On June 13, 2016 Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, reported that it presented data from multiple clinical trials evaluating the safety and efficacy of two selective HDAC6 inhibitors in combination with pomalidomide (Pom) (Pomalyst, Celgene) and dexamethasone (Dex) for the treatment of relapsed or relapsed-and-refractory multiple myeloma (RRMM) at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark (Press release, Acetylon, JUN 13, 2016, View Source [SID:1234513281]).

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Positive results from a Phase 2 clinical trial of ricolinostat were presented in an oral presentation by Noopur Raje, M.D. of Massachusetts General Hospital in Boston, Massachusetts. In addition, results of a Phase 1b clinical trial of an alternative liquid formulation of ricolinostat were presented in a poster presentation by Sumit Madan, M.D. of University of Texas Southwestern Medical Center. Early favorable results from a Phase 1a/1b clinical trial of ACY-241, a selective HDAC6 inhibitor administered in tablet form, were also presented as an e-poster.

“The data from these studies demonstrate that selective HDAC6 inhibition combines favorably with Pom and Dex, and support the continued clinical development of our selective HDAC6 inhibitors for the treatment of relapsed or relapsed-and-refractory multiple myeloma,” said Catherine Wheeler, SVP Clinical Development & CMO of Acetylon. “The results of the Phase 2 ACE-MM-102 trial have established proof of concept for selective HDAC6 inhibition and demonstrated that the addition of ricolinostat to Pom/Dex treatment increases response rate and progression-free survival compared to Pom/Dex alone in relapsed-and-refractory MM. We believe that this approach has the potential to become a powerful treatment option for patients with multiple myeloma without the severe side effects commonly seen with pan-HDAC inhibition. We are further encouraged by early results with ACY-241 in a similar patient population that it will deliver the same efficacy and safety as ricolinostat, however in a tablet form.”

Phase 2 ACE-MM-102 Data

The ACE-MM-102 clinical trial is a multicenter, single arm, open-label Phase 2 study designed to evaluate the safety and efficacy of ricolinostat administered at an optimal dose and schedule in combination with Pom and Dex in patients with RRMM. Results of this study indicated that treatment with ricolinostat in combination with Pom and Dex was very well tolerated, and toxicities were predominantly low grade. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses. Analysis of 67 efficacy-evaluable patients enrolled at least 6 months prior to the data cut confirmed an overall response rate (ORR) of 46%, a clinical benefit rate (CBR) of 58%, a disease control rate (DCR) of 82%, 9 months duration of response (DOR), and 7 months progression free survival (PFS). These data compare favorably to mature historical data for the MM-002 and MM-003 trials of Pom and Dex alone which demonstrated 31-33% ORR, 7-8 months DOR, and 4 months median PFS. More mature data on the entire 96 patient study population will be available by the end of the year.

Phase 1b ACE-MM-104 Data

The Phase 1b ACE-MM-104 clinical trial is a dose-escalation study of an alternative liquid formulation (ALF) of ricolinostat in combination with Pom and Dex in patients with RRMM. Daily dosing (QD) was better tolerated than twice-daily dosing. One dose-limiting toxicity (DLT), neutropenia, was observed at 180 mg QD, and cohort expansion to 6 patients showed no further DLTs. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses, with no evidence of ricolinostat accumulation or drug-drug interaction with Pom. Early efficacy data indicates a confirmed ORR of 53% and a DCR of 87% after 6 months median follow-up. These results demonstrate that the alternative liquid formulation of ricolinostat is well tolerated in combination with Pom and Dex at doses up to 180 mg QD without major toxicities. This formulation of ricolinostat is also being used in ongoing investigator-sponsored studies in combination with paclitaxel and abraxane to treat solid tumors.

Preliminary Phase 1a/1b ACE-MM-200 Data

The Phase 1a/1b ACE-MM-200 clinical trial utilizes a sequential monotherapy/combination trial design to establish the safety, pharmacokinetics, and pharmacodynamics of ACY-241 as both a monotherapy and in combination with Pom and Dex in patients with relapsed or relapsed-and-refractory MM. ACY-241 is an orally available selective HDAC6 inhibitor that is structurally similar to ricolinostat and administered in tablet form. Results of the study demonstrated that ACY-241 is well tolerated as a monotherapy and in combination with Pom and Dex, and toxicities did not differ substantially in frequency or severity from those reported with Pom and Dex alone. Pharmacokinetic and pharmacodynamic analysis indicated dose-linear increases in exposure and dose-dependent, selective increases in acetylated tubulin and histones. ACY-241 achieved exposures several fold higher than ricolinostat without severe toxicity, both alone and in combination with Pom and Dex. Early efficacy data for combination treatment indicates a confirmed ORR of 50% and a DCR of 95% after 3.5 months median follow-up. These results indicate that ACY-241 is well tolerated in combination with Pom and Dex, and early response data for combination treatment even with short follow-up are similar to those of ricolinostat in combination with Pom and Dex. Cohort expansion at biologically relevant combination doses is ongoing.

About HDAC6 Inhibition

Ricolinostat (ACY-1215) and ACY-241 selectively inhibit the intracellular enzyme HDAC6, which leads to an accumulation of excess protein and in addition may disrupt critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called “apoptosis,” with little or no effect on normal cells. Currently available HDAC drugs also affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and to enable the development of optimized treatment regimens, including maximally effective combination drug therapies.

On June 13, 2016 Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, reported that it presented data from multiple clinical trials evaluating the safety and efficacy of two selective HDAC6 inhibitors in combination with pomalidomide (Pom) (Pomalyst, Celgene) and dexamethasone (Dex) for the treatment of relapsed or relapsed-and-refractory multiple myeloma (RRMM) at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark (Press release, Acetylon, JUN 13, 2016, View Source [SID:1234513281]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Positive results from a Phase 2 clinical trial of ricolinostat were presented in an oral presentation by Noopur Raje, M.D. of Massachusetts General Hospital in Boston, Massachusetts. In addition, results of a Phase 1b clinical trial of an alternative liquid formulation of ricolinostat were presented in a poster presentation by Sumit Madan, M.D. of University of Texas Southwestern Medical Center. Early favorable results from a Phase 1a/1b clinical trial of ACY-241, a selective HDAC6 inhibitor administered in tablet form, were also presented as an e-poster.

"The data from these studies demonstrate that selective HDAC6 inhibition combines favorably with Pom and Dex, and support the continued clinical development of our selective HDAC6 inhibitors for the treatment of relapsed or relapsed-and-refractory multiple myeloma," said Catherine Wheeler, SVP Clinical Development & CMO of Acetylon. "The results of the Phase 2 ACE-MM-102 trial have established proof of concept for selective HDAC6 inhibition and demonstrated that the addition of ricolinostat to Pom/Dex treatment increases response rate and progression-free survival compared to Pom/Dex alone in relapsed-and-refractory MM. We believe that this approach has the potential to become a powerful treatment option for patients with multiple myeloma without the severe side effects commonly seen with pan-HDAC inhibition. We are further encouraged by early results with ACY-241 in a similar patient population that it will deliver the same efficacy and safety as ricolinostat, however in a tablet form."

Phase 2 ACE-MM-102 Data

The ACE-MM-102 clinical trial is a multicenter, single arm, open-label Phase 2 study designed to evaluate the safety and efficacy of ricolinostat administered at an optimal dose and schedule in combination with Pom and Dex in patients with RRMM. Results of this study indicated that treatment with ricolinostat in combination with Pom and Dex was very well tolerated, and toxicities were predominantly low grade. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses. Analysis of 67 efficacy-evaluable patients enrolled at least 6 months prior to the data cut confirmed an overall response rate (ORR) of 46%, a clinical benefit rate (CBR) of 58%, a disease control rate (DCR) of 82%, 9 months duration of response (DOR), and 7 months progression free survival (PFS). These data compare favorably to mature historical data for the MM-002 and MM-003 trials of Pom and Dex alone which demonstrated 31-33% ORR, 7-8 months DOR, and 4 months median PFS. More mature data on the entire 96 patient study population will be available by the end of the year.

Phase 1b ACE-MM-104 Data

The Phase 1b ACE-MM-104 clinical trial is a dose-escalation study of an alternative liquid formulation (ALF) of ricolinostat in combination with Pom and Dex in patients with RRMM. Daily dosing (QD) was better tolerated than twice-daily dosing. One dose-limiting toxicity (DLT), neutropenia, was observed at 180 mg QD, and cohort expansion to 6 patients showed no further DLTs. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses, with no evidence of ricolinostat accumulation or drug-drug interaction with Pom. Early efficacy data indicates a confirmed ORR of 53% and a DCR of 87% after 6 months median follow-up. These results demonstrate that the alternative liquid formulation of ricolinostat is well tolerated in combination with Pom and Dex at doses up to 180 mg QD without major toxicities. This formulation of ricolinostat is also being used in ongoing investigator-sponsored studies in combination with paclitaxel and abraxane to treat solid tumors.

Preliminary Phase 1a/1b ACE-MM-200 Data

The Phase 1a/1b ACE-MM-200 clinical trial utilizes a sequential monotherapy/combination trial design to establish the safety, pharmacokinetics, and pharmacodynamics of ACY-241 as both a monotherapy and in combination with Pom and Dex in patients with relapsed or relapsed-and-refractory MM. ACY-241 is an orally available selective HDAC6 inhibitor that is structurally similar to ricolinostat and administered in tablet form. Results of the study demonstrated that ACY-241 is well tolerated as a monotherapy and in combination with Pom and Dex, and toxicities did not differ substantially in frequency or severity from those reported with Pom and Dex alone. Pharmacokinetic and pharmacodynamic analysis indicated dose-linear increases in exposure and dose-dependent, selective increases in acetylated tubulin and histones. ACY-241 achieved exposures several fold higher than ricolinostat without severe toxicity, both alone and in combination with Pom and Dex. Early efficacy data for combination treatment indicates a confirmed ORR of 50% and a DCR of 95% after 3.5 months median follow-up. These results indicate that ACY-241 is well tolerated in combination with Pom and Dex, and early response data for combination treatment even with short follow-up are similar to those of ricolinostat in combination with Pom and Dex. Cohort expansion at biologically relevant combination doses is ongoing.

About HDAC6 Inhibition

Ricolinostat (ACY-1215) and ACY-241 selectively inhibit the intracellular enzyme HDAC6, which leads to an accumulation of excess protein and in addition may disrupt critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called "apoptosis," with little or no effect on normal cells. Currently available HDAC drugs also affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and to enable the development of optimized treatment regimens, including maximally effective combination drug therapies.

On June 13, 2016 Argos Therapeutics Inc. (Nasdaq:ARGS), an immuno-oncology company focused on the development and commercialization of truly individualized immunotherapies for the treatment of cancer based on the Arcelis technology platform, reported that the independent data monitoring committee (IDMC) for the Company’s pivotal Phase 3 ADAPT clinical trial of AGS-003 for the treatment of metastatic renal cell carcinoma (mRCC) has recommended the continuation of the trial based on results of the IDMC’s scheduled interim data review (Press release, Argos Therapeutics, JUN 13, 2016, View Source [SID:1234513245]). The next IDMC meeting is being planned to coincide with the Genitourinary Cancers Symposium in February 2017.

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"As the largest global Phase 3 trial ever performed in newly diagnosed, intermediate and poor risk mRCC patients, the ADAPT trial continues to progress," said Dr. Robert Figlin, the Steven Spielberg Family chair in hematology oncology, professor of medicine and biomedical sciences at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute and the co-principal investigator for the ADAPT trial. "With all the excitement regarding the clinical benefit of the emerging immuno-oncology therapies, a positive outcome of the ADAPT trial, because of AGS-003’s novel mechanism of action, could be a game changer in the treatment of mRCC."

AGS-003 is an individualized immunotherapy that captures both mutated and variant antigens that are unique to each patient’s tumor, and, therefore, specifically designed to induce an immune response targeting that patient’s particular tumor antigens. In an open-label Phase 2 trial, treatment with AGS-003 plus sunitinib resulted in median overall survival of more than 30 months in newly diagnosed, intermediate and poor risk mRCC patients. We have enrolled a total of 462 mRCC patients in our ongoing pivotal, randomized Phase 3 ADAPT trial evaluating AGS-003 in combination with standard targeted therapy, which has a primary endpoint of overall survival. AGS-003 is Argos’ most advanced Arcelis-based product candidate.

"The IDMC’s recommendation to continue with the ADAPT trial aligns with our expectations based on the patient population enrolled and the clinical benefit observed in the Phase 2 trial," said Lee F. Allen, MD, PhD, chief medical officer of Argos. "Based upon our internal projections, we believe that at this point we have reached more than half of the targeted number of events for our survival endpoint, and we anticipate having a sufficient number of events to permit the primary analysis and assessment of overall survival to occur in the first half of 2017. The focus of our clinical development group is now on the careful oversight of the ADAPT trial execution to ensure study data quality, and we have initiated cross functional activities to begin building the AGS-003 Biologics License Application (BLA)."

The positive outcome from the IDMC’s review of the ADAPT trial data triggers the second tranche of the financing under the Company’s previously announced March 2016 securities purchase agreement. Upon the closing of the second tranche, which is expected to occur within 30 days, the Company will receive a total of $29,824,520 from the sale of a total of 5,478,672 shares of common stock and warrants to purchase a total of 4,109,005 shares of common stock.

About the Arcelis Technology Platform
Arcelis is a precision immunotherapy technology that captures mutated and variant antigens that are specific to each patient’s disease. It is designed to overcome immunosuppression by producing a durable memory T-cell response without adjuvants that may be associated with toxicity. The technology is potentially applicable to a wide range of different cancers, and is designed to overcome many of the manufacturing and commercialization challenges that have impeded other personalized cancer immunotherapies. The Arcelis process uses only a small tumor or blood sample and the patient’s own dendritic cells, which are optimized from cells collected by a single leukapheresis procedure. The proprietary process uses RNA isolated from the patient’s disease sample to program dendritic cells to target disease-specific antigens. The activated, antigen-loaded dendritic cells are then formulated with the patient’s plasma and administered via intradermal injection.