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Sunday, December 2, 2018

Takeda: Positive Data in 1st Pivotal Phase 3 Trial of Proteasome Inhibitor at ASH


– Maintenance Therapy with NINLARO™ (ixazomib) Improved Progression-Free Survival in Adult Patients with Multiple Myeloma Following Autologous Stem Cell Transplant 
– Data will be presented at the 60th American Society of Hematology (ASH) Annual Meeting on December 2, 2018 –
Takeda Pharmaceutical Company Limited (TSE:4502) today announced that data from the Phase 3 randomized, TOURMALINE-MM3 study evaluating the effect of single-agent oral NINLARO™ (ixazomib) as a maintenance therapy in adult patients diagnosed with multiple myeloma who previously responded to high-dose therapy (HDT) and autologous stem cell transplant (ASCT) will be presented at the 60th American Society of Hematology (ASH) annual meeting on Sunday, December 2, 2018 in San Diego, California. NINLARO is currently not approved as a maintenance therapy for multiple myeloma following ASCT.
The trial achieved its primary endpoint with NINLARO resulting in a statistically significant improvement in progression-free survival (PFS) versus placebo in adult patients diagnosed with multiple myeloma who responded to HDT and ASCT as assessed by an Independent Review Committee (IRC) (HR 0.72; p-value=0.002). This corresponds to a 28 percent reduction in risk of progression or death and a 39 percent improvement in PFS with NINLARO compared with placebo. The safety profile of NINLARO in the maintenance setting is consistent with previously reported results of single-agent NINLARO use.
“A growing body of evidence has shown that maintenance therapy in multiple myeloma may prolong the duration of disease control,” said Meletios Dimopoulos, MD, Professor and Chairman of the Department of Clinical Therapeutics at the University Athens School of Medicine, Athens, Greece. “As currently approved options are limited and do not include a proteasome inhibitor, there is a need for additional maintenance treatments that can sustain response and have a tolerable safety profile. Data from the TOURMALINE-MM3 clinical trial supports single-agent NINLARO as a potential oral proteasome inhibitor maintenance therapy option post-ASCT.”
“The positive results from this pivotal study – the first and only Phase 3 placebo controlled study evaluating a proteasome inhibitor in this setting – support NINLARO as a potential maintenance therapy for patients who have undergone a stem cell transplant,” said Jesús Gómez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. “It is crucial that we continue to support patients by developing treatment options aimed to maintain or deepen response and delay disease progression. According to the findings, patients treated with NINLARO had improved progression-free survival over those in the control arm, which corresponds to a reduced risk of progression or death of nearly one-third.”
“As a result of continued research, the multiple myeloma treatment landscape is constantly evolving. While this is encouraging news for the multiple myeloma community, there is still work to be done to further our goal of addressing the unmet needs of patients,” said Brian GM Durie, M.D., Chairman of the Board, International Myeloma Foundation. “To that end, the development of additional safe and effective maintenance therapies is essential.”

Bellicum at ASH: Low Cancer Recurrence in Pediatric AML and ALL with Rivo-cel


Bellicum Pharmaceuticals, Inc. (NASDAQ:BLCM), a leader in developing novel, controllable cellular immunotherapies for cancers and orphan inherited blood disorders, today announced additional follow-up results from a subset of children with high-risk/relapsed acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The data showed durable anti-leukemic effects in patients treated with rivo-celTM (rivogenlecleucel, formerly BPX-501) following αβT-cell and B-cell depleted allogeneic hematopoietic stem cell transplantation (HSCT). The data were reviewed in an oral presentation today at the 60th Annual Meeting of the American Society of Hematology (ASH 2018) by Principal Investigator Franco Locatelli, M.D., Ph.D., Director of the Department of Hematology and Oncology and Cell/Gene Therapy at Ospedale Pediatrico Bambino Gesù in Rome, Italy.
“Cancer recurrence is one of the primary factors affecting the success rate of allogeneic HSCT. Rivo-cel appears to lower the rate of cancer recurrence in children receiving αβT-cell and B-cell depleted allogeneic HSCT—suggesting that the diverse population of donor T cells in rivo-cel product may reduce or eliminate residual cancer cells,” said Dr. Locatelli. “Moreover, while you might expect to see Graft versus Host Disease with this approach, the overall rates were low and rimiducid was effective for most patients who developed visceral GvHD or who were refractory to standard of care treatment for GvHD. These encouraging data support the potential of rivo-cel as an important treatment for children with blood cancers who need a stem cell transplant and lack a matched donor.”

Magenta Therapeutics to hold an investor and analyst event


Investor and Analyst Event to be held in conjunction with the ASH Annual Meeting will be held in San Diego, CA on December 2 at 11:30 pm.

Preventing herniated disc disorders


It is not always possible to prevent a herniated disc, but there are steps you can take to reduce your risk:
  • Use proper lifting techniques. Do not bend at the waist. Bend your knees while keeping your back straight and use your strong leg muscles to help you support the load.
  • Maintain a healthy weight. Excess weight puts pressure on the lower back.
  • Practice good posture when walking, sitting, standing, and sleeping. For example, stand up straight with your shoulders back, abdomen in, and the small of your back flat. Sit with your feet flat on the floor or elevated. Sleep on a firm mattress, and sleep on your side, not your stomach.
  • Stretch often when sitting for long periods of time.
  • Do not wear high-heeled shoes.
  • Exercise regularly to keep the muscles of your back, legs, and stomach strong. Engage in regular aerobic exercise. Try to balance flexibility with strengthening in a regular exercise program.
  • Stop smoking.
  • Eat healthy, well-balanced meals.

Saturday, December 1, 2018

ASH18: Cancer drug trials in need of modernization, NCI director says


Rapid progress from targeted therapies for cancer are changing how clinical trials are conducted and, in the process, raising new challenges for researchers and drug companies.
Today, approvals for new cancer drugs are often supported by data from only a few hundred patients or fewer, who are carefully screened and selected for genetic abnormalities made targetable by advances in sequencing and therapeutics. Undeniably good news for those patients, the shift is also spurring a re-think in study design.
“Modernizing the clinical trial infrastructure is a really important challenge for cancer research right now,” said Ned Sharpless, director of the National Cancer Institute, in an interview with BioPharma Dive at the American Society of Hematology’s annual meeting in San Diego.
Sharpless compared the expansive clinical studies used to test chemotherapies to recent datasets that have showed impressive benefit with far fewer patients.
“The reason that is occurring is because — rather than having 1,000-patient trials where everyone is heterogeneous and the delta between outcomes is 2% — we are doing 80-person trials or 120-patient trials, but they’re all molecularly defined,” he said. “We’re comparing apples to apples and not apples to oranges.”
Take acute myeloid leukemia, or AML. Japanese drugmaker Astellas needed efficacy data from only 138 patients to convince the Food and Drug Administration to approve its drug Xospata late last month. Xospata targets a mutation known as FLT3 found in about 25% or 30% of AML patients.
Xospata’s only the latest in a slate of drugs the FDA has cleared for use in AML, which remains in serious need of new treatment options. Five of the eight approved since 2017 target a specific mutation or antigen expressed by the cancer, and were supported by trials that enrolled between 174 and 717 patients.
The difficulty, Sharpless said, is that genetically defined trials can be much more complicated to administer, requiring the screening of hundreds or thousands of patients to enroll a study with narrowly defined inclusion criteria.
For that very reason, next-generation sequencing has become a crucial element of cancer research. But that brings challenges in cost as well as access.
“We need to understand how to use next-generation sequencing. It’s a costly test and it leads to the use of costly drugs,” Sharpless said. “There are a lot of challenges related to the broad, widespread implementation of next-generation sequencing.”
In a speech given later on Saturday, Sharpless pointed to one study that found the presence of p53 mutations in AML patients determines how well they respond to a standard chemotherapy. But that signal had gone unnoticed for years, a fact the NCI head described as a failure of data aggregation.
“If we’d aggregated data and we’d start putting large collections of AML patients together that had been genetically sequenced, this result, and many other results, would have been apparent almost immediately,” Sharpless said in his speech.
Sharing data and real-world evidence isn’t a given, though, especially if it’s held by private payers or drug companies for commercial use.
Highly active targeted therapies also raise questions about how to appropriately construct a control arm in clinical testing.
If early testing shows dramatic and clear responses to therapy, assigning hundreds of patients to a chemotherapy or other standard therapy arm may no longer be ethical.
“There’s nothing more convincing than randomized, controlled trials, but there’s also this issue of equipoise,” said Sharpless to BioPharma Dive, referring to the principle that researchers should be genuinely uncertain of which study group will see a greater benefit.
Returning to the AML example, studies supporting approval of Celgene and Agios’ Idhifa and Agios’ Tibsovo were single-arm trials, while those supporting Venclexta were open-label.
In response, researchers are also turning to newer clinical trial designs, like the “umbrella” format used in the Beat AML study sponsored by the Leukemia and Lymphoma Society.
Patients enrolled into Beat AML were genetically profiled before being assigned to an experimental targeted therapy. An initial report will be presented at ASH on Monday morning.
Still, while sequencing and targeted therapy can make more personalized studies possible, clinical benefit isn’t guaranteed to follow.
“We’ve had some really impressive and important progress, but it has been uneven,” Sharpless said, noting the recent approvals in AML are more “singles” or “doubles” rather than curative “home runs.”

Unpleasant Surprises With Blood Pressure Drug for PTSD


Contrary to expectations, the alpha-adrenergic blocker prazosin (Minipress, Pfizer), which is used to treat high blood pressure as well as posttraumatic stress disorder (PTSD), may worsen nightmares and insomnia and does not appear to reduce suicidal thoughts, new research suggests.
Dr William McCall
“I was unpleasantly surprised at the result. Prazosin had been gaining substantial traction as a treatment of choice for nightmares and other PTSD-related symptoms,” principal investigator William Vaughn McCall, MD, chair of the Department of Psychiatry and Health Behavior at the Medical College of Georgia at Augusta University, told Medscape Medical News.
This is the first study of prazosin in which all participants were experiencing suicidal ideation in addition to PTSD and nightmares.
“To state the obvious, the present literature shows that prazosin is clearly ‘not for everyone,’ and discretion is advised when prescribing,” said McCall.
The study was published online November 19 in the Journal of Clinical Psychopharmacology.

Conflicting Data

Two earlier studies of prazosin for PTSD-related sleep problems yielded mixed results.
A study of nonsuicidal military personnel with PTSD that was published in 2013 showed that twice-daily prazosin was beneficial in relieving nightmares.
A study published in February of this year failed to show a benefit of twice-daily prazosin over placebo in reducing PTSD-related nightmares. In this study, however, new or worsening suicidal ideation occurred as an adverse event in fewer patients taking prazosin than placebo (8% vs 15%).
McCall and colleagues conducted a pilot, randomized clinical trial to test whether treatment with prazosin would reduce suicidal ideation in 20 suicidal patients with PTSD and nightmares.
Patients were randomly assigned to receive escalating doses of prazosin or placebo at bedtime for 8 weeks. The final highest dose for men and women combined was 5.5 ± 3.5 mg for prazosin and 7.6 ± 5.3 mg for placebo.
All participants had comorbid mood disorders and were receiving stable doses of mood disorder medication. Outcomes of interest, measured weekly, included severity of suicidal ideation, nightmares, PTSD, insomnia, and depression.
Patients in both groups demonstrated improvement over time in all psychometric measures. However, compared with patients taking placebo, those taking prazosin had significantly less improvement in nightmares, as measured by the Disturbing Dreams and Nightmare Severity Index; insomnia, as measured by the Insomnia Severity Index; and depression, as demonstrated by Hamilton Rating Scale for Depression and Clinical Global Impression–Severity scores.
There was no significant change in suicidal ideation with prazosin.
The results failed to support the study’s main hypothesis that bedtime doses of prazosin would have a favorable effect on suicidal ideation, the researchers say. “Bedtime-only doses of prazosin had a significant effect on nighttime variables such as nightmares, insomnia, and depression scores (which include sleep items), albeit that the effects were in the direction opposite of expected,” they write.
One patient each in the prazosin and placebo groups required emergency psychiatric hospitalization for worsening suicidal ideation or worsening clinical condition. There were no suicide attempts or deaths.
McCall and colleagues say the differences between their findings and those of prior randomized controlled trials of prazosin in PTSD could be related to the high psychiatric and medical acuity of the sample and to the complexity of the psychotropic medication regimens.
Overall, studies to date provide a “confusing, mixed picture of the clinical and physiologic effects of prazosin in PTSD,” they conclude.
McCall told Medscape Medical News that, in his opinion,”the entire approach to prazosin in PTSD needs to be rethought out.
“We need to reconcile how is it that we had 10 years of data saying prazosin is good for nightmares in PTSD, a big study this February indicating it has essentially no effect, and now a smaller study showing it can worsen some aspects. We need to know what it all means,” he added in a news release.
McCall said he would advise against giving prazosin to suicidal PTSD patients taking complicated psychopharmacology regimens “and that consideration be given to discontinuing it if the patient shows equivocal response after a month or two.”

Findings “Concerning”

Reached for comment, Matthew Johnson, PhD, of the Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, said the results are “noteworthy” and “concerning for the use of the drug in PTSD patients.
“However, it should be noted that this is a relatively small sample of 10 vs 10 patients in the drug and placebo groups & — very few for a between-subjects randomized design. In order to be more confident that the worse insomnia and nightmares really are an effect of prazosin, a larger study would be needed,” said Johnson.
The study was supported by a grant from the American Foundation for Suicide Prevention. Dr McCall receives royalties from Wolters Kluwer Health and research support from MECTA and Merck and is a scientific advisor for Sage Therapeutics. Dr Johnson has disclosed no relevant financial relationships.
J Clin Psychopharmacol. Published online November 19, 2018. Abstract

Former President George H.W. Bush Dies


George Herbert Walker Bush, the nation’s oldest living former president, has died at the age of 94.
“George H.W. Bush was a man of the highest character and the best dad a son or daughter could ask for,” said his son, former president George W. Bush, in a statement.
Bush, the nation’s 41st president (1989-1993), had vascular parkinsonism, a condition caused by one or more small strokes. He was often seen in a wheelchair during the last few years of his life, but he kept a positive attitude.
He was admitted to Houston Methodist Hospital in April, a day after his wife Barbara Bush’s funeral, “after contracting an infection that spread to his blood,” a family spokesman told The Washington Post.
Before that, Bush had a few other health setbacks. He was hospitalized for shortness of breath in December 2014. He also was hospitalized in Maine in 2015 after he fell at his summer home and broke a bone in his neck. In 2012, he spent Christmas in intensive care, reportedly for a bronchitis-related cough, among other issues.
Although his public appearances were rare as he grew older, he marked the 75th anniversary of the Japanese attack on Pearl Harbor in 2016 at a ceremony at his library at Texas A&M University in College Station. In 2015, he threw out the first pitch at the Houston Astros’ playoff game against the Kansas City Royals, appearing in a wheelchair with a brace on his neck.
To celebrate his 90th birthday, Bush did a tandem parachute jump near his Kennebunkport, Maine, home. Skydiving was a passion of his.

About Vascular Parkinsonism

Vascular parkinsonism typically affects adults over age 60.
Although scientists are still working to define exactly what the disease is, it’s thought to be the result of mini-strokes affecting a part of the brain called the basal ganglia. The gradual loss of nerve cells causes classic Parkinson’s disease.
The strokes may not even be noticeable, except by MRI or CT scan, says neurologist Joseph Jankovic, MD, director of the Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston. Symptoms — including an unstable lower body, rigid muscles, a shuffling gait, and a broad-based stand — may appear over time or suddenly. People with parkinsonism usually do not have tremors, which characterize Parkinson’s disease.
Jankovic says many older people with parkinsonism mistakenly believe that their trouble walking and standing are an inevitable result of aging.
“People say, ‘Well, I’m getting old,’ but if they require assistance walking, that should be a signal to them that this is not just aging; there’s something else going on,” says Jankovic, a Bush acquaintance. He did not treat Bush.
“It’s probably much more common than we think,” he says. “I see patients on the street with a shuffling, broad-based gait, and I wonder if they’ve ever been evaluated. Most have been told they’ll have to live with it.”
Another reason people with vascular parkinsonism may not attribute symptoms to a disease is that it tends not to affect their thinking skills as much.
Getting a correct diagnosis is important to begin treatment and reduce the risk for further strokes, says Jankovic.
The dopamine-enhancing medication levodopa, used to treat Parkinson’s, is not all that effective for vascular parkinsonism. About half of VP patients see improvement in their symptoms when they take it, says Jankovic.
The treatment is focused on cutting the odds of more strokes, so patients adopt a low-salt, low-fat diet, quit smoking, take an aspirin a day (if recommended by a doctor), and control diabetes and hypertension.
Regular exercise also is especially important for vascular parkinsonism patients.
“Many patients with vascular parkinsonism can go for years without a significant progression of symptoms, especially if stroke risk factors are minimized,” Jankovic says. While it doesn’t affect a person’s lifespan, “it’s clearly a disabling condition,” he says. “Patients may require ambulatory assistance, like a walker or sometimes a wheelchair.”
When asked about his medical condition in the Parade interview, Bush said the vascular parkinsonism “just affects the legs. It’s not painful. You tell your legs to move and they don’t move.” He said he missed being active, “but you just face the reality and make the best of it.”

Bush’s Life

Born on June 12, 1924, in Milton, Massachusetts, Bush was a decorated naval pilot during World War II and a Yale man who graduated Phi Beta Kappa. He became a Texas oilman and two-term congressman before he was picked to be Ronald Reagan’s running mate in 1980.
Before serving as vice president from 1981 to 1989, Bush was U.S. ambassador to the United Nations, chairman of the Republican National Committee, chief of the U.S. Liaison Office in China, and director of the Central Intelligence Agency.
Bush was the first president since 1837 to ascend from the vice presidency to the presidency. He also was one of only two presidents with a son who also served as commander-in-chief. (The other was John Adams, whose son John Quincy Adams became the nation’s sixth president). George W. Bush is the oldest of the Bush children and served two terms (2001-2009) as the nation’s 43rd president; another son, Jeb Bush, was Florida governor from 1999 to 2007. He announced a run for the presidency in 2015 but dropped out in 2016. The Bushes all are Republicans.
George H.W. Bush told the Parade magazine interviewer that he was proud his administration was “scandal free” and said one of his greatest accomplishments was “the liberation of Kuwait.” He had put together a coalition of more than 30 countries to push former Iraqi dictator Saddam Hussein out of the Arab state in the Gulf War, from 1990 to 1991.
Bush also signed into law the Americans with Disabilities Act and amendments to the Clean Air Act, and he negotiated the North American Free Trade Agreement (NAFTA).

Bush’s Humanitarian Work

After leaving office, Bush helped raise hundreds of millions of dollars for charity. Among his causes were the M.D. Anderson Cancer Center; the Points of Light Institute; and C-Change, a coalition of cancer organizations.
President Bill Clinton, who succeeded Bush in the White House, later came to regard Bush as a father figure, according to Barbara Bush. The two men joined forces in fundraising after the tsunami in southeast Asia and Hurricane Katrina on the Gulf Coast. In 2008, they formed the Bush-Clinton Gulf Coast Recovery Fund to help reconstruction after Hurricane Ike.
In 1994, the George H.W. Bush Presidential Library and Museum opened on the campus of Texas A&M University as part of the George Bush Presidential Library Foundation, Bush School of Government and Public Service, and the Annenberg Presidential Conference Center. Bush remained active in the organizations bearing his name.
President Barack Obama awarded Bush the 2010 Presidential Medal of Freedom, the nation’s highest civilian honor, for his commitment to service and ability to inspire volunteerism throughout the country, encouraging citizens to be “a thousand points of light.”
He and Barbara divided their time between Houston and Kennebunkport.

Sources:
George Bush Presidential Library: “Biography of George Herbert Walker Bush.”
Parade magazine, interview with George H.W. and Barbara Bush, by Mark Updegrove, July 13, 2012.
Joseph Jankovic, MD, professor of neurology, distinguished chair in movement disorders; director, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Department of Neurology, Houston.
Baylor College of Medicine, Parkinson’s Disease Center and Movement Disorders Clinic: “Vascular parkinsonism.”
New Jersey Neuroscience Institute, JFK Medical Center, Edison, NJ: “Vascular (Multi-Infarct) Parkinsonism.”
Whitehouse.gov: “George W. Bush.”
FoxNews.com: “Former President George HW Bush released from hospital, aide says.”
The Washington Post: “George H.W. Bush hospitalized one day after the funeral for his wife, Barbara.”