Long-term HRT Tied to Greater Risk for Alzheimer Disease

Postmenopausal women who received hormone replacement therapy (HRT) had a “small absolute increased risk” of developing Alzheimer disease in a nationwide case-control study from Finland.

“The present study indicates that the use of systemic hormone therapy, once claimed to be protective against Alzheimer’s disease, is accompanied with a 9–17% increase in the risk of the disease in postmenopausal women, whereas the exclusive use of vaginal estradiol shows no risk,” the researchers report in an article published online March 6 in the BMJ.

“Even though the absolute risk increase for Alzheimer’s disease is small, our data should be implemented into information for present and future users of hormone therapy,” Hanna Savolainen-Peltonen, MD, PhD, Department of Obstetrics and Gynecology, University of Helsinki, Finland, and colleagues conclude.

The findings showed that “particularly long-term exposure to hormone therapy is associated with an increased risk of Alzheimer’s disease,” they add. The increase in risk “is not dependent” on the age at which treatment starts.

Thus, the “evidence is reassuring for women needing a few years’ treatment for menopausal symptoms,” Pauline M. Maki, PhD, Departments of Psychiatry, Psychology, and Obstetrics and Gynecology, University of Illinois at Chicago, and colleagues observe in an editorial that accompanies the article.

“For women in early menopause with bothersome vasomotor symptoms, no compelling evidence exists of cognitive concern from randomized trials” of HRT, according to the editorialists, “and instead there is reassurance about cognitive safety.”

On the other hand, they too stress that “concerns about longer term use of estrogen plus progestin on cognitive outcomes remain.”

Does HRT Prevent or Promote Alzheimer Disease?

Observational studies have reported that HRT is associated with a reduced risk for Alzheimer disease, the authors note, but the studies lacked a placebo group, and the women who received HRT may have been healthier to start with.

This criticism “gained strong support” when the placebo-controlled Women’s Health Initiative Memory Study (WHIMS) reported that postmenopausal women who took estrogen had an increased risk for impaired cognition and probable dementia.

However, WHIMS was criticized because the women started taking HRT at age 65, long after menopause started and later than usual in clinical practice.

To investigate this issue further, the researchers conducted a case-control analysis, using data from national registries in Finland.

They identified 84,739 postmenopausal women who received a diagnosis of Alzheimer disease from a neurologist or geriatrician between 1999 and 2013.

The investigators matched these women with 84,739 women who were the same age and lived in the same area (hospital district) but who did not develop Alzheimer disease.

Alzheimer disease was mostly diagnosed when the women were aged 80 years or older (56%) or 70 to 79 years (37%), and rarely when they were younger than this (7%).

Of the women with Alzheimer disease, 69% had not used HRT, 13% had used vaginal estradiol, and 1% had used tibolone (multiple brands).

The remainder had used systemic HRT — more often, estrogen/progestin therapy (63%). The remainder took estradiol only.

Of the patients who took systemic estradiol, 90% used an oral formulation; the remaining 10% used transdermal formulations (either patches or gels).

Overall, women who received systemic HRT that only contained estradiol had a 9% increased risk of developing Alzheimer disease (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.05 – 1.14).

Women who received systemic HRT consisting of estrogen plus progestin had a 17% increased risk (OR, 1.17; 95% CI, 1.13 – 1.21) of developing this disease. The risk was similar for different progestins.

The researchers estimate that nine to 18 excess cases of Alzheimer disease per year would be diagnosed in 10,000 women aged 70 to 80 years who used HRT, especially if they used it for more than 10 years.

Large Sample Size, but Limitations to Registry Studies Remain

The researchers say this is one of the largest studies of the association between HRT and Alzheimer disease; it used data from a reliable registry, and the patients’ diagnoses were confirmed.

The editorialists agree: “There are many advantages to examining hormone use and Alzheimer’s disease in Finland,” including the large sample size of almost 85,000 women, the availability of national drug registries that document hormone therapy prescriptions and purchases, long follow-up, and well-validated dementia diagnoses.

These strengths, however, “are countered by the substantial limitations common to all registry studies,” they point out. These include the lack of information on potential confounding factors, such as hysterectomy/oophorectomy, cardiovascular risk factors, diabetes, apolipoprotein E4 genotype, and other risk factors for dementia.

In addition, because it is an epidemiologic observational study, cause and effect cannot be determined, the researchers acknowledge.

The study was supported by a Helsinki University Hospital research grant and the Jane and Aatos Erkko Foundation. Savolainen-Peltonen has received speaker and consulting fees from Mylan and funding for congress trips from Merck Sharp & Dohme. Disclosures of the other authors’ relevant financial relationships are listed in the original article. Maki has received honorarium from Mylan for talks that were unrelated to the current topic. The other editorialists have disclosed no relevant financial relationships.

BMJ. Published online March 6, 2019. Full text, Editorial

https://www.medscape.com/viewarticle/910006#vp_1

Amazon abruptly stops buying products from many wholesalers, Bloomberg says

Amazon has abruptly halted purchasing products from many of its wholesalers, creating panic amongst vendors, Bloomberg’s Spencer Soper reports. The ecommerce giant is encouraging vendors to instead sell directly to consumers on its marketplace, Soper notes. The company makes more money that way by offloading the cost of buying, storing and shipping products, while it can charge suppliers for these services and take a commission on each transaction, Soper says.
https://thefly.com/landingPageNews.php?id=2876271

Centene, PBM partner promise disruption, but meet skepticism

"Disruption” and “unparalleled savings” are some of the buzzwords touted by upstart pharmacy benefit manager RxAdvance as it attempts to enter a market dominated by giants like CVS and UnitedHealth Group.

As traditional PBMs draw the ire of regulators and other skeptics, Centene is partnered with the new venture and moving away from CVS. But the relative newcomer faces stiff competition and some remain skeptical about whether it can deliver on its claims.

The privately-held 6-year-old Massachusetts-based RxAdvance markets itself as a more transparent PBM and claims it can find more savings than traditional PBMs.

Its CEO said the company is making money but said it could not disclose the company’s financial performance or its initial results from its work with Centene.

“There are significant savings but we are unable to disclose it [to] the public because of restrictions,” RxAdvance CEO Ravi Ika told Healthcare Dive when asked about early results, costs savings and details about the risk-based arrangement set up in the Centene contract.

RxAdvance has backing of some big name business executives like John Sculley of Apple fame, who sits on the company’s board. Oscar Salazar, co-founder of Uber, previously sat on the board.

But industry experts question what sets RxAdvance apart from traditional players.

“No idea — I haven’t been able to penetrate the Silicon Valley hype bubble either,” Adam Fein, president of Pembroke Consulting, who runs the website Drug Channels, told Healthcare Dive.

But Centene is betting big on the small player, moving its business from industry giant CVS Caremark. CVS notified investors last month that Centene was taking its business elsewhere.

Centene’s total pharmaceutical spend is around $10 billion, “of which billions is at risk” to CVS, Eric Coldwell, an analyst with Baird, told Healthcare Dive.

The process of moving to RxAdvance’s platform is expected to last until 2020.

Taking on more risk

PBMs typically work on behalf of health plans and employers to negotiate rebates or discounts with drug manufacturers. Those rebates can influence whether a drug is placed on a preferred tier, promoting greater uptake to patients. Extracting the biggest discounts works particularly well when PBMs can pit two similar drugs against one another that are vying for a preferred tier status.

“[PBMs] pull patients together from different health plans and use their size and the volume of drugs that go through them as a negotiating leverage,” Chris Sloan of consulting firm Avalere told Healthcare Dive.

Traditionally, PBMs are paid a percentage of the savings or the rebates they are able to secure, he said.

But instead of getting paid for services, there has been movement — just like in the rest of the industry — to set up PBM contracts that reward for better outcomes. And many health plans and PBMs are already working to do things differently in that space, Sloan said.

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RxAdvance says that’s what sets it apart from its peers. It claims it’s able to take on more risk-based contracts and has a better technology platform accessible to payers and providers throughout the continuum of care. ​

​”PBMs only provide transactional services, and do so for fairly decent margin, without taking any medical or financial risks,” RxAdvance said in a statement.

Political pressure building

As patients bear a greater share of prescription drug costs due in part to high-deductible plans, PBMs have faced mounting scrutiny over their role in soaring drug prices.

President Donald Trump’s administration wants to do away with the current rebate system for government plans — not commercial — by removing safe harbor protections for drug rebates. The proposed change would legally allow fixed-fee arrangements between PBMs and drugmakers and discounts to help patients at the counter. Analysts say this would alter drug negotiations within the Medicare program, and would ultimately have a ripple effect on commercial plans.

That proposal comes after blockbuster mergers — including CVS’ acquisition of Aetna — have dramatically changed the PBM landscape. Now, the nation’s top PBMs are all hitched to an insurance provider. The nation’s largest insurer, UnitedHealth, already has its own PBM in-house, OptumRx. CVS was a relatively early mover when it bought Caremark in 2006.

In recent years, some PBMs have started to disclose how much of the rebate dollars — or savings — get passed back to the client.

But because the employer or health plan client sits between the PBM and consumer, it’s hard to know how much (if any) of the rebate gets passed on to the actual consumer.

Express Scripts, which was recently acquired by Cigna for $67 billion, says its health plan and employer clients decide how much of the rebate they want back. About half of their clients opt for 100% pass through, said Brian Henry, a spokesman for Cigna.

On average, Express Scripts passes through 95% of the rebates to its clients. CVS says in 2018 it passed through 98% of the rebates it negotiated to clients, according to spokeswoman Christine Cramer. CVS also announced late last year that it will offer a new program in which clients can choose to collect 100% of the rebates.

RxAdvance says its passes on all the negotiated rebates to its clients.

Last year, Centene announced it had made an initial investment in RxAdvance and would use it as a PBM partner. A few months later, Centene’s Mississippi insurance plan, Magnolia Health, was the first in its portfolio to make the switch to RxAdvance.

Since its founding in 2013, RxAdvance says its clients (besides Centene) include Midwest Employee Benefit Funds Coalition and SMART (International Association of Sheet Metal, Air, Rail and Transportation Workers).

Avera Health was a client of RxAdvance but moved to CVS two years ago, Ika said.

Ika’s idea to start the PBM came after he found success with a health insurance software vendor called ikaSystems, which was sold to Blue Cross Blue Shield of Michigan for an undisclosed sum in 2015. That system was able to significantly reduce costs, he said.

“The PBM industry is an industry that has long been awaiting innovation, as it is encumbered with huge administrative inefficiencies, obsolete transaction methodologies, legacy systems, limited service offerings, and a lack of a single point of accountability,” he said in a letter on the company’s website.

But RxAdvance still has to prove it can deliver on its promised savings. “I think at this time it is unclear if this is truly disruptive to incumbents,” Leerink analyst Ana Gupte told Healthcare Dive.

https://www.healthcaredive.com/news/centene-and-its-pbm-partner-promise-disruption-but-analysts-are-skeptical/548071/

Free-standing ERs costs 22 times more than doctor’s office: UnitedHealth study

• The vast majority of free-standing emergency department (FSED) visits are for non-emergency care, and treating those common conditions cost an average of $3,217 — 22 times more than at a physician office ($146) and 19 times ($167) more than at an urgent care center, UnitedHealth Group reported in a new study of Texas facilities.
• UnitedHealth, the largest U.S. private payer, said shifting regular care from FSEDs to physicians offices and urgent care centers in Texas would cut health costs by 95%. That would mean a savings of more than $3,000 per visit.
• There were at least 566 FSEDs in the country in 2016, which was a 42% increase from the previous year and a 155% increase from 2008. Texas alone has 266 FSEDs that account for more than a quarter of ED visits in Texas.

Free-standing ERs have sprung up in certain areas in the U.S., namely Texas. While there are 266 FSEDs in that state, the rest of the country only has 300 such facilities. UnitedHealth said the growth of FSEDs comes from a combination of consumer demand and high profit potential.

However, the report argues that these facilities aren’t filling an urgent care need. The most common diagnoses in Texas FSEDs are for fever, acute bronchitis and a sore throat. All of those ailments can been treated in a lower-cost physician’s office settings.

UnitedHealth echoed earlier criticisms of FSEDs —  namely, they serve affluent communities that already have access to providers. The payer added that FSEDs often don’t offer services for critical conditions, such as trauma or stroke. They usually don’t have an operating room on site or receive ambulances.

In other words, FSEDs aren’t helping poor areas, contributing to an area’s emergency care or provider shortage. That finding echoes a 2017 Health Affairs report that said Texas FSEDs open in wealthier locations that have high rates of insured people. That report suggested policymakers should scrutinize where FSEDs pop up “to prevent the exacerbation of disparities involving the medically underserved.”

UnitedHealth stands to gain business from its proposal to shift care to lower-cost facilities. The payer acquired MedExpress, an urgent care provider in 2015. MedExpress has more than 250 locations across the country and continues to expand.

https://www.healthcaredive.com/news/free-standing-ers-costs-22-times-more-than-doctors-office-unitedhealth-st/549904/

AbbVie/Roche seek first-line CLL use for Venclexta combo

AbbVie and Roche’s Venclexta is making headway as a second-line chronic lymphocytic leukaemia (CLL) treatment, and a new US filing could extend its use into the first-line setting.

Roche has filed for approval in the US for BCL-2 inhibitor Venclexta (venetoclax) plus its anti-CD20 drug Gazyva (obinutuzumab) for patients with previously untreated CLL with co-existing medical conditions and has been granted a breakthrough designation from the FDA that could set up a speedy review.

The filing is based on the results of the phase 3 CLL14 trial which showed that the combination was able to achieve a significant reduction in the risk of disease worsening or death (progression-free survival) compared to Gazyva plus chemotherapy, which has become a standard first-line therapy in this setting since getting approval in 2013.

The FDA is reviewing Venclexta plus Gazyva under its real-time oncology review (RTOR) pilot programme, which came into effect in September 2018 and means that the agency can start to evaluate clinical data as soon as trial results become available.

It is one of a series of initiatives implemented under outgoing FDA Commissioner Scott Gottlieb  designed to accelerate access to new therapies, and means that the agency can approve a new indication soon after an applicant files a marketing application. AbbVie said recently it was hoping for an approval before the end of the year.

Venclexta already has a fairly broad label in the relapsed/refractory CLL population, but the previously-untreated patient group represents another 20,000 or so potential patients in the US alone, according to Roche’s chief medical officer Sandra Horning.

If the regulator does give the go-ahead for the regimen, oncologists will have another treatment option that avoids the use of chemotherapy, along with AbbVie/Johnson & Johnson’s Bruton’s tyrosine kinase (BTK) inhibitor Imbruvica (ibrutinib) plus Gazyva which was approved for first-line use in January.

Many newly-diagnosed CLL patients are ineligible for intensive chemotherapy, says Horning, and Venclexta plus Gazyva provides an alternative that – unlike Imbruvica plus Gazyva which is given indefinitely – has a fixed-duration regimen.

“We are working closely with the agency to bring this new option to people with previously untreated chronic lymphocytic leukaemia as quickly as possible,” she added.

Roche co-markets Venclexta in the US with AbbVie, with the latter selling it on its own elsewhere as Venclyxto, and the drug is a key growth product for both companies.

Sales have been somewhat sluggish since it was first approved for CLL in 2016, but have started to gather pace after its label was extended to include second-line treatment as a monotherapy and in combination with Roche’s older CD20-targeting drug Rituxan (rituximab) in relapsed CLL last year, and for newly-diagnosed acute myeloid leukaemia.

The drug made $344 million in sales worldwide last year, more than double its turnover in the previous year, and $124 million in the last quarter. AbbVie has said it expects sales this year to more than double once again to $725 million.

AbbVie is also testing Venclexta in combination with Imbruvica as another chemo-free option, as well as triple therapy of the drug with both Imbruvica and Gazyva. Meanwhile it’s also in trials for multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and myelodysplastic syndrome (MDS).

https://pharmaphorum.com/news/abbvie-roche-seek-first-line-cll-use-for-venclexta-combo/

Gilead announces data supporting development of GS-6207 in HIV therapies

Gilead Sciences announced findings from two studies that support the further development of GS-6207, a novel, selective, first-in-class inhibitor of HIV-1 capsid function, for potential future use as part of long-acting HIV combination therapy. Interim blinded data from a Phase 1 study in healthy trial participants demonstrated that single doses of GS-6207 of up to 450 mg, administered subcutaneously, achieved sustained concentration levels and were well-tolerated. Separately, in vitro data demonstrated picomolar potency with GS-6207, including against HIV strains resistant to other antiretroviral classes. GS-6207 was evaluated in 40 healthy trial participants in an ongoing Phase 1 randomized, blinded, placebo-controlled, safety, tolerability and PK study. The in vitro study evaluated the pharmacological profile of GS-6207 – which demonstrated up to greater than100-fold greater potency than certain commonly prescribed ARVs and synergistic antiviral activity when combined with the ARVs tenofovir alafenamide, efavirenz, dolutegravir or darunavir. The in vitro study also demonstrated that GS-6207 retains full potency against a broad range of HIV-1 strains resistant to other ARV classes.
https://thefly.com/landingPageNews.php?id=2876265

Bio-Path Jumps Nearly 600% In 2 Days: What You Need To Know

Bio-Path Holdings Inc BPTH 222.62% shares are on a tear, advancing over 160 percent on roughly 37 times their average volume Wednesday and trading up more than 200 percent Thursday afternoon.

What has led to the buoyant sentiment toward this thinly traded nano-cap biotech?

The Catalyst

Bio-Path released updated Phase 2 data for its lead candidate prexigebersen, codenamed BP1001, for treating acute myeloid leukemia, or AML, and also divulged a plan of action for taking the compound through clinical development toward registration.

Updated data from the Stage 1 of the Phase 2 study that evaluated the efficacy and safety of prexigebersen in conjunction with the low-dose chemotherapy regimen cytarabine in 17 newly diagnosed AML patients revealed that the proportion of patients showing a response increased from 47 percent when assessed in April 2018 to 65 percent.

Of the patients showing a response, 5, or 29 percent, showed a complete response compared to the benchmarked percentage of 7-13 percent.

AML: A Cancer Of Blood Cells

AML is a form of blood cancer that develops in the bone marrow, where blood cells originate. It afflicts a group of white blood cells called myeloid cells that develop into mature blood cells such as red blood cells, white blood cells and platelets.

A patient with AML will see rapid accumulation of immature myeloid cells in the blood, resulting in a drop of other blood cell types.

BP1001’s Mode Of Action

Prexigebersen is a neutral-charge, liposome-incorporated antisense drug designed to inhibit protein synthesis of growth factor receptor bound protein 2, or Grb2.

Grb2 has a role to play in cancer cell activation via the RAS pathway.

Inhibition of Grb2 is found to halt cell proliferation and enhance cell killing by chemotherapeutic agents without added toxicity.

A Lucrative Market

AML accounts for roughly 36 percent of all leukemias, with about 20,000 new cases diagnosed each year, Bio-Path said, citing National Cancer Institute estimates.

A critically unmet need exists for non-toxic therapies for older, fragile AML patients who are unfit or ineligible for high-dose chemotherapy or a stem cell transplant.

What’s Next

Bio-Path said it believes it now has a plan with definable paths to registration; the company some changes to the clinical program with an eye toward registration.

It plans to amend the Stage 2 prexigebersen + decitabine Phase 2 AML cohort in untreated new patients to add untreated high-risk myelodysplastic syndrome, or MDS, patients.

The company also intends to cancel the Stage 2 prexigebersen + LDAC Phase 2 AML cohort in untreated de novo patients.

It also plans to test a triple combo of prexigebersen + decitabine + venetoclax for untreated AML and high-risk MDS patients in a registration-directed trial to determine if more durable responses and longer survival are observed compared to patients treated with the decitabine + venetoclax combination.

BioPath shares were trading up 236.94 percent to $40.50 at the time of publication Thursday.

Incidentally, the company enacted a 1-for-20 reverse stock split in January.

https://www.benzinga.com/general/biotech/19/03/13319982/bio-path-jumps-nearly-600-in-2-days-what-you-need-to-know