|Karyopharm Reports Data on Selinexor; Alnylam Initiates Phase 1 Clinical Trial with ALN-AT3|
|By Staff and Wire Reports|
|Wednesday, 22 January 2014 20:53|
Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a clinical-stage pharmaceutical company focused on the discovery and development of novel first-in-class drugs directed against nuclear transport targets for the treatment of cancer and other major diseases, announced data from two poster presentations at the American Society of Clinical Oncology (ASCO) 2014 Gastrointestinal (GI) Cancers Symposium that took place January 16-18 in San Francisco, California. The data presented included an update (as of December 16, 2013) from the ongoing Phase 1 study of oral Selinexor in solid tumors that show preliminary evidence of antitumor activity in metastatic colorectal cancer (CRC) patients. Additionally, data were presented on novel, oral p21-activated kinase 4 (PAK4) inhibitors that show anti-proliferative activity and tolerability in a preclinical pancreatic cancer model.
"We are very pleased with these preliminary results showing that single agent oral Selinexor has the potential to provide disease control in a subset of patients with heavily pretreated CRC. We are currently continuing our Phase 1 dose expansion cohorts and expect to report more data at the annual ASCO conference in June," stated Sharon Shacham, Ph.D., founder, Chief Scientific Officer and President of Karyopharm. "In addition, the preliminary preclinical data on our compounds that selectively inhibit PAK4 support our continued development of these potential therapies towards first-in-human studies."
Dr. Morten Sorensen (Rigshospitalet – Copenhagen University Hospital, Copenhagen, Denmark) presented an update on 35 patients with heavily pretreated metastatic CRC (2-8 prior regimens including anti-folates, irinotecan, and oxaliplatin as well as bevacizumab, cetuximab, and/or regorafenib in many patients) whose tumors were progressing on study entry, from the ongoing Phase 1 dose escalation study in solid tumors. Patients were treated with oral Selinexor at doses ranging from 3 to 35 mg/m^2. One patient had a partial response by standard RECIST (Response Evaluation Criteria In Solid Tumors) criteria and had remained on study for eight months. Eleven patients had stable disease; ten for eight weeks or longer with four of those ten patients (11%) demonstrating stable disease for over 25 weeks. Two patients were not evaluable for response, and 21 had progressive disease at first evaluation.
Adverse events associated with Selinexor in the Phase 1 study were primarily Grade 1 or 2, and were reduced or eliminated with standard supportive care. Clinically significant grade 3 or 4 adverse events were uncommon, and were reversible with supportive care and dose adjustment. Cumulative toxicities were rare, and no major organ dysfunction was noted. The most common adverse events were GI in nature including nausea (71%), vomiting (57%), anorexia (51%), weight loss (46%), taste alterations (49%), and diarrhea (26%). Grade 1/2 fatigue occurred in 49% of patients. Grade 1/2 blurred vision occurred in 20% of patients with no objective findings except for worsening of pre-existing cataracts in one patient, which was considered possibly related to Selinexor. Grade 3 hyponatremia (26%) was usually associated with dehydration, and grade 3 fatigue (23%) was rapidly reversible with supportive care and dose adjustment. Myelosuppression was uncommon with the most common form being grade 3/4 thrombocytopenia, which was reversible and not associated with bleeding.
Results supporting the possible mechanism of action of Selinexor in heavily pretreated CRC patients were also reported, as well as dose- and time-dependent pharmacodynamics analyses. Several of the patients in the study underwent pretreatment and on-treatment tumor biopsies. Microscopic analyses of the tumor lesions that shrunk, as detected by CT scan, showed that Selinexor induced nuclear localization of the tumor suppressor proteins p53 and/or FOXO1, reductions in proliferation rates as assessed by Ki67 staining, and increased apoptosis levels. In addition, in many of the tumor biopsies, malignant tumor cells were replaced by non-proliferative stromal (connective) tissue. Regarding pharmacodynamics, results presented in the patients with CRC showed that Selinexor induced a dose- and time-dependent increase in XPO1 messenger RNA in circulating white blood cells, and that the effects lasted 24-48 hours. There was a trend to higher levels of XPO1 mRNA in patients who achieved stable disease or partial responses.
Dr. Sorensen commented, "This cohort of heavily pretreated patients with advanced CRC has received as many as eight prior regimens, each with several anti-cancer agents. These are incredibly sick patients with tumors that are growing on study initiation so we are excited about these early data with single-agent oral Selinexor. We look forward to obtaining additional data from cohorts at higher doses and from combination studies of oral Selinexor with already available anti-cancer agents."
Dr. Asfar Azmi (Wayne State University, Detroit, Michigan) presented data from a preclinical model of pancreatic cancer using some of Karyopharm's highly selective covalent allosteric inhibitors of PAK4. These compounds induced the death of pancreatic cancer cells in vitro, and showed preliminary tolerability in mouse studies, with efficacy models ongoing.
Dr. Azmi noted, "We are quite intrigued with the data we have generated to date in preclinical models of pancreatic cancer – one of the most difficult cancers to treat. Karyopharm's novel oral PAK4 inhibitor may represent a new approach to the treatment of this and other cancers, and we look forward to continuing work on these compounds."
Alnylam Pharmaceuticals (Nasdaq: ALNY), a leading RNAi therapeutics company, announced it has initiated a Phase 1 study with ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD). ALN-AT3 has demonstrated efficacy in animal models of hemophilia, including in non-human primate models of induced hemophilia. Moreover, pre-clinical studies of ALN-AT3 support a wide therapeutic index in the hemophilia setting. ALN-AT3 is a key program in the company's “Alnylam 5x15” product strategy, which is aimed at advancing multiple RNAi therapeutic genetic medicine programs into clinical development. Alnylam recently announced that it expects to exceed its original “Alnylam 5x15” guidance with six to seven genetic medicine programs in clinical development by the end of 2015, including at least two programs in Phase 3 and five to six programs that will have achieved human proof-of-concept results supporting further development.
“Hemophilia and other rare bleeding disorders are characterized by deficiencies in specific clotting factors that ultimately lead to inadequate thrombin generation and a bleeding diathesis. ALN-AT3 is aimed at correcting these bleeding disorders by knockdown of AT - an endogenous anticoagulant - thus, increasing thrombin generation and improving hemostasis,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “Our pre-clinical results have demonstrated a promising activity profile for ALN-AT3 in hemophilia animal models, and our results in non-human primate studies are particularly encouraging in light of the excellent human translation we have seen with RNAi therapeutics. In addition, we have shown in preclinical studies that ALN-AT3 administration is associated with a very wide therapeutic index in the hemophilia setting. We are excited to be advancing this product candidate – notably, our second GalNAc-conjugate program – into a Phase 1 trial, and look forward to sharing initial data by the end of the year.”
The Phase 1 study is being conducted in the U.K. as a single- and multi-dose, dose-escalation study consisting of two parts. Part A will be a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, enrolling up to 24 healthy volunteer subjects. The primary objective of this part of the study is to evaluate the safety and tolerability of a single low dose of ALN-AT3, with the potential secondarily to show changes in AT plasma levels at sub-pharmacologic doses. Part B of the study will be an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate to severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in thrombin generation at pharmacologic doses of ALN-AT3. Thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia (Dargaud, et al., Thromb Haemost; 93, 475-480 (2005)). The company expects to present initial data from the Phase 1 study in late 2014.
“The unmet need for new therapeutic options to treat people with hemophilia remains very high, particularly in those patients that develop inhibitory antibodies to their replacement factor. Indeed, availability of a safe and effective subcutaneously administered therapeutic with a long duration of action would represent a marked improvement over currently available approaches for prophylaxis,” said Claude Negrier, M.D., head of the Hematology Department and director of the Haemophilia Comprehensive Care Centre at Edouard Herriot University Hospital in Lyon. “I continue to be encouraged by Alnylam's progress to date with ALN-AT3, including pre-clinical data demonstrating correction of impaired thrombin generation in a non-human primate ‘inhibitor' model. These results are particularly important since clinical studies have demonstrated that thrombin generation correlates strongly with bleeding phenotype; severe hemophilia patients have low thrombin generation as compared to moderate and mild patients who have significantly higher levels. I look forward to the continued advancement of this innovative therapeutic candidate in clinical studies.”
Alnylam presented pre-clinical data at the XXIV Congress of the International Society on Thrombosis and Haemostasis (ISTH) in July 2013. Results showed that ALN-AT3 achieves rapid, dose-dependent, and durable knockdown of AT in rodents and non-human primates. In non-human primates, weekly subcutaneous doses as low as 0.125 mg/kg led to a 50% knockdown of AT, while weekly doses of 0.50 mg/kg led to approximately 90% knockdown. In addition, ALN-AT3 administration was found to normalize thrombin generation and improve hemostasis in hemophilia mice and fully correct thrombin generation in a non-human primate (NHP) hemophilia “inhibitor” model. More recently, at the 55th Annual Meeting of the American Society of Hematology (ASH) in December 2013, Alnylam presented pre-clinical results showing that repeat administration of ALN-AT3 was well tolerated in Hemophilia A (HA) mice, with no adverse findings up to dose levels 200 times greater than those required to achieve 50% AT knockdown. Results from these studies also demonstrated that ALN-AT3 administration achieved complete correction of the activated Partial Thromboplastin Time (aPTT) - an ex vivo measure of blood coagulation that is significantly prolonged in hemophilia - in HA mice. Collectively, the company believes these data suggest a substantially expanded therapeutic index of AT knockdown in the hemophilia disease condition, and confirm the potential of ALN-AT3 to reset insufficient thrombin generation and improve hemostasis in people with hemophilia.
In early 2014, Alnylam formed a broad multi-product, geographic alliance with Genzyme, a Sanofi company, related to the global development and commercialization of Alnylam's “5x15” and future genetic medicine programs. In the case of ALN-AT3, Genzyme will have the right to opt-in after completion of human proof-of-concept to either co-develop and co-promote with Alnylam in North America and Western Europe - with Genzyme commercializing in the rest of world (ROW) - or to commercialize the product in the ROW. In both circumstances, Alnylam will lead and control development and commercialization in North America and Western Europe. This transaction has been approved by the boards of both companies, and is subject to customary closing conditions and clearances under the Hart-Scott Rodino Antitrust Improvements Act.
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