Out of the starting gate

A roundup of clinical trial startups and initial breakthroughs

Jeffrey Bouley
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CAMBRIDGE, Mass.—BeiGene Ltd., a clinical-stage biopharmaceutical company developing molecularly targeted and immuno-oncology drugs for the treatment of cancer, in late January announced the initiation of a global, randomized Phase 3 trial of its investigational Bruton’s tyrosine kinase (BTK) inhibitor BGB-3111 in patients with Waldenström’s macroglobulinemia (WM). The study is designed to determine whether the quality of response with BGB-3111 in WM is superior to that of ibrutinib, the currently approved BTK inhibitor. Approximately 170 patients are expected to be enrolled at clinical sites in North America, Europe, Australia and New Zealand.
“The recently presented data from the Phase 1 study of BGB-3111 in B cell malignancies demonstrated a high response rate in patients with WM, including a very good partial response rate of 34 percent. In addition, no cases of disease progression have been observed, and only one patient out of the 45 enrolled at the time of the data cutoff discontinued treatment for any reason,” said Dr. Constantine Tam, at Peter MacCallum Cancer Centre in Australia and a member of the steering committee of the Phase 3 study. “These data, reflective of BGB-3111’s demonstrated ability to produce complete and continuous BTK inhibition in both blood and lymph nodes, are sufficiently encouraging to warrant a superiority comparison with ibrutinib, the current treatment standard for WM.”
“BGB-3111 is the first BTK inhibitor to be evaluated in a head-to-head Phase 3 trial designed to establish superiority over ibrutinib. In addition to WM, we will continue to develop BGB-3111 broadly in B cell malignancies and also look forward to initiating pivotal studies for BGB-3111 in China in the first half of 2017,” commented Dr. Jane Huang, chief medical officer for hematology at BeiGene.
The China news didn’t take long to follow, with March 2 bringing an announcement of the dosing of the first patient in a pivotal clinical trial of BGB-3111 in Chinese patients with relapsed or refractory mantle cell lymphoma (MCL). 
“We are pleased to announce the beginning of the first pivotal clinical trial of BGB-3111 in China. BGB-3111 has been under clinical investigation since August 2014, and over 300 patients with various B cell malignancies have been treated with BGB-3111 in Australia, New Zealand, the United States, Korea and China,” commented John V. Oyler, BeiGene’s founder, CEO and chairman.
Read on for more news of early trial news and trial initiations.
Georgetown trial of nilotinib in Alzheimer’s disease begins
WASHINGTON, D.C.—Late January saw a clinical trial to examine the effect of nilotinib on clinical outcomes and biomarkers in people with mild to moderate Alzheimer’s disease open at Georgetown University Medical Center (GUMC). This is a Phase 2, randomized, double-blinded, placebo-controlled study to evaluate the impact of low doses of the cancer drug nilotinib (Tasigna). 
The rationale for using nilotinib is based on laboratory and clinical research conducted by the Georgetown Translational Neurotherapeutics Program (TNP). Nilotinib appears to aid in the clearance of accumulated beta-amyloid (Abeta) plaques and Tau tangles in the brain. Both are hallmarks of Alzheimer’s disease. Nilotinib appears to penetrate the blood-brain barrier and turn on the “garbage disposal” machinery inside neurons (a process known as autophagy) to clear the Tau, Abeta and other toxic proteins.
“In a 2015 proof-of-concept study at Georgetown, patients with Parkinson’s disease or dementia with Lewy bodies were treated with nilotinib. As my colleagues reported, those who completed the study had a reversal in disease progression, observed both clinically and in key biomarkers—the same biomarkers seen in Alzheimer’s,” explains Dr. Scott Turner, medical co-director of the TNP, who will serve as principal investigator for the study. “But even before the Parkinson’s study, research in the laboratory strongly supported studying this drug in people with Alzheimer’s. The promising results of the Parkinson’s study give an even stronger rationale.”
Cx611 in severe sepsis
LEUVEN, Belgium—TiGenix NV, a biopharmaceutical company focused on developing and commercializing novel therapeutics from its proprietary platforms of allogeneic expanded stem cells, announced at the end of January that the first patient had been enrolled and treated in its Phase 1b/2a clinical trial for Cx611—an intravenous injection of allogeneic expanded adipose-derived stem cells—in the treatment of severe sepsis in community-acquired pneumonia.
The SEPCELL trial is a multicenter, international clinical trial to evaluate Cx611's safety profile at 90 days, the reduction in the duration of mechanical ventilation and/or vasopressors, as well as the overall survival rate, clinical cure and other efficacy-related endpoints. 
“Patients suffering from severe sepsis are in need of new therapies; however, the development of new drugs has proven to be difficult due to the variety of patient profiles. We have built on lessons learned from past experiences and designed the SEPCELL trial with strict inclusion and exclusion criteria within a very specific patient population, therefore addressing one of the major pitfalls of previous clinical trials in this indication,” said Prof. Pierre-François Laterre, principal investigator within the SEPCELL project and chief of the Intensive Care Service at Cliniques Universitaires Saint-Luc of Catholic University in Belgium.
Confronting advanced cervical cancer
PRINCETON, N.J.—Advaxis Inc., a clinical-stage biotechnology company developing cancer immunotherapies, has announced that the first patient has been enrolled and dosed in its AIM2CERV (Advaxis IMmunotherapy 2 prevent CERVical recurrence) trial, the only company-sponsored global Phase 3 trial enrolling patients with advanced-stage cervical cancer.
The primary objective of the trial is to compare disease-free survival in patients receiving axalimogene filolisbac to patients receiving placebo, with secondary objectives including overall survival, safety and tolerability. 
“While some women with cervical cancer are considered cancer-free after chemotherapy and radiation, a significant number will experience a recurrence of the disease that is often more aggressive and results in a poor prognosis. The global reach of the AIM2CERV study is intended to determine whether treatment with axalimogene filolisbac after chemotherapy and radiation can help prevent or delay such recurrences,” said Daniel J. O’Connor, president and CEO of Advaxis. “Following recently published data that revealed cervical cancer mortality rates may be exponentially higher in African-American women and significantly underestimated for all women, coupled with research last year showing fewer than half of patients with locally advanced cervical cancer receive standard-of-care therapy, the need for new treatment options is more clear now than ever.”
Bardoxolone methyl, CKD and Alport syndrome
IRVING, Texas—In late-February, Reata Pharmaceuticals Inc. announced the initiation of patient screening in a Phase 2/3 trial to evaluate bardoxolone methyl (bard) in patients with chronic kidney disease caused by Alport syndrome. The purpose of this study is to determine the safety and efficacy of bard in Alport syndrome patients and to determine if Alport syndrome patients experience improvements in kidney function similar to those observed in multiple previous trials of bard in patients with other forms of CKD. Reata expects data from the Phase 2 portion of the trial to be available, and to decide on entering the Phase 3 portion, by year-end 2017.
The Alport Syndrome Foundation’s Executive Director Gina Parziale said, “As there are currently no FDA approved treatments for those with Alport Syndrome, the Alport Syndrome Foundation encourages the development of therapies that will delay or prevent the need for dialysis and transplantation.  We are grateful to Reata for engaging us in this process and for recognizing the crucial role of the patient perspective.”
“Based on our extensive clinical experience with bardoxolone methyl in patients with diabetic CKD, as well as in our ongoing Phase 2 and Phase 3 trials for bardoxolone in other orphan diseases, we hope to demonstrate that bardoxolone methyl can serve as a meaningful new treatment option for patients with Alport syndrome,” said Warren Huff, Reata’s CEO and president.
Going after osteoarthritis of the knee
BURLINGTON, Mass.—Flexion Therapeutics Inc. recently reported it has enrolled the first patient in a clinical trial to evaluate the safety of repeat administration of its investigational drug candidate Zilretta (also known as FX006) in patients with osteoarthritis (OA) of the knee. The open-label study is expected to enroll approximately 200 patients at up to 20 clinical sites in the United States. 
“This trial is an important part of our ongoing clinical investigation of Zilretta in individuals who are confronting pain from OA of the knee,” said Dr. Michael Clayman, president and CEO of Flexion. “Previous clinical trials evaluating a single injection suggest Zilretta has an acceptable safety profile with side effects similar to placebo and active-control, and we look forward to reporting the results from the repeat administration study when the trial reads out in 2018.”
The primary endpoint of the trial is overall safety and general tolerability of repeat administration of Zilretta in patients with symptomatic OA of the knee. 

Jeffrey Bouley

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