Out of the starting gate

A roundup of clinical trial startups and initial breakthroughs

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BURLINGTON, Mass.—Flexion Therapeutics Inc. in late April reported it had enrolled the first patient in a clinical trial to assess the effects of its lead drug candidate, Zilretta (also known as FX006), on blood glucose levels in approximately 36 adults with osteoarthritis (OA) of the knee who also have type 2 diabetes.
“This clinical trial in patients with OA of the knee will assess whether Zilretta, an investigational intra-articular sustained-release steroid (triamcinolone acetonide, or TCA) treatment, can avoid the substantial elevations in blood glucose levels that often occur in diabetic patients treated with immediate-release TCA,” said Dr. Michael Clayman, Flexion Therapeutics’ president and CEO. “Following an IA injection of immediate-release TCA, plasma concentrations of TCA rise rapidly to levels that may cause hyperglycemia in this patient population. Because peak plasma concentrations after a Zilretta injection, as demonstrated in clinical trials, are more than an order of magnitude lower than with immediate-release TCA, we believe it’s reasonable to expect that injections of Zilretta may avoid these increases in blood sugar. If the data support this expectation, Zilretta could confer an important safety advantage for the 750,000 people in the U.S. with knee OA who have diabetes and receive IA corticosteroid injections annually.”
Zilretta was designed using proprietary microsphere technology and is intended to provide localized and long-lasting pain relief over a period of months while minimizing systemic exposure and avoiding serious side effects common to oral therapies prescribed for OA pain.
Following is news of other companies reporting trial starts and very early trial information:
Loxo Oncology announces first pediatric response to LOXO-101
STAMFORD, Conn.—Loxo Oncology Inc., a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, in mid-April announced the publication of a manuscript in the online edition of the journal Pediatric Blood and Cancer describing a confirmed RECIST partial response in the first patient enrolled in the recently opened pediatric Phase 1 dose-escalation trial of LOXO-101.
The peer-reviewed manuscript describes a 16-month old female patient with advanced infantile fibrosarcoma (IFS), a rare pediatric cancer. Genetic testing revealed an ETV6-NTRK3 fusion, which is frequently found in IFS. Following multiple unsuccessful surgeries and courses of chemotherapy, the patient was enrolled in the pediatric Phase 1 trial of LOXO-101, which employs a liquid formulation of the drug designed specifically for pediatric patients unable to swallow capsules.
“Most infants and children with infantile fibrosarcoma can be cured through surgery and chemotherapy. When our patient’s disease progressed in spite of these treatments, the only other viable treatment option was radiation therapy, which posed devastating long-term consequences for our patient,” said Dr. Ramamoorthy Nagasubramanian, first author of the manuscript and division chief of pediatric hematology-oncology at Nemours Children's Hospital, as well as an assistant professor of pediatrics at the University of Central Florida College of Medicine. “The rapid, dramatic reduction in tumor size shows early but promising evidence of the potential for LOXO-101 to provide significant benefit for pediatric patients harboring NTRK gene fusions.”

Phase 3 trial of enzalutamide initiated in hormone-sensitive prostate cancer
SAN FRANCISCO & TOKYO—Medivation Inc. and Astellas Pharma Inc. in late March announced that the ARCHES Phase 3 registrational trial, which will evaluate the efficacy and safety of enzalutamide with androgen deprivation therapy (ADT) vs. placebo with ADT in metastatic hormone-sensitive prostate cancer (mHSPC) patients, has been initiated and the first patient has been randomized.
Androgen deprivation therapy, which reduces the levels of male hormones, is the standard of care for patients with mHSPC. The ARCHES trial will investigate whether the addition of enzalutamide to ADT may benefit this patient population compared to ADT alone.

Celldex initiates Phase 1/2 study of glembatumumab vedotin
HAMPTON, N.J.—Celldex Therapeutics Inc. announced April 12 that it had initiated an open-label Phase 1/2 safety and tolerability study of glembatumumab vedotin in patients with unresectable stage IIIB or IV, gpNMB-expressing, advanced or metastatic squamous cell carcinoma (SCC) of the lung, who have progressed on prior platinum-based chemotherapy. Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate (ADC) that targets gpNMB, a protein overexpressed by multiple tumor types, including SCC of the lung, where approximately 85 percent of patients overexpress the marker.
“While checkpoint inhibitor therapy has been an important development for patients with squamous cell lung cancer, the majority of patients still require new, effective treatment options—especially targeted therapies,” said Dr. Thomas Davis, executive vice president and chief medical officer of Celldex. “gpNMB, the target of glembatumumab vedotin, is strongly expressed in the vast majority of squamous cell lung cancers. Glembatumumab vedotin has consistently induced notable response rates in other difficult-to-treat cancers that overexpress gpNMB. We hope to elicit similar activity in squamous cell carcinoma and look forward to completing this study.”

Inovio partners will begin hepatitis C trial
PLYMOUTH MEETING, Pa.—Inovio Pharmaceuticals Inc. announced recently its immunotherapy for hepatitis C (INO-8000) will be evaluated in a Phase 1 trial in chronically infected patients who are not receiving other hepatitis C virus (HCV) treatments. The study will enroll patients who are in the early stages of chronic HCV infection to determine the therapy’s ability to decrease and potentially eliminate HCV viral load, measure HCV-specific immune responses and durability of these immune responses, and evaluate safety and tolerability. In this dose-escalation study INO-8000 will be combined with increasing doses of DNA-based IL-12 (INO-9012), an immune activator, which in previous studies has been shown to increase the therapeutic immune response to DNA immunotherapies.

ABIVAX cleared in Spain for Phase 2a clinical trial of ABX464
PARIS—ABIVAX announced in April that its second Phase 2a study with ABX464, a first-in-class drug candidate for the treatment of patients with HIV/AIDS, has been approved by regulatory and ethics committees in Spain. Additional approvals in Belgium and France are expected in the near future.
ABX464 is an orally available small-molecule therapeutic candidate that is currently in mid-stage clinical testing in HIV patients. It works by inhibiting HIV replication through a novel mechanism (i.e. the modulation of RNA splicing) that may not be vulnerable to the development of resistance by the HIV virus, and may have a sustained effect in patients.

Cytokinetics begins Phase 2 trial of omecamtiv mecarbil in Japanese subjects
SOUTH SAN FRANCISCO, Calif.—Early April saw Cytokinetics Inc. announce the start of a double-blind, randomized, placebo-controlled, multicenter Phase 2 clinical trial to evaluate the safety, pharmacokinetics and efficacy of omecamtiv mecarbil in Japanese subjects with heart failure and reduced ejection fraction. Omecamtiv mecarbil, a novel investigational cardiac myosin activator that increases cardiac contractility, is being developed by Amgen in collaboration with Cytokinetics for the potential treatment of heart failure.
“Advancing the clinical investigation of omecamtiv mecarbil in Japan represents an important step for our novel cardiac myosin activator program,” said Dr. Fady I. Malik, Cytokinetics' executive vice president of research and development. “Omecamtiv mecarbil holds promise as a potential new treatment for patients with heart failure, and we look forward to learning about its clinical application in Japanese patients.”

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