaceuticals Ltd, was to have the trade name Adlumiz. The oral drug acts as an agonist at receptors of ghrelin, the so-called hunger hormone, which results in the release of growth hormone.

Results From Clinical Trials 

Data from two clinical trials with anamorelin were presented at the 2014 European Society for Medical Oncology (ESMO) annual meeting, as reported by Medscape Medical News at the time.  "For the first time ever, we have seen a consistent benefit" from a drug in cancer cachexia, commented one of the investigators, David Currow, MD, from the palliative and supportive services at Flinders University in Adelaide, Australia. "We never thought that we would change this without changing the underlying cancer," he said.

The two trials, known as ROMANA 1 (n = 484) and ROMANA 2 (n = 495), were both placebo-controlled. They were conducted in patients with unresectable advanced non-small cell lung cancer (70% with stage IV disease) who had greater than 4 months' life expectancy and who had lost 5% or more body weight in the last 6 months or who had a body mass index below 20 kg/m². The average body weight was 68 kg in one trial and 63 kg in the other. Many of the patients (60% to 80%) were receiving chemotherapy or radiotherapy, or a combination of both.

Over the course of 12 weeks, patients receiving anamorelin had significantly improved lean body mass, while the patients in the placebo control group continued to lose weight, reported principal investigator, Jennifer Temel, MD, from the Department of Medicine at the Massachusetts General Hospital in Boston.

In the ROMANA 1 study, the median increase in lean body mass was 1.10 kg with anamorelin, compared with a loss of 0.44 kg in the placebo group. In ROMANA 2, the increase was 0.75 kg, compared with a loss of 0.96 kg in the placebo group (P < .0001 for both studies).

In ROMANA 1, body weight increased by an average of 2.2 kg with anamorelin vs 0.14 kg with placebo. In ROMANA 2, body weight increased by an average of 0.95 kg in the anamorelin group but decreased by 0.57 kg in the placebo group (P < .0001 for both studies).

Another endpoint was hand-grip strength. This did not differ between the two groups; it declined in both. However, Dr Temel said that patients appeared to have had problems using this equipment.

Negative Opinions From CHMP 

The CHMP appears to have reviewed exactly these same data at its recent May meeting. In its statement, it says that it reviewed results of two placebo-controlled trials conducted in a total of around 1000 patients with NSCLC and cachexia, in which the main endpoints were changes in lean body mass and hand-grip strength.

The CHMP concluded that the studies showed a marginal effect of anamorelin on  lean body mass and no proven effect on hand-grip strength or patients' quality of life.

In addition, after an inspection at clinical study sites, the CHMP considered that the safety data on the medicine had not been recorded adequately.

"This meant that a thorough evaluation of potential risks with anamorelin was not possible," it states. "Therefore the CHMP was of the opinion that the benefits of anamorelin did not outweigh its risks and recommended that it be refused marketing authorization."

Another Product for Cachexia Refused  

Another product aimed at cachexia was also refused a recommendation for approval at the same meeting. Human IgG1 monoclonal antibody specific for human interleukin-1α (XBiotech Germany GmbH) was intended to treat debilitating symptoms of advanced colorectal cancer, including cachexia.

The product works by blocking the actions of human interleukin-1α, which is expected to slow down the growth of the cancer, thus relieving patients' symptoms, the CHMP explains.

The company presented results of a placebo-controlled study in 333 patients that looked at the effects of this medicine on lean body mass and quality of life.

The CHMP says that it had several concerns. First, the study did not show clear improvements in either lean body mass or quality of life. Second, patients taking the medicine had increased risk for infection, which was not considered acceptable in vulnerable patients who will be receiving palliative care. Last, there were inadequate controls of the manufacturing process to ensure the medicine would have the same quality as the product used in clinical trials.

Drug for Mastocytosis Refused

In addition, the CHMP also refused another product, masitinib (Masipro, AB Science), which was intended to treat the rare condition of systemic mastocytosis.

In this condition, the body produces too many mast cells in the skin, bones, and various body organs, causing symptoms such as itchy skin, hot flushes, palpitations, fainting, bone pain, weakness, vomiting, diarrhea, and depression.

Masitinib acts as a tyrosine kinase inhibitor, and these enzymes are found, among other places, in some receptors in mast cells, including those involved in stimulating the cells to grow and divide. By blocking these enzymes, masitinib helps to slow down the growth of the mast cells, the CHMP explains on its website.  

The company presented data from a placebo-controlled study involving 135 patients with systemic mastocytosis who had severe symptoms, including at least one of the following: itching, hot flushes, depression, and weakness. The main endpoint was an improvement in any of these four symptoms after 24 weeks of treatment.

However, the CHMP says it was concerned about the reliability of the study results because a routine good clinical practice inspection at the study sites revealed serious failings in the way the study had been conducted. In addition, major changes were made to the study design while the study was ongoing, which made the results difficult to interpret. Finally, data on the safety of the medicine were limited, and there were concerns regarding the drug's side effects, including neutropenia and effects on the skin and liver, which were relevant particularly because the medicine was to be used long term. Therefore, the CHMP was of the opinion that the benefits did not outweigh risks and recommended that the drug be refused marketing authorization.

Application for Vosaroxin Withdrawn 

In addition, the CHMP notes that the application for marketing authorization of vosaroxin (Qinprezo, Sunesis Pharmaceuticals) has been withdrawn by the company. This drug was intended to be used in combination with cytarabine for the treatment of acute myeloid leukemia (AML).

Vosaroxin works by blocking topoisomerase II, an enzyme involved in DNA replication, which prevents cancer cells from dividing, eventually killing them.

The company presented data from a main study in 711 patients with relapsed or refractory AML, in which vosaroxin plus cytarabine was compared with cytarabine alone, with the endpoint of overall survival.

The CHMP notes that it had already evaluated the initial documentation. It had several concerns about the data and had a provisional negative opinion. Benefit on overall survival was lacking, and there were concerns of an increased rate of infection. The CHMP was of the opinion that the benefits did not outweigh its risks.

The company withdrew its application for marketing authorization because it was unlikely to succeed — the data from the main study were not convincing enough. The company decided to focus resources on other priorities.