DUBLIN – AB Science SA took a step closer to its first product approval, with a first positive read out of its tyrosine kinase inhibitor masitinib in a phase III trial. The Paris-based firm disclosed last week that it had reached the primary endpoint of a phase III study in severe systemic mastocytosis. It released detailed data from the trial Monday.

Mastocytosis refers to a range of rare conditions of varying severity caused by an abnormal proliferation of mast cells and a subsequent invasion of other tissues, including the skin and bone marrow. Symptoms include those commonly associate with allergy, such as itching, flushing, abdominal cramping, and, in certain cases, shock. Nausea and vomiting, musculoskeletal pain, ulcers and diarrhea can also occur, as can intestinal complications and hematological problems, such as anemia.

The AB Science study, led by Olivier Lortholary, of Hôpital Necker-Enfants Malades in Paris, assessed the efficacy of masitinib plus symptomatic therapy versus that of placebo plus symptomatic therapy. The primary endpoint comprised reductions in four key symptoms: pruritus (itching), flushes, depression and asthenia (fatigue). At baseline, patients had between one of four the following inclusion criteria: a pruritus of at least nine; at least eight flushes per week; a depression rating of least 19 on the Hamilton rating scale; and a minimum fatigue impact rating scale score of 75.

The primary endpoint, referred to as a "4H75%" response, represented a cumulative improvement over 24 weeks with respect to baseline of at least 75 percent on each of the four symptoms. Of those assigned to the drug treatment group, 18.4 percent attained a 4H75% response, whereas 7.4 percent did in the control arm. The result was statistically significant (p=0.01). Those data refer to a modified intent-to-treat population. In the per-protocol population, 20.1 percent of those in the drug treatment group attained a 4H75% response, vs. 7.4 percent of those in the control group.

The drug was superior to placebo on each of the four symptoms, although its effect on fatigue, while statistically significant, was the smallest. The company attributed this to its insensitivity to detecting changes in fatigue over time, a finding that only came to light during the trial.

Masitinib also demonstrated an effect on tryptase levels, a marker of mast cell burden and activity. Those in the drug treatment group had a mean reduction in baseline of 18 percent, whereas those in the control group had an increase of 2.2 percent over the same period (p<0.0001). The treatment effect was also maintained over two years, based on an analysis of data from an extension study.

Mastocytosis is generally sporadic and can arise from a gain-of-function mutation in the c-Kit gene, which encodes a tyrosine kinase normally activated by stem cell factor. The most commonly observed mutation in mastocytosis, D816V, results in the c-Kit becoming constitutively activated, leading to over-activation of the mast cell population.

Although the scientific rationale for the therapy is clear, its commercial potential in mastocytosis is debatable. Although AB Science bills the drug as a first-in-class treatment in systemic mastocytosis, Basel, Switzerland-based Novartis AG gained FDA approval for Gleevec (imatinib mesylate) in aggressive systemic mastocytosis almost a decade ago – in February 2006 – in patients with the D816V c-Kit mutation or of unknown c-Kit mutational status. AB Science has an open opportunity in Europe, however, as Novartis withdrew its application in mastocytosis in that region. Investigator-imitated trials of several other agents are underway, including Gleevec, the tyrosine kinase inhibitor midostaurin, the Bruton's tyrosine kinase inhibitor Imbruvica (ibrutinib) and the antibody-drug conjugate Adcetris (brentuximab vedotin.)

Shares in AB Science (PARIS:AB) closed Monday at €13.91, up just 0.14 percent, having reached €14.57, a three-month high, during the day's trading.