Gilead Announces Topline Data From Phase 3 STELLAR-4 Study of Selonsertib in Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)

Gilead Sciences, Inc. (Nasdaq: GILD) announced that STELLAR-4, a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of selonsertib, an investigational, once-daily, oral inhibitor of apoptosis signal-regulating kinase 1 (ASK1), in patients with compensated cirrhosis (F4) due to nonalcoholic steatohepatitis (NASH), did not meet the pre-specified week 48 primary endpoint of a ≥ 1-stage histologic improvement in fibrosis without worsening of NASH.

 

In the study of 877 enrolled patients who received study drug, 14.4 percent of patients treated with selonsertib 18 mg (p=0.56 vs. placebo) and 12.5 percent of patients treated with selonsertib 6 mg (p=1.00) achieved a ≥ 1-stage improvement in fibrosis according to the NASH Clinical Research Network (CRN) classification without worsening of NASH after 48 weeks of treatment, compared with 12.8 percent of patients who received placebo. Selonsertib was generally well-tolerated and safety results were consistent with prior studies.

“While we are disappointed that the STELLAR-4 study did not achieve its primary endpoint, we remain committed to advancing therapies for patients with advanced fibrosis due to NASH, where there is a significant unmet need for effective and well-tolerated treatments. Gilead has a long-term commitment and proven track record of addressing significant challenges in the field of liver diseases. Data from this large study of patients with compensated cirrhosis due to NASH, including the extensive set of biomarkers collected, will further advance our understanding of the disease and inform our broader NASH development programs,” said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead. “We are grateful to the patients and investigators who participated in the STELLAR-4 study, and we now await the upcoming results from the Phase 3 STELLAR-3 trial of selonsertib in patients with bridging fibrosis (F3) due to NASH and the Phase 2 ATLAS combination trial of selonsertib, cilofexor (GS-9674) and firsocostat (GS-0976) in patients with advanced fibrosis due to NASH later this year.”

Further in-depth analysis of the findings is ongoing and the data will be submitted to an upcoming scientific conference. Gilead will work with the Data Monitoring Committee and investigators to conclude the STELLAR-4 study in a manner consistent with the best interests of each patient.

Selonsertib, cilofexor and firsocostat, alone or in combination, are investigational compounds and are not approved by the U.S. Food & Drug Administration (FDA) or any other regulatory authority. Safety and efficacy have not been established for these agents.

About Selonsertib and the STELLAR-4 Study

Selonsertib is an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis (cell death) and fibrosis in settings of oxidative stress. Oxidative stress can be increased in many pathological conditions including liver diseases such as NASH.

The STELLAR-4 study is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of selonsertib in patients with compensated cirrhosis (F4) due to NASH. Eligible adults ages 18 to 70 years were randomized and received selonsertib 18 mg (n=354), selonsertib 6 mg (n=351) or placebo (n=172) for up to 240 weeks. Either selonsertib or placebo is being administered orally once daily. The primary endpoints of the study are a composite of the proportion of patients who achieve a ≥ 1-stage improvement in fibrosis according to the NASH CRN classification without worsening of NASH at week 48 and event-free survival at week 240 as assessed by time to the first clinical event. Further information about the clinical study can be found at www.clinicaltrials.gov.

https://pubchem.ncbi.nlm.nih.gov/compound/Selonsertib#section=2D-Structure

Theravance Biopharma Announces First Patient Dosed in Registrational Phase 3 Study of Ampreloxetine (TD-9855) for the Treatment of Symptomatic Neurogenic Orthostatic Hypotension

 Theravance Biopharma, Inc. (NASDAQ: TBPH) ("Theravance Biopharma" or the "Company")  announced dosing of the first patient in a registrational Phase 3 clinical trial of ampreloxetine (TD-9855) in patients with symptomatic neurogenic orthostatic hypotension (nOH). Ampreloxetine is an investigational, once-daily norepinephrine reuptake inhibitor (NRI) in development for the treatment of patients with symptomatic nOH.

The Phase 3 study is a four-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy, safety and tolerability of ampreloxetine in approximately 188 patients with symptomatic nOH caused by primary autonomic failure associated with multiple system atrophy (MSA), Parkinson's disease (PD) and pure autonomic failure (PAF). Patients will be randomized to receive a single 10 mg dose of ampreloxetine or placebo once daily for four weeks. The primary endpoint of the study is change from baseline in dizziness severity, as measured by Orthostatic Hypotension Symptom Assessment (OHSA) Question #1 (OHSA #1, a measure of dizziness, lightheadedness or the sensation of being about to black out) at four weeks for ampreloxetine as compared to placebo. The study will evaluate additional efficacy assessments, as well as safety and tolerability measures.

"Given the limitations of currently available therapeutic options, we recognize a significant opportunity exists for a potentially safe and durable treatment for nOH. Positive four-week results achieved in our Phase 2 study provide the basis for advancing ampreloxetine into this registrational Phase 3 program," said Brett Haumann, MD, chief medical officer at Theravance Biopharma. "We are pleased to begin 2019 with this milestone, and in the near term we also anticipate dosing the first patient in the Phase 2b/3 study of TD-1473, our gut-selective JAK inhibitor, in patients with ulcerative colitis."

Theravance Biopharma previously announced positive four-week results from a Phase 2 clinical trial of ampreloxetine in patients with nOH. Findings showed that a majority of patients enrolled in the study's single ascending dose portion demonstrated durable improvements in nOH symptom severity as measured by OHSA #1. Patients treated in the extension phase of the study showed a mean symptom improvement of 2.4 points at four weeks. Importantly, mean symptom improvement was greatest (3.8 points) in nOH patients who reported dizziness symptoms (OHSA #1 > 4) at baseline, a pre-defined regulatory and clinical threshold that will be used to enroll patients in Phase 3. Additionally, ampreloxetine consistently increased systolic blood pressure (SBP), including clinically meaningful increases in standing SBP at the three-minute assessment at all time points on all weekly clinic visits. There were no drug-related serious adverse events reported, and ampreloxetine was generally well tolerated in the study.

http://www.dcchemicals.com/product_show-DC11076.html

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Theravance Biopharma Announces First Patient Dosed in Registrational Phase 3 Study of Ampreloxetine (TD-9855) for the Treatment of Symptomatic Neurogenic Orthostatic Hypotension 

FDA Orphan Drug Designation to Amplyx Pharmaceuticals for APX001 for Treatment of Cryptococcosis

Amplyx Pharmaceuticals, a company developing first-in-class products for life-threatening infections, announced  that the U.S. Food and Drug Administration (FDA) Office of Orphan Product Development has granted orphan drug designation to APX001, the company’s lead drug candidate, for treatment of cryptococcosis.

Orphan drug designation qualifies APX001 for seven years of market exclusivity in the U.S. upon FDA approval of a new drug application (NDA) for the orphan designated indications. APX001 had previously received orphan drug designation for the treatment of invasive candidiasis, invasive aspergillosis, coccidioidomycosis, and rare mold infections caused by Scedosporium spp., Fusarium spp., and Mucorales fungi (including Mucor spp., and Rhizopus spp.). In addition to orphan designations, FDA had previously granted Qualified Infectious Disease Product (QIDP) designation for APX001 for treatment of cryptococcosis, invasive candidiasis, invasive aspergillosis, and coccidioidomycosis. QIDP provides significant development incentives including eligibility for Fast Track designation, priority review and when combined with orphan drug designation, a total of twelve years of marketing exclusivity.

“Orphan and QIDP designations highlight the potential for APX001 to address unmet needs of patients with rare, life-threatening infections,” said Ciara Kennedy, Ph.D., President and Chief Executive Officer of Amplyx. “And with the FDA’s recent addition of cryptococcal meningitis to its list of neglected tropical diseases, Amplyx has the potential to obtain a valuable Tropical Disease Priority Review Voucher from the FDA, creating additional value for Amplyx and its stakeholders.”

Cryptococcosis is an infectious disease of the lungs or central nervous system (the brain or spinal cord) caused by the fungus Cryptococcus (either Cryptococcus neoformans or Cryptococcus gattii), which is typically found in the environment and inhaled. Brain infections due to the fungus Cryptococcus are called cryptococcal meningitis. Infection is most often seen in people with a weakened immune system, including those who are infected with HIV/AIDS, take high doses of corticosteroid medicines, have had an organ transplant, are receiving immune suppressing therapies for cancer or other diseases, or have Hodgkin’s disease.

“While antiretroviral therapy has successfully extended the lifespan of HIV patients, cryptococcal meningitis remains a leading cause of death in HIV patients, particularly in low and middle-income countries,” said Michael Hodges, MD, Chief Medical Officer of Amplyx. “The standard therapy of intravenous amphotericin B plus flucytosine requires inpatient hospitalization and has been known to cause significant side effects including anemia and kidney toxicity. APX001, Amplyx’s first-in-class antifungal agent, in combination with fluconazole, has the potential to be a transformational life-saving, once daily, all oral treatment for cryptococcal meningitis.”

http://www.probechem.com/products_APX001.aspx

Researchers find clues that depression may speed brain aging

In continuation of my updates on depression and its causes

Memory and thinking skills naturally slow with age but now scientists are peeking inside living brains to tell if depression might worsen that decline—and finding some worrisome clues. Depression has long been linked to certain cognitive problems, and depression late in life even may be a risk factor for the development of Alzheimer's. Yet how depression might harm cognition isn't clear.

One possibility: Brain cells communicate by firing messages across connections called synapses. Generally, good cognition is linked to more and stronger synapses. With cognitive impairment, those junctions gradually shrink and die off. But until recently, scientists could count synapses only in brain tissue collected after death.

Yale University scientists used a new technique to scan the brains of living people—and discovered that patients with depression had a lower density of synapses than healthy people the same age.

The lower the density, the more severe the depression symptoms, particularly problems with attention and loss of interest in previously pleasurable activities, Yale neuroscientist Irina Esterlis said Thursday at a meeting of the American Association for the Advancement of Science. She wasn't studying just seniors but a range of ages including people too young for any cognitive changes to be obvious outside of a brain scan—on the theory that early damage can build up.

"We think depression might be accelerating the normal aging," she said.

Her studies so far are small. To prove if depression really worsens that decline would require tracking synaptic density in larger numbers of people as they get older, to see if and how it fluctuates over time in those with and without depression, cautioned Jovier Evans, a staff scientist at the National Institute on Mental Health.

Esterlis is planning a larger study to do that. It's delicate research. Volunteers are injected with a radioactive substance that binds to a protein in the vesicles, or storage bins, used by synapses. Then during a PET scan, areas with synapses light up, allowing researchers to see how many are in different regions of the brain.

Esterlis said there are no medications that specifically target the underlying synapse damage.

But other brain experts said the preliminary findings are a reminder of how important it is to treat depression promptly, so people don't spend years suffering.

"If your mood isn't enough to make you go and get treated, then hopefully your cognition is," said Dr. Mary Sano, who directs the Mount Sinai Alzheimer's Disease Research Center in New York and wasn't involved in the new research.

Still, she cautioned that normal cognitive aging is a complicated process that involves other health problems, such as heart disease that slows blood flow in the brain. It might be that depression, rather than worsening synaptic decline, just makes it more obvious, Sano noted.

With depression "at any age, there's a hit on the brain. At an older age the hit may be more visible because there may already be some loss," she explained.

Indeed, another way the brain ages: The blood-brain barrier, which normally protects against infiltration of damaging substances, gradually breaks down, Daniela Kaufer of the University of California, Berkeley, told the AAAS meeting. That triggers inflammation, setting off a cascade that can cause cognitive impairment. Her lab found a specific molecular culprit and is developing, in studies with mice, a way to block the inflammatory damage.

The University of Toronto's Etienne Sibille is developing a compound to target yet another piece of the puzzle, brain receptors that are impaired with both aging and depression. Mouse studies showed it could reverse stress-induced memory loss, he said. Any human testing is at least several years away.

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Researchers find clues that depression may speed brain aging

Statins Help the Heart, No Matter What Your Age

Cholesterol-lowering statins are already known to help cut heart risks for seniors and the middle-aged. Now, research confirms the meds can also help people aged 75 and older.

"Statin therapy has been shown to prevent cardiovascular disease in a wide range of people, but there has been uncertainty about its efficacy and safety among older people," said lead investigator Anthony Keech. He's a professor of medicine, cardiology and epidemiology at the University of Sydney in Australia.

He and colleagues at the University of Oxford in England analyzed the findings of 28 large clinical trials of statins. The trials involved nearly 187,000 people in six age groups: younger than 55; 55 to 60; 60 to 65; 65 to 70; 70 to 75; and older than 75.

"Our study summarized all the available evidence from major trials to help clarify this issue. We found that there were significant reductions in major vascular events in each of the six age groups considered, including patients [who were] aged over 75 at the start of treatment," Keech said in an Oxford news release.

Major vascular events included heart attack, stroke and procedures to clear clogged arteries.

"Statin therapy appears to be just as effective in people aged over 75 years as it is in younger people," study co-investigator Jordan Fulcher said in the news release. Fulcher is a cardiovascular research fellow at the University of Sydney.

"We have definitive evidence that statins benefit older people who have suffered a heart attack or stroke. Fewer healthy older people were represented in these trials, so more information in this group of people would help confirm the same benefits that we see in our overall trials population," he said.

Fulcher noted that a new randomized trial in Australia is exploring whether statins prolong disability-free survival in a healthy population.

The risk of heart attacks and strokes rises sharply with age, yet statins are not used as widely in older people as they should be, study co-investigator Colin Baigent said in the news release. He's director of Oxford's Medical Research Council Population Health Research Unit.

"Since the risk of heart attack and stroke increases with age, the potential benefits are likely to be even greater for older people," he said.

"Therefore, there is a need to ensure that patients at risk of cardiovascular disease due to their age are offered statin therapy where there is good reason to believe that it will be beneficial," Baigent said.

Anyone with concerns about whether statin therapy is right for them should discuss it with their health care provider, he added.

Sunovion Receives Complete Response Letter from FDA for Apomorphine Sublingual Film (APL-130277)

 Sunovion Pharmaceuticals Inc. (Sunovion) announced today that the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) for the New Drug Application (NDA) for apomorphine sublingual film (APL-130277) to treat OFF episodes (the re-emergence or worsening of Parkinson’s symptoms otherwise controlled by medications) experienced by people living with Parkinson’s disease (PD).

Upon review of the application, the FDA determined that it was unable to approve the apomorphine sublingual film NDA in its present form. The Agency requested additional information and analyses, but no new clinical studies are required.

“OFF episodes are a common and challenging part of Parkinson’s disease with few existing treatment options,” said Antony Loebel, M.D., Executive Vice President and Chief Medical Officer at Sunovion, Head of Global Clinical Development for Sumitomo Dainippon Pharma Group. “Sunovion remains committed to working with the FDA to address its requests so that we can bring apomorphine sublingual film to patients as expeditiously as possible.”

About Apomorphine Sublingual Film (APL-130277)

APL-130277, a novel formulation of apomorphine and a dopamine agonist, is being developed for the on-demand management of OFF episodes associated with Parkinson’s disease (PD). Apomorphine is currently FDA approved for the acute, intermittent treatment of hypomobility, “OFF” episodes (“end-of-dose wearing OFF” and unpredictable “ON/OFF” episodes) associated with advanced PD, and it is currently available in the U.S. as a subcutaneous injection. APL-130277 is intended to rapidly convert people living with PD from the OFF to the ON state and has been studied for treatment of motor OFF episodes up to five times per day and no sooner than two hours from the previous dose. APL-130277 has not been approved by the FDA. In October 2016, Sunovion acquired Cynapsus Therapeutics Inc. along with its product candidate APL-130277. The Michael J. Fox Foundation funded in part two Phase I trials of APL-130277 – a comparative biostudy in healthy volunteers and a dosing study in people with Parkinson's disease.

Alkermes Receives Complete Response Letter From U.S. Food and Drug Administration for ALKS 5461 New Drug Application

In continuation f my update on ALKS 5461

 Alkermes plc (Nasdaq: ALKS) announced that it received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding its New Drug Application (NDA) for ALKS 5461 for the adjunctive treatment of major depressive disorder (MDD). 

The CRL states that the FDA is unable to approve the ALKS 5461 NDA in its present form and is requesting additional clinical data to provide substantial evidence of effectiveness of ALKS 5461 for the adjunctive treatment of MDD. Alkermes plans to meet with the FDA to discuss the contents of the CRL and potential next steps for ALKS 5461. This interaction with the Agency will inform whether there is a viable path forward for the ALKS 5461 program.

The NDA submission for ALKS 5461 was based on results from a clinical efficacy and safety package with data from more than 30 clinical trials and more than 1,500 patients with MDD. Throughout the clinical development program, ALKS 5461 demonstrated a consistent profile of antidepressant activity, safety and tolerability in the adjunctive treatment of MDD.

About ALKS 5461

ALKS 5461 is a proprietary, investigational, once-daily oral medicine that acts as an opioid system modulator and represents a novel mechanism of action for the adjunctive treatment of major depressive disorder (MDD) in patients with an inadequate response to standard antidepressant therapies. ALKS 5461 is a fixed-dose combination of buprenorphine, a partial mu-opioid receptor agonist and kappa-opioid receptor antagonist, and samidorphan, a mu-opioid receptor antagonist.

About Major Depressive Disorder (MDD)

According to the DSM-5® (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), major depressive disorder (MDD) is a condition in which patients exhibit depressive symptoms, such as a depressed mood or a loss of interest or pleasure in daily activities consistently for at least a two-week period, and demonstrate impaired social, occupational, educational or other important functioning. An estimated 16.2 million people in the U.S. suffered from MDD in 2016,1 the majority of whom may not adequately respond to initial antidepressant therapy.

https://en.wikipedia.org/wiki/Buprenorphine/samidorphan

Alkermes Receives Complete Response Letter From U.S. Food and Drug Administration for ALKS 5461 New Drug Application

SK Life Science Announces FDA Acceptance of NDA Submission for Cenobamate, an Investigational Antiepileptic Drug

  SK Life Science, Inc., a subsidiary of SK Biopharmaceuticals Co., Ltd., an innovative biopharmaceutical company focused on developing and bringing to market treatments for central nervous system (CNS) disorders, announced today that the U.S. Food and Drug Administration (FDA) has accepted the filing of its New Drug Application (NDA) for cenobamate. Cenobamate, an investigational antiepileptic drug for the potential treatment of partial-onset seizures in adult patients, is the first molecule discovered and developed from inception through to the submission of an NDA without partnering or out-licensing from a Korean pharmaceutical company. SK life science plans to commercialize cenobamate independently.

The NDA submission is based on data from pivotal trials that evaluated the efficacy and safety of cenobamate. Results from the clinical trial program, which enrolled more than 1,900 patients, have been presented at medical conferences including the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) Annual Meetings.

"The FDA's acceptance of our NDA filing is a critical step toward our goal of introducing a new treatment option for people with uncontrolled epilepsy," said Marc Kamin, M.D., chief medical officer at SK life science. "We look forward to working with the FDA during their review of our data on cenobamate."

Despite the availability and introduction of many new AEDs, overall treatment outcomes for people with epilepsy have not improved in 20 years1 and the CDC states that nearly 60 percent of people with epilepsy are still experiencing seizures, showcasing a great unmet need for patients and their families.2Additionally, while some patients may experience a reduction in seizure frequency with current treatments, they continue to live with seizures.2 The impact of continued seizures can be debilitating and life-altering and the complications of epilepsy can include depression and anxiety, cognitive impairment and SUDEP (sudden unexpected death in epilepsy)

https://pubchem.ncbi.nlm.nih.gov/compound/Cenobamate#section=2D-Structure

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SK Life Science Announces FDA Acceptance of NDA Submission for Cenobamate, an Investigational Antiepileptic Drug

Pain Therapeutics Announces Feedback from Recent Meeting With FDA on Remoxy

     

In continuation of my update on Remoxy ER (oxycodone)

Pain Therapeutics, Inc. (Nasdaq: PTIE), a clinical-stage drug development company, today announced feedback from a meeting held January 31, 2019 with the U.S. Food and Drug Administration (FDA) regarding the drug candidate, Remoxy ER.  Remoxy is the trade name for a new type of abuse-deterrent, extended-release gel formulation of oxycodone (CII) with physical/chemical properties intended to deter abuse.  As previously disclosed, we requested this meeting to resolve disagreement around comments and conclusions made by FDA in 2018 during a regulatory review of a New Drug Application (NDA) for Remoxy.

During this meeting, we learned that i) FDA denies making math errors, material mistakes or misrepresentations during a June 2018 Advisory Committee Meeting for Remoxy, despite clear evidence to the contrary; ii) comparator data is irrelevant for the evaluation of abuse-deterrent properties, despite FDA written guidance which explicitly states the opposite; and (ii) that we would need to rely on the Freedom of Information Act to access additional data generated by FDA with Remoxy.  As a result of our recent meeting with FDA, we believe we are no closer today to product approval than we were over a year ago.

“Remoxy remains an odyssey without a homecoming,” said Remi Barbier, President & CEO of Pain Therapeutics. “We had hoped for a fair, neutral and impartial review of the Remoxy data. Instead, we walked out of this meeting feeling a bit disoriented by FDA’s lack of transparency, clarity or helpfulness.  It’s a rare occasion when two parties can’t agree on simple math.  We can’t work with shambolic regulations.  This is not how you win support for innovation.”

Historically, the lead candidate in our pipeline has been Remoxy, an analgesic drug that we conceived, patented, developed and tested in collaboration with corporate and academic partners.  Over the years, we have conducted a successful clinical development program for Remoxy, including a large, well-controlled pivotal Phase III efficacy study whose primary endpoints met statistical significance (p<0.05).  The clinical safety or analgesic efficacy of Remoxy for its intended purpose is not in question. Its abuse-deterrent properties, however, are subject of a difference of opinion.  Abuse deterrence refers to properties that are embedded into an opioid formulation to prevent certain common methods of abuse. During the long development history of Remoxy, we generated nearly 9,000 unique data points in over 50 studies at a cost in excess of $100 million.  Studies were designed in consultation with FDA and conducted by independent labs.  Collectively, we believe these studies adequately characterize Remoxy’s abuse-deterrent properties. In particular, we demonstrated that the two currently marketed extended-release oxycodone products -- OxyContin® and Xtampza® -- which both benefit from abuse-deterrent label claims, can both be defeated for purposes of abuse in under a minute using common household items.  In contrast, Remoxy requires a significant investment of time, effort and equipment to defeat, and even then, results in less release of oxycodone.  During our recent meeting with FDA we were informed they believe Remoxy capsules lack abuse deterrence via the injection route of abuse because “oxycodone can be extracted from the product”, regardless of how much time, effort, frustration or equipment is required to so do. We are unable to follow the logic by which a drug product should never release drug. More generally, as the regulatory requirements for Remoxy have changed frequently and suddenly over time, we have experienced significant delays and have incurred unanticipated expenses related to the overall Remoxy development program.

-more-

We believe innovative products such as Remoxy can serve a meaningful social purpose and, potentially, may save lives during the worst drug crisis in American history.  By necessity, however, we rely on reasonably predictive regulatory pathways to guide our product candidates through development in preparation for commercialization.  We also rely on principles of good governance, in which similar drugs receive similar regulatory treatment under rules that are clear, publicized, and evenly applied.  In our experience with Remoxy, the regulatory environment around abuse-deterrence lacks these essential qualities.

There are procedures in place at the FDA and other government agencies to help promote a fair resolution of disputes.  Such procedures can be complex and may not be rapid, predictable or even viable.  Going forward, we will generally be silent regarding our plans or future expectations for Remoxy, unless a significant material event occurs that compels us to update our public disclosures around this product candidate.

https://www.drugbank.ca/drugs/DB00497

https://medlineplus.gov/druginfo/meds/a682132.html

Pain Therapeutics Announces Feedback from Recent Meeting With FDA on Remoxy

FDA Grants Priority Review for Daiichi Sankyo’s New Drug Application for CSF1R Inhibitor Pexidartinib for Treatment of Patients with TGCT, a Rare, Debilitating Tumor

  

Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced that the U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) and granted Priority Review for pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations, and which is not amenable to improvement with surgery.  TGCT, also referred to as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS), is a non-malignant tumor of the joint or tendon sheath, which can be locally aggressive and debilitating in some patients. There are no currently approved systemic therapies for TGCT.

A Priority Review designation is granted by the FDA to drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications. Under Priority Review, the FDA aims to take action on an application within six months, as compared to ten months under standard review. The FDA has designated August 3, 2019 as the PDUFA Action date for this application. 

On January 31, 2019, the American Society of Clinical Oncology (ASCO) recognized “Progress in Treating Rare Cancers” as the “Advance of the Year”, and selected pexidartinib as one of five significant advancements in rare disease treatment, calling it the first promising investigational therapy for TGCT.

The NDA is based on results of the pivotal phase 3 ENLIVEN study of oral pexidartinib, the first placebo-controlled study of a systemic investigational therapy in patients with TGCT. Results of the phase 3 ENLIVEN study were presented during an oral presentation at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.

“We are pleased to announce that the FDA has accepted our application for pexidartinib with Priority Review designation, potentially bringing a treatment option to patients for whom there is no approved therapy,” said Dale Shuster, Ph.D., Executive Director, Global Oncology R&D, Daiichi Sankyo. “Current treatment options for TGCT are largely limited to surgery, but for some patients the disease is debilitating and not amenable to improvement with surgery. We are committed to working with the FDA to potentially bring pexidartinib to carefully-selected patients as soon as possible.”

“We are excited about the first-in-class potential of pexidartinib, another targeted therapy discovered by Plexxikon,” said Gideon Bollag, Ph.D., Chief Executive Officer of Plexxikon Inc., Daiichi Sankyo’s small molecule structure-guided R&D center in Berkeley, CA and a member of the Daiichi Sankyo Group. “Our drug discovery process uses structural data and a specialized scaffold-like screening library to identify and optimize novel drug candidates.”

ENLIVEN is a pivotal, double-blind, randomized, global multi-center phase 3 study that evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomized (1:1) to receive either pexidartinib or placebo at 1000 mg/d for 2 weeks followed by 800 mg/d for 22 weeks in order to evaluate the efficacy and safety of pexidartinib versus placebo. The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (Week 25), as assessed with centrally-read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness and measures of pain reduction.

The ENLIVEN study met its primary endpoint of overall response rate. In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib versus placebo (AST or ALT ≥3X ULN: 33 percent, total bilirubin ≥2X ULN: 5 percent, N=61). Eight patients discontinued pexidartinib due to hepatic adverse events (AEs); four were serious nonfatal AEs with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, two severe liver toxicity cases (one required liver transplant, one was associated with death) were observed.

https://en.wikipedia.org/wiki/Pexidartinib