4SC AG, a discovery and development company of targeted small molecule drugs for autoimmune diseases and cancer, announced positive topline data from its phase II SAPHIRE trial with resminostat, its oral pan HDAC inhibitor, in patients with relapsed/refractory Hodgkin's Lymphoma (HL). Resminostat monotherapy exhibited substantial anti-tumour activity, including complete and partial tumour responses. Analysis of tumour response assessments revealed that the study achieved its primary endpoint. Furthermore the study verified the drug to be safe and well tolerated in this advanced stage patient population.

In June 2011 the SAPHIRE trial completed patient enrolment. 33 patients have been evaluated for tumour response which, according to the study protocol, represents the targeted number of patients required for efficacy analyses. Central assessment of patient tumour data by an independent expert review board revealed objective tumour responses in 11 patients, constituting a 33.3 per cent overall response rate (ORR) and thereby successfully achieving the pre-defined requirements of the primary endpoint of the study. This ORR of 33.3 per cent together with a clinical benefit recorded in total for 54.5 per cent of the patients (disease control rate) demonstrates the substantial anti-tumour activity of resminostat monotherapy in an advanced and heavily pre-treated Hodgkin's Lymphoma patient population for which there is currently no established standard therapy available. Prior to study entry, the patients enrolled received a median of 6 treatments consisting of various chemo- and radiation therapies including autologous stem cell transplantation in 57% of the cases.

The clinical activity of resminostat was measured through PET/CT, the combination of Positron-Emission Tomography (PET) and computer tomography (CT). Study responders included 1 complete response (CR) and 3 partial responses (PR) according to Cheson criteria1. Furthermore, 7 patients experienced Partial Metabolic Responses (PMR) according to EORTC criteria2. An additional 7 patients achieved stabilization of their disease. Thus, in total 18 of 33 patients, representing 54.5% of all patients evaluated for efficacy, received a clinical benefit from resminostat treatment. Additional two patients are currently continuing on study therapy in the optional follow-up phase, and have therefore not been subject to final response evaluation by the independent review board.

Treatment with resminostat was generally well tolerated with common grade 2-3 adverse events3 mainly being of gastrointestinal (nausea) or haematological (anaemia, thrombocytopenia) origin. All adverse events were well manageable by dose modification or symptomatic treatment. Assessment of pharmacokinetic (PK) parameters confirmed the favourable profile of the oral administration route and dose dependent resminostat plasma concentrations.

“We are very encouraged by the results from this trial in a very heavily pre-treated patient population. With an overall response rate of 33.3 per cent and with more than half of the patients experiencing a clinical benefit resminostat could become a novel therapy in Hodgkin's Lymphoma,” said Ulrich Dauer, chief executive officer of 4SC. “This excellent efficacy data in patients with no further established treatment options combined with the very positive safety profile of resminostat provides us with the information we need to initiate the next development steps for this compound. We intend to discuss the path towards registration with the regulatory agencies in the near future.”

Final data from this trial, including secondary endpoints, will be presented at an upcoming international scientific conference.

The SAPHIRE trial included HL patients that had relapsed after high dose chemotherapy and/or Autologous Stem Cell Transplantation (ASCT) or had become refractory to treatment. The study was designed as an open-label, single-arm, international trial consisting of two recruitment stages according to the Simon's Minimax design. Resminostat has been administered orally at a once daily dose of 600 mg during the 1st recruitment stage and due to its good tolerability at a higher daily dose of 800 mg in the 2nd stage. Patients were treated in 14-day cycles of five consecutive days followed by a nine-day treatment-free period (5+9 schedule). Patients underwent assessment of their disease status by computed tomography in combination with positron emission tomography (PET/CT) after Cycle 3 and Cycle 6 and thereafter every fourth cycle during an optional follow-up period in which patients could continue treatment until disease progression. The primary endpoint of the study was defined as the overall objective response rate (ORR) based on the best objective response during treatment. Secondary endpoints include time to response (TTR), duration of response (DOR), progression free survival (PFS), overall survival (OS), safety and tolerability and the evaluation of drug regulated biomarkers including the assessment of TARC levels.

HL is a cancer of the lymphatic system, which is part of the immune system, and leads to the abnormal growth of lymphatic cells that compromise the immune system's ability to fight infection and may even spread beyond the lymphatic systems to other organs. Typical symptoms of HL include the painless swellings of the lymph nodes, spleen or other tissue and an overall impairment of the hematopoietic system, as well as fever, weight loss or night sweats. The main causes for the development of HL are still unknown. Recent research shows that this cancer has its origin from a degenerated lymphatic cell, the B lymphocyte.

HL is a curable malignant lymphoma in the majority of cases. However, not all patients can be cured and available therapies for this disease can have significant long-term toxicity. The incidence of HL in 2008 was 11,777 new cases in Europe and 8,220 new cases in the US. The age distribution is bimodal; the first peak occurs between the ages of 15 and 30 years and the second in the sixth decade.

Therapy options for HL patients depend on the stage of the disease and number and regions of lymph nodes affected. The first treatment line for HL, after the initial diagnosis, consists of chemotherapy and/or radiation, achieving cure rates of up to 80%. Standard of care for patients with refractory or relapsing disease after initial therapy comprises salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation. Patients relapsing after second line therapy have a 5-year overall survival rate of only 17 per cent. Since there is no standard of care in patients with resistant/refractory HL, there is an especially high need to develop novel therapies for these patients.

Resminostat (4SC-201) is an oral pan-histone-deacetylase (HDAC) inhibitor. HDAC inhibitors modify the DNA structure of tumour cells to cause their differentiation and programmed cell death (apoptosis) and are therefore considered to offer a mechanism of action that has the particular potential to halt tumour progression and induce tumour regression. Resminostat is currently being investigated in the phase II SHELTER study as a second-line treatment for advanced hepatocellular carcinoma and in the phase I/II SHORE study as a second-line treatment in colorectal cancer in KRAS-mutant patients. The SHELTER study is expected to report phase II results in 2011. Initial results of the SHORE study are expected in 2012.

The reported phase II SAPHIRE trial for resminostat as a third-line therapy in Hodgkin's lymphoma is still ongoing as two patients are continuing on study therapy in the optional follow-up phase beyond 12 weeks of treatment.