Intercept’s Upcoming NASH Data Is A Major Pivotal Point

Intercept expects to report results from its phase 3 REGENERATE study using Ocaliva to treat patients with NASH fibrosis in Q1 of 2019.

Ocaliva has already been approved by the FDA as a combination with ursodeoxycholic acid to treat patients with PBC.

The NASH market is expected to reach $20 billion to $35 billion in the coming years.

Intercept acquired U.S. rights for a PPAR inhibitor known as Bezafibrate, which is first expected to be initiated in a combination study with Ocaliva to treat patients with PBC.

The acquisition of Bezafibrate by Intercept is a good move in that it will allow the drug to be explored alone or in combination with OCA to treat a range of liver diseases including NASH.

Recently, Intercept Pharmaceuticals (ICPT) provided an update for both its non-alcoholic steatohepatitis (NASH) and primary biliary cholangitis (PBC) programs. The main portion of the update deals with Intercepts upcoming results from the phase 3 REGENERATE study which is treating patients with NASH fibrosis. This study is expected to be readout in Q1 of 2019 and good data will give Intercept a stronghold in the NASH space.

Phase 3 REGENERATE Study

The most important item, as noted above, is the upcoming results for the phase 3 REGENERATE study. This study was established to recruit up to 2,370 patients with F2/F3 NASH fibrosis. Patients were randomized to receive either 10 mg, 25 mg of Ocaliva or placebo. The goal of the study is to see if Ocaliva performs better from baseline to 18 months of treatment compared to placebo. One thing to point out is that the upcoming results in Q1 2019 is an interim analysis and in no way will be final data. However, investors are viewing this as a highly major event. That’s because if the primary endpoints are not established at the interim analysis, it could cause the stock to be cut in half by 50% or more. Intercept already has Ocaliva approved by the FDA to treat patients with PBC but in combination with ursodeoxycholic acid (UDCA). In other words, these were patients who either didn’t respond to UDCA treatment or who were not able to tolerate it. The market potential for PBC is large, but not as much as the NASH market. It is estimated that the NASH market could reach between $20 billion to $35 billion in the coming years. The REGENERATE study is far more important in terms of Intercept’s future. There are two primary endpoints for this study. The first primary endpoint is the amount of Ocaliva treated patients that achieve at least one stage of liver fibrosis improvement with no worsening of NASH compared to placebo. In addition, the proportion of Ocaliva treated patients that achieve NASH resolution with no worsening of liver fibrosis compared to placebo. The other primary endpoint involves all-caused mortality and related liver clinical outcomes. There are also a host of other secondary endpoints as well that may prove to be useful for analysis as well like resolution of fibrosis.

https://seekingalpha.com/article/4233519-intercepts-upcoming-nash-data-major-pivotal-point-success

FDA advisory panel votes on Zynquista as treatments for adults with diabetes

FDA advisory committee votes on Zynquista as treatments for adults with diabetes  The and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration voted eight to eight on the question of whether the overall benefits of Zynquista outweighed the risks to support approval. Sotagliflozin is an investigational oral dual SGLT1 and SGLT2 inhibitor under regulatory review as an adjunct to insulin for the treatment of adults with type 1 diabetes. While the FDA is not required to follow the committee’s vote, the agency considers the committee’s recommendations when making its decision, which is anticipated by March 22, 2019. Sotagliflozin, developed by Sanofi (SNY) and Lexicon (LXRX), has the potential to be the first oral antidiabetic drug approved in the United States together with insulin therapy to improve glycemic control in adults with T1D.

https://thefly.com/landingPageNews.php?id=2850628

Acorda: secondary endpoints supportive of primary endpoint in INBRIJA trial

Acorda Therapeutics announced that The Lancet Neurology published results from SPANSM-PD, the Phase 3 pivotal efficacy trial of INBRIJA, also referred to as CVT-301. In the study, INBRIJA 84 mg significantly improved motor function at 30 minutes during OFF periods in people with Parkinson’s taking carbidopa/levodopa, the study’s primary endpoint. Onset of action was seen as early as 10 minutes and the reduction at 30 minutes was maintained at 60 minutes. Multiple secondary endpoints were supportive of the primary endpoint. Data from the study were first presented at the 2017 International Congress of Parkinson’s Disease and Movement Disorders. “A well-tolerated, effective treatment for OFF periods between doses of scheduled medications can help fulfill one of the most important unmet needs for people with Parkinson’s,” said lead author of the publication Peter LeWitt, M.D., Director of the Parkinson’s Disease and Movement Disorders Program at Henry Ford Hospital and professor of neurology at Wayne State University School of Medicine. “The data published in The Lancet Neurology support INBRIJA as such a treatment option, delivering levodopa, the current ‘gold standard’ of Parkinson’s treatment, in a novel, inhaled form.”

https://thefly.com/landingPageNews.php?id=2850635

Joint Corp initiated with a Buy at DA Davidson

DA Davidson analyst Michael Kawamoto initiated Joint Corp with a Buy rating and a price target of $10, citing the company’s position as the “leading franchised chiropractic concept with great visibility to growth and margin expansion”. The analyst expects the company to continue rapidly expanding its retail presence beyond the 422 current locations, with potential of as many as 1,700 stores nationwide over the long term. Kawamoto also believes that chiropractic services are becoming more popular, with “several well regarded medical organization” validating their benefits.

https://thefly.com/landingPageNews.php?id=2850640

Immunomedics receives response from FDA on Sacituzumab Govitecan BL

Immunomedics receives response from FDA on Sacituzumab Govitecan BLA  announced it has received a Complete Response Letter from the FDA for the Biologics License Application, or BLA, seeking accelerated approval of sacituzumab govitecan for the treatment of patients with metastatic triple-negative breast cancer who have received at least two prior therapies for metastatic disease. Michael Pehl, President and Chief Executive Officer of Immunomedics said: “The issues related to approvability in the CRL were exclusively focused on Chemistry, Manufacturing and Control matters and no new clinical or preclinical data need to be generated. We are going to request a meeting with the FDA as soon as possible to gain a full understanding of the Agency’s requirements and timelines for approval and we will work closely with the FDA with the goal of bringing this important medicine to patients as soon as possible.”

https://thefly.com/landingPageNews.php?id=2850644

Connecting dots between colitis and colon cancer

Lingering inflammation in the colon is a known risk factor for colorectal cancer and now scientists report one way it resets the stage to enable this common and often deadly cancer.

Inflammation is supposed to be a short-term response to an infection or other irritant in the body that is essential to eliminating it. But when inflammation persists, it can contribute to a myriad of common conditions, from cancer to cardiovascular disease.

In their quest to determine just how chronic inflammation of our large intestines, or colon, enables cancer, a scientific team led by Dr. Kebin Liu at the Medical College of Georgia and Georgia Cancer Center at Augusta University has found it turns one more protective mechanism against us and silences another.

The pathway to cancer they delineated in the journal Cell Reportsgoes like this: The chronic inflammation of ulcerative colitis prompts high levels of myeloid-derived suppressor cells, or MDSCs, to accumulate in the colon. High levels of MDSCs, in turn, produce higher levels of IL-10, a cytokine known to suppress inflammation. But at this high level, the function of IL-10, like the environment in the colon, changes. IL-10 instead activates STAT3, a protein that works as a gene regulator, which in turn increases expression of two genes — DNMT1 and DNMT3b — in the colon. These genes alter the DNA of and ultimately silence a tumor suppressor called interferon regulator factor 8, or IRF8.

Liu notes that the pathway they found that ends with silencing IRF8, likely is not a factor for non-colitis associated colon cancer.

Next steps include finding ways to inhibit high expression of IL-10 in the colon.

“IL-10 has a dual function. It can either be promoting or interfering with an immune response,” says Liu. “What we found here is IL-10 promotes colon cancer.”

In a healthy state, IL-10 and IRF8 have no known interaction but both work in different ways to protect against invaders, says Liu, a cancer immunologist in the MCG Department of Biochemistry and Molecular Biology.

The scientists set out to look at whether and how the two are connected in a chronically inflamed colon and test the hypothesis that IRF8 functions as a colorectal cancer suppressor.

They created a mouse missing IRF8 in the epithelial cells that line the colon and found plenty of evidence to support their hypothesis. The mice were much more susceptible to chronic inflammation, had less normal cell death in this high-cell turnover area and got more tumors. They also found that in the face of chronic inflammation, IRF8 is silenced, and that in human cancer, IRF8 is downregulated compared to normal colon tissues.

Meanwhile, they showed that in this altered environment, MDSCs and the IL-10 they produce were at higher levels and so were the two genes that ultimately silence IRF8. They found the same shifts in human colon cancer.

Liu says it’s likely the high levels and timing that transform the role of IL-10 from suppressor of inflammation to suppressor of IRF8.

Colorectal cancer is among the top five common cancers and causes of cancer death in men and women in the United States, according to the Centers for Disease Control and Prevention.

Interleukin 10, or IL-10, is a cytokine, or signal that influences the behavior of nearby cells. It’s known to suppress chronic inflammation, including inflammation-driven colitis and colorectal cancer. It has even known to suppress other cells cancer might commandeer like regulatory T cells, or Tregs, which can suppress an antitumor response.

IRF8 is a transcription factor, which means it helps regulate the activity of genes, and it plays an important role in the differentiation of red blood cells. It’s normally expressed by the epithelial cells that line the colon as a layer of protection against the food and drink we put in our mouths.

MDSCs, are at low levels in most healthy people, and are adept at helping protect us from invaders, producing immune cells like macrophages, as well as IL-10. Like inflammation, MDSCs should be on the scene and active just until the problem is eliminated. But when chronically stimulated, like in chronic inflammation and cancer, they work instead to suppress the immune system.

Colitis is when the colon’s lining becomes chronically inflamed and its important barrier function gets compromised by the increased number of immune cells that have moved in, likely in response to the immune system inexplicably recognizing common things like food and commensal bacteria in the gut as invaders.

Colitis affects males and females alike, often surfaces in the 30s, and can run in families. Symptoms of colitis include loose and more urgent bowel movements, diarrhea, abdominal pain and blood in the stool, according to the Crohn’s & Colitis Foundation. Patients may have a loss of appetite, weight and energy.

The research was funded by the National Institutes of Health and a Department of Veterans Affairs Merit Review Award.

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Story Source:

Materials provided by Medical College of Georgia at Augusta University. Original written by Toni Baker. Note: Content may be edited for style and length.

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Journal Reference:

1. Mohammed L. Ibrahim, John D. Klement, Chunwan Lu, Priscilla S. Redd, Wei Xiao, Dafeng Yang, Darren D. Browning, Natasha M. Savage, Phillip J. Buckhaults, Herbert C. Morse, Kebin Liu. Myeloid-Derived Suppressor Cells Produce IL-10 to Elicit DNMT3b-Dependent IRF8 Silencing to Promote Colitis-Associated Colon Tumorigenesis. Cell Reports, 2018; 25 (11): 3036 DOI: 10.1016/j.celrep.2018.11.050

https://www.sciencedaily.com/releases/2019/01/190116185215.htm

World Trade Center responders at increased risk for head and neck cancers

A Rutgers study has found a significant increase in head and neck cancers among workers and volunteers who responded to the 9/11 terrorist attacks on the World Trade Center (WTC), pointing to newly emerging risks that require ongoing monitoring and treatment of those who were exposed during the initial response.

The study, which is the first to report on head and neck cancers in WTC first responders, found a 40 percent increase in diagnosis of these diseases between 2009 and 2012.

The study appears in the International Journal of Cancer.

The findings highlight the need to examine the potentially carcinogenic effects of WTC exposure in the context of other strong risk factors and the need for continued medical monitoring of WTC responders, particularly the police and military.

“Since cancers are diseases of long latency, the findings of significant excess cancer in this period point to a newly emerging trend that requires ongoing monitoring and treatment of WTC-exposed persons,” said lead author Judith Graber, an associate professor at Rutgers School of Public Health and a researcher at Rutgers Environmental and Occupational Health Sciences Institute.

The results were part of a two-year study funded by the U.S. Centers for Disease Control and Prevention examining whether first responders were at greater risk of human papillomavirus (HPV) — related throat and tongue cancer because of their exposure during recovery efforts in lower Manhattan.

The most prevalent increases were oropharyngeal cancers, which are often associated with HPV infection, and laryngeal cancer, but not oral and nasal cancers. The study also found that head and neck cancers were most associated with responders who were over 55, were non-Hispanic whites or who worked in military or protective service occupations and performed rescue and recovery and maintained the perimeter after the attacks.

The research began when clinicians treating WTC-exposed responders at Rutgers’ World Trade Center Health Program became concerned about an usually high number of patients with cancers of the head and neck. They compared the incidence of head and neck cancers in 73 people among the program’s 33,809 WTC responders from 2003 through 2012 to the number of expected cases based on the New Jersey State Cancer Registry.

“This excess occurrence in head and neck cancers is plausible since first responders inhaled debris clouds containing many known carcinogens,” said Graber, who is also an associate member in the Cancer Prevention and Control Program at Rutgers Cancer Institute of New Jersey. “In addition, these carcinogenic exposures might add to or increase the effect of known personal risk factors for some head and neck cancers, such as tobacco smoking, heavy alcohol use and oral HPV infection.”

The findings highlight the need to examine the potentially carcinogenic effects of WTC exposure in the context of other strong risk factors and the need for continued medical monitoring of WTC responders.

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Story Source:

Materials provided by Rutgers University. Original written by Patti Verbanas. Note: Content may be edited for style and length.

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Journal Reference:

1. Judith M. Graber, Gerald Harris, Kathleen Black, Roberto G. Lucchini, Christopher R. Dasaro, Michael B. Steinberg, Anna R. Giuliano, Michael A. Crane, Jacqueline M. Moline, Denise J. Harrison, Benjamin J. Luft, Andrew C. Todd, Iris G. Udasin. Excess HPV-related head and neck cancer in the World Trade Center Health Program General Responder cohort. International Journal of Cancer, 2018; DOI: 10.1002/ijc.32070

https://www.sciencedaily.com/releases/2019/01/190117090432.htm