T-cell costimulation typically occurs in a defined microenvironment that is not recapitulated by agonistic antibody therapy (Abstracts, Heat Biologics, JUN 30, 2016, View Source [SID1234517429]). To deliver such stimulation under more favorable conditions, we investigated whether an allogeneic cell-based vaccine that secreted Fc-OX40L, Fc-ICOSL, or Fc-4-1BBL would activate and expand T cells comparably to systemically administered agonist antibodies. Among these costimulators, locally secreted Fc-OX40L provided superior priming of antigen-specific CD8+ T cells, compared to combinations with OX40 antibodies or vaccine alone. Vaccine-expressed Fc-OX40L also stimulated IFNγ, TNFα, granzyme B, and IL2 by antigen-specific CD8+ T cells similarly to OX40 antibodies, without off-target consequences such as proinflammatory cytokine induction. Vaccine-secreted Fc-OX40L increased CD127+KLRG-1- memory precursor cells during the contraction phase, resulting in improved proliferation upon secondary antigen challenge, as compared to OX40 antibody. A cell-based vaccine co-secreting gp96-Ig and Fc-OX40L led to even more pronounced tumor control, complete tumor rejection, and increased tumor antigen-specific T-cell proliferation, including in TILs, as compared to combinations of gp96-Ig vaccine and OX40 antibodies, in mice with established melanoma or colorectal carcinoma. These data suggest that local modulation of the vaccine microenvironment has unexpected advantages over systemic costimulation with agonistic antibodies, which may simplify the clinical translation of such combination immunotherapies into humans.
On June 30, 2016 OPKO Health, Inc. (NASDAQ:OPK) and Transition Therapeutics Inc. (NASDAQ:TTHI, TSX:TTH) reported the signing of a definitive agreement under which OPKO will acquire Transition Therapeutics, a clinical stage biotechnology company (Press release, Opko Health, JUN 30, 2016, View Source [SID:1234514821]).
Under the terms of the agreement approved by the Boards of Directors of both companies, Transition Therapeutics security holders will receive approximately 6.4 million shares of OPKO common stock. Based on the moving average price of OPKO common stock for the five trading days preceding the signing of the agreement, the transaction is valued at approximately US$60 million, or US$1.55 per share of Transition Therapeutics common stock, based on current outstanding shares. The companies expect the transaction to close during the second half of 2016, subject to approval of Transition Therapeutics stockholders and other customary conditions.
The Transition Therapeutics clinical portfolio includes:
TT401, a once or twice weekly oxyntomodulin for type 2 diabetes and obesity. We believe TT401 to be the most clinically advanced drug candidate among the new class of GLP1-glucagon receptor dual agonists. In a recently completed phase 2 study of 420 patients with type 2 diabetes, subjects receiving the highest dose of TT401 peptide once weekly demonstrated significantly superior weight loss compared with currently approved extended release exenatide and placebo after 12 and 24 weeks of treatment. TT401 also provided a reduction in HbA1c, a marker of sugar metabolism, similar to exenatide at weeks 12 and 24. TT401 strengthens OPKO’s existing pipeline of oxyntomodulin drug candidates for the treatment of type 2 diabetes and obesity. OPKO’s MOD-6031, currently in a phase 1 study, is a once weekly oxyntomodulin with a proprietary delivery system to slowly release the natural oxyntomodulin, which allows the molecule to penetrate the blood brain barrier. The potential of MOD-6031 to interact with CNS, as well as peripheral receptors, is expected to mimic the natural effect of oxyntomodulin for its effects on satiety and weight loss.
TT701 is a once daily oral selective androgen receptor modulator for patients with androgen deficiency. In a 12-week study of 350 male subjects, it resulted in significantly decreased fat mass and increased lean body mass and muscle strength without significantly changing prostate specific antigen levels. The selective and antagonistic properties of TT701 appear to be well suited to provide anabolic therapeutic benefits to specific patient populations, while potentially avoiding, or even reducing, prostate hypertrophy.
ELND005, a neuropsychiatric drug candidate. ELND005 is an orally administered small molecule that has completed phase 2 clinical studies in Alzheimer’s disease and Down syndrome patients.
"This acquisition provides OPKO with two late stage drug candidates, each of which holds exceptional market potential," stated Phillip Frost, M.D., CEO and Chairman of OPKO. "We believe TT401, a once-weekly dual GLP1/Glucagon agonist that recently showed success in a 420-patient phase 2 study, will complement OPKO’s existing oxyntomodulin product candidate (MOD-6031), which may provide enhanced therapeutic benefit through targeted delivery."
Dr. Frost added, "The selective androgen receptor modulator, TT701, could meet an important need in patients who can benefit from its anabolic effects without the risks associated with testosterone products. We believe it fits well with our Claros 1 point-of-care diagnostic products under development for testosterone and PSA, which could serve as companion diagnostics."
"OPKO is ideally positioned to leverage the potential of Transition’s clinical programs and bring these novel therapeutics to market for the benefit of patients," said Tony F. Cruz, Ph.D., CEO and Chairman of Transition Therapeutics, "Further, OPKO has a strong pipeline of products coming to market that can provide future value for Transition Therapeutics stockholders."
About Transition Therapeutics
Transition Therapeutics is a biopharmaceutical development company advancing novel therapeutics for CNS, metabolic diseases and androgen deficiency indications. The company’s wholly-owned subsidiary, Transition Therapeutics Ireland Limited, has two development programs: CNS drug candidate ELND005 for the treatment of Alzheimer’s disease and Down syndrome; and selective androgen receptor modulator drug candidate TT701. Transition’s lead metabolic drug candidate is TT401 for the treatment of type 2 diabetes and accompanying obesity. For additional information about the Company, please visit www.transitiontherapeutics.com.
On June 30, 2016 Merrimack Pharmaceuticals, Inc. (NASDAQ: MACK) reported a newly presented analysis of the Phase 3 NAPOLI-1 data shows patients treated with ONIVYDE (irinotecan liposome injection), also known as "nal-IRI," in combination with fluorouracil (5-FU) and leucovorin, maintain similar baseline quality of life at 12 weeks despite the addition of a second chemotherapeutic agent when compared to 5-FU and leucovorin alone (Press release, Merrimack, JUN 30, 2016, View Source [SID:1234513642]). These findings were presented in an oral session by Dr. Richard Hubner, an investigator on the NAPOLI-1 trial and a Consultant Medical Oncologist at Christie NHS Foundation Trust, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 18th World Congress on Gastrointestinal Cancer in Barcelona, Spain.
Previously reported Phase 3 NAPOLI-1 data demonstrate that the ONIVYDE combination regimen significantly improves overall survival and progression-free survival when compared to 5-FU and leucovorin alone1. ONIVYDE in combination with 5-FU and leucovorin was approved by the U.S. Food and Drug Administration (FDA) in October 2015 for the treatment of patients with metastatic adenocarcinoma of the pancreas whose disease progressed after gemcitabine-based therapy. It is the first and only FDA-approved therapy in this setting and was recently designated category 1 status by the National Comprehensive Cancer Network.
"This quality of life analysis of the NAPOLI-1 data underscores the significant clinical benefit the ONIVYDE regimen provides to a patient population with few treatment options," said Dr. Richard Hubner, investigator on the NAPOLI-1 trial and Consultant Medical Oncologist at Christie NHS Foundation Trust. "Fluorouracil and leucovorin is recognized as a well-tolerated therapy for metastatic pancreatic cancer patients. The addition of ONIVYDE, a second chemotherapeutic agent, to this treatment regimen demonstrated significant improvement in median overall survival, progression-free survival and overall response rate2 with little or no impact on baseline quality of life at 12 weeks, as shown in this analysis. This further supports the growing recognition that the ONIVYDE combination regimen is a clinically beneficial treatment option for metastatic pancreatic cancer patients who have progressed on gemcitabine-based therapy."
Methodology and Results:
Effects of nal-IRI (MM-398) ± 5-fluorouracil on quality of life (QoL) in NAPOLI-1: A phase 3 study in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy (Abstract O-004)
Quality of life was assessed using the European Organization for Research and Treatment of Cancer quality of life core questionnaire, which includes functional scales (physical, role, cognitive, emotional and social), symptom scales (appetite loss, constipation, diarrhea, dyspnea, fatigue, insomnia, nausea and vomiting and pain), and a global health and quality of life scale.
Patients completed the European Organization for Research and Treatment of Cancer quality of life core questionnaire at treatment start, every 6 weeks and 30 days post-follow-up visit. A total of 154 patients (ONIVYDE in combination with 5-FU and leucovorin, n=71; 5-FU and leucovorin, n=83) comprised the population for this analysis. Sixty-nine percent (49/71) of patients in the ONIVYDE combination regimen group and 53% (44/83) in the 5-FU and leucovorin group had evaluable data at 12 weeks. No substantial differences are identified in the percentage of patients exhibiting improved, stable or worsening quality of life in the global health status, functional scale or symptom scale scores between the two study arms. The analysis demonstrates that in the NAPOLI-1 study, evaluable patients treated with the ONIVYDE combination regimen were able to maintain quality of life over 12 weeks and there were no significant differences versus the 5-FU and leucovorin-treated patients in quality of life response despite the addition of a second chemotherapeutic agent.
On June 30, 2016 ArQule, Inc. (Nasdaq:ARQL) reported that preliminary data presented at ESMO (Free ESMO Whitepaper) GI demonstrate evidence of anticancer activity, defined by objective response rate and disease control rate in an ongoing phase 1/2 biomarker driven trial with ARQ 087 in intrahepatic cholangiocarcinoma (iCCA) (Press release, ArQule, JUN 30, 2016, View Source [SID:1234513641]). Activity was observed in patients with FGFR2 genetic alterations. ARQ 087 is a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor (FGFR) family.
The presentation titled "ARQ 087, an Oral Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitor, in Patients with Advanced and/or Metastatic Intrahepatic Cholangiocarcinoma (iCCA)" can be viewed at www.arqule.com/wp-content/uploads/ARQ-087-iCCA-ESMO-GI-2016.pdf.
Preliminary Data Results from Phase 1/2 iCCA Trial with ARQ 087
The data is comprised of 21 patients dosed with ARQ 087, 14 of which presented with FGFR2 genetic alterations and seven of which did not.
Of the 14 iCCA patients with FGFR2 genetic alterations, 12 patients were evaluable.
Among the 12 evaluable patients with FGFR2 genetic alterations, the objective response rate was 25% (three partial responses) and disease control rate was 75% (three partial responses and six patients with stable disease). Patients were evaluated using Standard RECIST (Response Evaluation Criteria in Solid Tumors).
In addition to the three patients with partial responses, three patients had a minor response, defined as a 15-29% tumor reduction. Durable disease control, defined as greater than 16 weeks, was observed in 50% of patients. Progressive disease was the best response in 25% of the patients.
ARQ 087 showed a manageable safety profile with mostly Grade 1 and 2 adverse events.
This data is derived from the phase 1 and 2 portions of the phase 1/2 trial in iCCA.
"Intrahepatic cholangiocarcinoma is a rare liver cancer with a high mortality rate and limited treatment options," said Dr. Brian Schwartz, Head of Research and Development and Chief Medical Officer at ArQule. "There is scientific evidence that this disease can be caused by a number of different genetic alterations, one being FGFR2, thus making the use of precision medicine essential in treating these patients. The data we presented, while preliminary, are very encouraging and offer evidence that ARQ 087 is active in those patients with a FGFR2 genetic alteration. We look forward to concluding the study late in the third quarter of 2016."
The company has been granted orphan drug designation by the U.S. Food and Drug Administration and European Medicine’s Agency for ARQ 087 in this indication.
About Intrahepatic Cholangiocarcinoma
Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC)1. Depending on the anatomic location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA), and extrahepatic (eCCA). iCCA originates from the intrahepatic biliary ductal system and forms an intrahepatic mass. The average age adjusted incidence rate for iCCA is approximately one in 100,000 per year in the United States and Europe2,3.
About FGFR and ARQ 087
ARQ 087 is a multi-kinase inhibitor designed to preferentially inhibit the fibroblast growth factor receptor ("FGFR") family with demonstrated efficacy in FGFR2 genetic alterations. The FGFR pathway is disrupted in several ways in human cancer, thus providing numerous therapeutic targets for an inhibitor of this pathway. ARQ 087 has demonstrated in vivo inhibition of tumor growth and downstream signaling in tumors whose growth is driven by FGFR targets.
Signals of single agent activity with this drug were observed in phase 1a testing. Phase 1b expansion cohorts with ARQ 087 include patients with cholangiocarcinoma and adrenocortical tumors, as well as those with FGFR translocations, amplifications and mutations. Clinical development of ARQ 087 has advanced into phase 2 for intrahepatic cholangiocarcinoma (iCCA) following the observation of two confirmed responses in this patient population in the phase 1 portion of the program.
On June 30, 2016 Leap Therapeutics, an immuno-oncology company, reported updated results from a clinical trial of its lead candidate DKN-01, a monoclonal antibody against the Dickkopf-1 (DKK1) protein (Press release, Leap Therapeutics, JUN 30, 2016, View Source [SID:1234513644]). Data from the trial demonstrated clinical activity in patients with relapsed or refractory cancer of the esophagus or gastro-esophageal junction (GEJ), indications with few or no approved therapies.
In Study Parts A and B, the dose escalation and dose confirmation phases, eight of 22 patients achieved a partial response (“PR”) per RECIST v1.1. Preliminary data indicated an overall progression-free survival (“PFS”) of 3.9 months, and 6.2 months and 3.2 months for patients with adenocarcinoma (AC) and squamous cell carcinoma (ESCC), respectively. DKN-01 was generally well tolerated. The data were presented today by Deva Mahalingam, M.D., of the University of Texas Health Science Center and an investigator on the trial, at the European Society for Medical Oncology’s World Congress on Gastrointestinal Cancer in Barcelona.
“Relapsed or refractory esophageal carcinomas are typically highly invasive and have a poor prognosis. The clinical activity we have seen to-date has been promising and is greater than expected compared to historical controls,” commented Dr. Mahalingam.
“The results from the study of DKN-01 in combination with paclitaxel are promising. We look forward to the data from the next phases of this trial and further interrogating the activity of DKN-01 in additional trials going forward,” commented David Ryan, M.D. of Massachusetts General Hospital and an investigator on the trial.
Results from Part A and Part B of the P102 Study of DKN-01 in Esophageal Carcinoma:
Twenty-seven patients with cancer of the esophagus or GEJ were enrolled in Parts A and B; 22 were evaluable per the protocol at the date of this analysis
The combination of DKN-01 and paclitaxel was safe and well tolerated at all doses with no treatment related severe adverse events (SAEs) related to either DKN-01 or paclitaxel
The most frequently reported DKN-01-related AEs were fatigue, diarrhea, and decreased appetite
Eight patients (36.4%) had PRs and nine (40.9%) patients had best responses of Stable Disease, with a total disease control rate of 77%
Durable responses with patients remaining on therapy for 12+ months
Two long-term patients (one AC, one ESCC) with PRs continue on DKN-01 monotherapy with continued deepening of response as a single agent
Preliminary overall PFS for patients with adenocarcinoma of the esophagus or GEJ of 6.2 months and patients with squamous cell carcinoma of 3.2 months
About Esophageal Cancer
Esophageal cancer is an aggressive disease with 17,000 patients diagnosed annually in the US and 400,000 diagnosed worldwide. Over 50% of patients are diagnosed with advanced disease, with an expected overall survival limited to 8-12 months. There are no approved therapies for relapsed or refractory disease of the esophagus, with the majority of patients receiving single-agent paclitaxel as a 2ND-line therapy. While studies of efficacy are limited, response rates have historically ranged between 5-15% and progression-free survival of 1-3 months.
DKN-01 is a humanized IgG4 monoclonal antibody with neutralizing activity against the Dickkopf-1 (DKK1) protein. DKK1 expression in cancer tissue has been associated with poor prognosis in multiple cancers, and recent literature suggests DKK1 has a critical role in mediating an immuno-suppressive tumor microenvironment. DKN-01 is currently being studied in clinical trials in esophageal cancer and cholangiocarcinoma. DKN-01 additionally demonstrated single agent activity in NSCLC in a Phase 1 dose escalation study that was presented at ASCO (Free ASCO Whitepaper) 2014.?