Teva: Migraine med OK by mid-June date unlikely

• Generics giant Teva Pharmaceutical Industries no longer expects to win U.S. approval of its migraine treatment fremanezumab by the June 16 decision date originally set by the Food and Drug Administration.
• Instead, Teva anticipates a later approval and subsequent launch sometime before the end of 2018, following a pre-approval inspection of production facilities used by contract manufacturer Celltrion Inc. to make the CGRP blocker. That inspection is set to occur in the coming months, Teva said Thursday.
• While the delay is a blow to Teva — potentially meaning fremanezumab enters the market behind two competing products instead of one — the disruption doesn’t appear to knock the drugmaker completely off track.

Long underserved, the market for preventative migraine treatments looks set to see several new entrants over the next year. Amgen and Novartis expect to win U.S. approval for their CGRP inhibitor Aimovig (erenumab) sometime this month, and Eli Lilly could also see a nod from the FDA for its similar drug galcanezumab by the fall.

Teva had hoped to come into the market behind Amgen and Novartis, previously securing a June 16 target action date for fremanezumab by using a coveted priority review voucher.

But GMP violations at Celltrion’s manufacturing plant in Incheon, Korea, threw a wrench in Teva’s plans. In a January warning letter, the FDA detailed regulatory lapses which included poor aseptic behavior among others. The regulator later issued a Complete Response Letter to the Korean drugmaker for two biosimilar drug applications, further dimming Teva’s prospects of winning an on-time approval.

Teva’s admission, announced during an earnings presentation on May 3, leave little doubt of fremanezumab’s fate in the near term.

“We do not expect to receive FDA approval on our Biologics License Applications (BLA) for fremanezumab on the mid-June PDUFA date,” the company said in a statement, while noting they remain engaged in “constructive dialogue” with the FDA.

Celltrion is currently Teva’s sole supplier of active pharmaceutical ingredient for fremanezumab, although the drugmaker plans to develop another source of supply.

Despite the delay, Teva’s chances of competing may not be all that damaged over the longer term.

On a recent earnings call, Lilly’s head of Bio-Medicines, Christi Shaw, noted several months might not move the needle much in terms of market share for the rival CGRP drugs.

“In general though three to four months is not a big deal. By the time you get your label and get approved, then you’re talking about access, really it’s not a big difference,” Shaw said. “If you are looking at bigger delay and you have two agents in the marketplace and you are 12 to 18 months later that is a detriment for share.”

While Shaw was discussing galcanezumab, the comments could reflect a market dynamic that allows Teva to bounce back quickly from the disruption for its drug. That’s, of course, if Teva is actually able to secure an FDA nod by the end of the year as it expects.

Elsewhere, Teva reported a better-than-expected first quarter, paying down debt and raising its estimates for free cash flow in 2018. Competition to Teva’s MS drug Copaxone (glatiramer acetate) and falling generics prices still stung, however, leading to a 10% drop in revenues compared to the same period a year ago.

https://bit.ly/2FIXh6X

Screen All Men Age 85 and Older for Osteoporosis

All men 85 years and older should be screened for osteoporosis, and men as young as 65 years should be tested if they have certain risk factors for fracture, according to a new study.

Cathleen Colon-Emeric

“Osteoporosis is often considered a disease of women, but it actually has a major impact on men,” said Cathleen Colon-Emeric, MD, from the Duke University School of Medicine in Durham, North Carolina.

“Men are the forgotten population for this particular condition,” she said here at the American Geriatrics Society 2018 Annual Scientific Meeting.

“For example, a man has a higher risk of having a major osteoporotic fracture than getting prostate cancer, but nobody really thinks of screening men for osteoporosis. We’re trying to address that,” she told Medscape Medical News.

A man has a higher risk of having a major osteoporotic fracture than getting prostate cancer, but nobody really thinks of screening men for osteoporosis.

Clinical practice guidelines are clear on when women should be screened but not when men should be tested. “There are multiple conflicting recommendations around the world on whether to screen men for osteoporosis at all and, if so, when, which men, and at what age,” she explained.

Colon-Emeric and her colleagues wanted to determine whether there is a benefit to screening men for primary osteoporosis.

The team assessed data on 2,539,812 men 65 to 99 years of age with no history of fracture from the Centers of Medicare and Medicaid Services and Veterans Administration.

They used propensity scores to match men who had undergone osteoporosis screening with dual energy x-ray absorptiometry during routine care with men who had similar risk factors for fracture and a similar probability of being screened but who had not undergone any screening.

Of the 183,943 men who had undergone screening, 33,224 (18%) were older than 80 years.

Fracture rates were 15% lower in the screened population than in the overall population (hazard ratio, 0.85; 95% confidence interval, 0.81 – 0.90).

Slightly more men older than 80 years than younger men met the threshold to receive at least one prescription for an osteoporosis medication (16.3% vs 13.4%).

For men with no known risk factors for fracture, the age at which screening becomes more effective than not screening is approximately 85 years.

“Our findings not only support universal osteoporosis screenings for all men over age 85, but also suggest that men as young as 65 may benefit from diagnostic evaluation when certain risk factors are present,” Colon-Emeric reported. “In the younger men with risk factors, there is a 10% reduction in hazard with screening.”

Certain medications, such as steroids and those for prostate cancer, are risk factors, as are certain chronic conditions, such as chronic lung disease, chronic liver disease, rheumatoid arthritis, diabetes, thyroid disease, and Parkinson’s disease.

“Any man age 85 and older, as long as we think he is going to have a 2-year life expectancy and live long enough to benefit from osteoporosis treatment, should be considered for screening,” she added.

There is actually “a real crisis in the treatment of osteoporosis,” said Colon-Emeric. “Treatment and adherence rates started going down around the time we started to see some news stories coming out in the New York Times and other places reporting serious but very rare side effects of those medications. It scared a lot of people.”

Educating patients about the risks and benefits of osteoporosis medication requires a careful discussion, she explained.

“In general, if you’re at high risk for fracture, the benefits of these medications far outweigh the very small risk. The National Bone Health Alliance, the National Osteoporosis Foundation, and the American Society of Bone and Mineral Research are doing media and educational campaigns to help patients understand that, certainly, there are risks for any medication, but there are also substantial benefits,” she pointed out.

A Landmark Study

Alayne Markland

This “landmark study” adds “significant evidence” for the benefit of osteoporosis screening for men 85 years and older, said Alayne Markland, DO, from the University of Alabama at Birmingham, who is associate director of the Birmingham/Atlanta Geriatrics Research Education and Clinical Center.

The findings “affect clinical care and guidelines for community-dwelling men,” she told Medscape Medical News.

Although 85 years might seem old, “the data show that 85 years is the inflection point at which screening made a difference. We are seeing our population live longer and, even at 85, at least that’s a starting point for screening with some evidence behind it,” she said.

“A hip fracture can take someone 85 years or older who is fully functional and who has a 5-year life expectancy to being nonfunctional with a life expectancy of perhaps 1 year or less, so screening can have a profound impact if osteoporosis is found and treated appropriately,” Markland said.

This study was supported by the US Department of Defense. Colon-Emeric reports being a consultant for Novartis and Amgen and receiving research support from Amgen. Markland has disclosed no relevant financial relationships.

American Geriatrics Society (AGS) 2018 Annual Scientific Meeting: Abstract P2. Presented May 3, 2018.

https://wb.md/2IiBacT

Endocrine-Disrupting Agents Found in Black Women’s Hair Products

Hair care products commonly used by black women and children in the United States to relax or straighten hair contain chemicals associated with endocrine disruption and asthma, researchers report.

Specifically, 18 tested hair care products each contained 6 to 30 endocrine-disrupting or asthma-associated chemicals.

This early research step may help explain why black women have higher levels of certain hormone-disturbing chemicals in their bodies, as well as hormone-related biological differences such as earlier puberty, and higher rates of asthma, say Jessica S. Helm, PhD, from the Silent Spring Institute in Newton, Massachusetts, and colleagues. Their study was published online April 23 in Environment Research.

“In general, many of the chemicals that we detected weren’t labeled,” Helm told Medscape Medical News.

“These results indicate the need for more information about the contribution of consumer products to [chemical] exposure [racial] disparities,” according to Helm and her coauthors.

“A precautionary approach would reduce the use of endocrine disrupting chemicals in personal care products and improve labeling so women can select products consistent with their values,” they conclude.

Data in Line With CDC Figures, Detox Me App Could Help

The research is in line with data from the US Centers for Disease Control and Prevention (CDC), which shows that black women have higher levels of some phthalates (used as a solvent in fragrances) and parabens (used as a preservative) in their bodies than white women.

“Products that we tested frequently contained higher levels of the parabens and diethyl phthalates, suggesting that [hair care products] are potentially a source of some of those [higher levels in the bodies of] black women,” Helm noted.

“Diethyl phthalate is frequently a fragrance ingredient, so by looking for products that don’t have paraben or fragrance on the label, [consumers] can reduce…exposure to those chemicals.” People can also look for ingredients from natural sources, she advised.

“And we have our [free] Detox Me app, which contains these and other tips” to lower exposure to potential toxins in personal care and other products, she noted.

Straighteners and Frizz Tamers

Black women have earlier puberty, higher rates of hormone-related uterine fibroids and infertility, and more aggressive forms of breast and uterine cancer, with rates of these cancers increasing, Helm and colleagues note.

And different hair care products used by black women and children are a potential source of these disparities in hormone-related health.

The researchers aimed to determine, for the first time, the concentrations of 66 endocrine-disrupting chemicals (parabens, phthalates, bisphenol A, antimicrobials, alkylphenols, fragrance, cyclosiloxanes, and UV filters) and asthma-associated chemicals (phthalates, bisphenol A, antimicrobials, ethanolamines, fragrances, and glycol ethers) in six types of hair care products commonly used by black women and children.

Based on a survey of black women living in New York City in 2004–2005, they identified 18 commonly used hair care products: six hair lotions, four root stimulators, three hair relaxers (including two for children), three anti-frizz agents, one hot-oil treatment, and one leave-in conditioner.

Using gas chromatography/mass spectroscopy researchers detected 45 of these 66 chemicals in the 18 products purchased in 2008. Details are provided in the online supplement to their article.

All products contained fragrance. Most (78%) contained parabens and 72% contained a UV filter (used as a sunscreen and to prevent product degradation).

Anti-frizz products contained cyclosiloxanes, used to increase spreadability, levels of which were the highest of all chemicals.

Root stimulators, hair lotions, and relaxers frequently contained nonylphenols, parabens, diethyl phthalate, and fragrances.

And 11 products contained endocrine-disrupting chemicals prohibited in the EU Cosmetics Directive (bisphenol A, benzyl butyl phthalate, bis[2-ethylhexyl] phthalate, 4-t-nonylphenol, diethanolamine) or regulated under California’s Proposition 65 because of their links to reproductive toxicity and cancer.

The hair relaxers for children had the highest levels of five chemicals prohibited in the European Union or regulated in California.

Incomplete Labeling Is Worrisome

Importantly, most chemicals (84%) were not specifically identified on the product label and may have been listed as “fragrance,” for example. However, chemicals detected at higher concentrations (more than 0.1% by weight) were more often listed on the label.

“Incomplete labeling is worrisome,” the researchers write, “because product ingredient labels are often the only source of information for individuals seeking to reduce their exposure to a chemical of concern.”

It is also important to note, Helm said, that women may use multiple products over a long time and effects could be cumulative.

“This study is evidence that hair products are an important source of toxic chemicals and that we need to remove these risks to protect black women’s lives and prevent harm,” Janette Robinson Flint, executive director of Black Women for Wellness, a nonprofit based in California that conducts research and education on toxic chemicals in personal care products through its Healthy Hair Initiative, said in a statement.

The study was partially funded by the Rose Foundation, Goldman Fund, and Hurricane Voices Breast Cancer Foundation.

Environ Res. Published online April 25, 2018. Full text

https://wb.md/2wdWifI

Docs Often Skip Counseling Arthritis Patients on Weight Loss

Although weight-loss counseling has increased, more than half of adults with arthritis and overweight or obesity do not receive it from their clinician, a study published in the May 4 issue of the Morbidity and Mortality Weekly Reportsuggests.

“From 2002 to 2014, the percentage of adults with arthritis and overweight or obesity who reported receiving provider weight-loss counseling increased by 10.4 percentage points,” write Dana Guglielmo, MPH, from the National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, and colleagues.

“These improvements are encouraging; however, approximately 75% of adults with overweight and 50% of those with class 1 obesity are not receiving provider weight-loss counseling.”

In the United States, more than 54 million adults have arthritis. One third or more of these individuals also have overweight or obesity, and the American College of Rheumatology recommends weight loss among this patient population to help manage their osteoarthritis symptoms.

Indeed, according to Guglielmo and colleagues, adults with overweight or obesity who receive weight loss counseling from their clinician are approximately four times more likely to attempt weight loss than are patients who do not receive counseling. And one of the aims of the Healthy People 2020 initiative is to improve clinician weight loss counseling among patients with arthritis with overweight or obesity.

With this in mind, the researchers examined changes in clinician counseling for weight loss among this patient population, using data from the National Health Interview Survey from 2002 to 2014. They included responses from adults aged 18 years and older with arthritis who have overweight or obesity.

Overall, 28.3 million adults in 2002 and 38.9 million in 2014 had both arthritis and overweight or obesity.

The prevalence of clinician counseling for weight loss among these individuals increased by 10.4% during the study period, rising from 35.1% (95% confidence interval [CI], 33.0% – 37.3%) in 2002 to 45.5% (95% CI, 42.9% – 48.1%) in 2014 (P< .001).

“By obesity subgroup, the prevalence increased 11.8 percentage points among persons with class 1 obesity (40.8% to 52.6%; p<0.001) and 15.5 percentage points among those with class 3 obesity (69.0% to 84.5%; p<0.001),” the authors write.

In contrast, the increase in weight loss counseling prevalence among individuals with class 2 obesity was not significant, remaining between 60% and 70% throughout the study.

However, despite the overall rise in counseling, the authors stress that approximately 75% of adults with arthritis and overweight, and 50% of those with class 1 obesity, are still not receiving weight loss counseling from their clinicians.

Guglielmo and colleagues suggest that including clinical decision supports in electronic medical records could help improve counseling rates. Increased training for clinicians around supporting patient self-management of weight loss might also help.

The authors also acknowledge some limitations of their study. In particular, they stress that the National Health Interview Survey data are self-reported, and some features might be susceptible to recall or social desirability bias, the latter of which could lead to underestimation of body mass index. Survey response rates were also low, they add, which could also bias results.

Nevertheless, they applaud the increase in clinician counseling for weight loss among adults with arthritis and overweight or obesity from 2002 to 2014, and stress that continued progress in this area can help ensure that as many of these patients as possible receive appropriate guidance and support for weight loss.

“Through combined counseling for weight loss, physical activity, and self-management education, and by making referrals to evidence-based programs, providers can help their patients with arthritis make meaningful improvements in quality-of-life and long-term health outcomes,” the authors conclude.

The authors have disclosed no relevant financial relationships.

Morb Mortal Wkly Rep. 2018;67:485-490. Full text

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Less Cancer Recurrence After Lumpectomy than Previously Thought

The decision by women with breast cancer to undergo lumpectomy rather than mastectomy appears to be a safer choice than previously believed, researchers reported.

Data from nine clinical trials over the last decade and a half show that compared with for historic protocols, use of modern multi-modality lumpectomy significantly reduced breast cancer recurrence at the original tumor site.

Specifically, the researchers found a 4.2% local recurrence rate for women who had lumpectomy and modern-era chemotherapy or other systemic therapies along with radiation therapy. This compares favorably with the “generally accepted” 5-10% rate for lumpectomy recurrence, said Heather Neuman, MD, of the University of Wisconsin School of Medicine and Public Health, who presented the findings at the annual meeting of the American Society of Breast Surgeons.

Speaking at a news conference at the meeting, Neuman pointed out that while the survival rates for both lumpectomy and mastectomy are similar, women have had a difficult choice between the two because of the greater risk of local recurrence with lumpectomy. However, she explained, the historical data on local recurrence with lumpectomy is based on older treatment protocols and over the last decade breast cancer therapies have become more personalized — and more effective — for a patient’s particular disease profile.

Neuman and her colleagues therefore sought to evaluate the recurrence rates after lumpectomy in a cohort of patients who had received modern-era therapy. Accordingly, the team evaluated data from nine Alliance for Clinical Trials in Oncology legacy clinical trials that included 6,927 women with stages I-III breast cancer between 1997 and 2011.

The researchers used Kaplan-Meier curves to estimate 5-year rates of local recurrence and used multivariable Cox proportional hazards models to identify factors associated with time to local recurrence, such as age, tumor size, node status, and molecular tumor subtype.

The overall rate of local recurrence at 5 years was 4.2% (95% CI 3.7-4.8%). There were variations seen based on receptor type, with the lowest rates seen for triple-positive patients that are ER/PR positive and HER2 positive (3%, 95% CI 1.9-4.8%). The team also found that the highest rates were for patients with ER/PR- HER2neu- (6.9%, 95% CI 5.6-8.4%).

“When looking at the Cox model that controlled for age, tumor size, and nodal status, receptor type remained very strongly associated with local recurrence,” Neuman said. “Additionally, older age was associated with a lower risk of local recurrence, and more positive nodes were associated with a higher risk of local recurrence.”

The study demonstrates “that in the modern era, the rate of local recurrence after breast-conserving surgery is quite low — lower than what has often been used historically to counsel women. These modern-era estimates should be used to inform discussions between patients and surgeons regarding the decision between breast conservation and mastectomy.”

Neuman also noted that as the knowledge of breast cancer biology grows, it has led to advances in breast-conservation therapies, such as more effective radiation therapy — which, she believes, has had the biggest impact on preventing tumor recurrence.

“By analyzing a large group of patients treated in the modern era, this study provides physicians with more current information to provide patients regarding local recurrence rates following breast-conserving therapy,” observed Carla Fisher, MD, medical director of Breast Surgical Oncology at Indiana University School of Medicine in Indianapolis, who was not involved in the study. “Encouragingly, [the researchers] note very low recurrence rates with variability by receptor status.

“These findings, along with the recent changes in the American Joint Committee on Cancer staging, further emphasize the importance of biologic factors in patient outcomes. Additionally, the study provides support for patients choosing breast-conserving therapy who are treated with modern, multimodal therapy.”

• Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

• Primary Source

  American Society of Breast Surgeons

  Source Reference: Neuman H, et al “Local recurrence rates after breast-conserving therapy in patients receiving modern era therapy” American Society of Breast Surgeons Annual Meeting 2018; Abstract 403956.

https://bit.ly/2IhScI2

To ‘rethink drug design,’ AI star Koller eyes machine learning venture

Daphne Koller has been busy.

Just two months since the high profile AI expert exited Google’s anti-aging biotech Calico Labs, where she was chief computing officer, Koller has gathered a group of marquee investors to back a tech upstart — insitro — with plans to develop a machine learning platform equipped with custom-built datasets to create a new and far more efficient approach to drug discovery and development.

AI circles have been buzzing with speculation and queries about what the former Stanford professor planned to do after exiting Calico, where she had been developing computational methods for analyzing biological data sets. She answered at least some of those questions with a blog post late Tuesday that spelled out her commitment to “invest heavily” in creating new datasets that can accelerate the use of machine learning in biopharma.

Koller has some high rollers backing the startup, including some venture groups well known for blockbuster fundraising and a yen for transformational ventures. They are: Arch Venture Partners, Foresite Capital, a16z, GV (formerly Google Ventures) and Third Rock.

Insitro, she says, will “collect and use a range of very large data sets to train ML models that will help address key problems in the drug discovery and development process. To enable the machine learning, we will use high-quality data that has already been collected, but we will also invest heavily in the creation of our own datasets using high throughput experimental approaches, datasets that are designed explicitly with machine learning in mind from the very start. The ML models that are developed will then help guide subsequent experiments, providing a tight, closed loop integration of in silico and in vitro methods (an insitro paradigm).”

According to Koller, the low hanging fruit in drug discovery has been picked. Reaching higher, going for much better drugs, will require “a different approach to drug development.” Spending billions to develop new drugs — and then passing the cost to patients — is not sustainable.

In launching insitro with a group of hyper connected backers, Koller is instantly making herself a top player in a field that has Big Pharma’s rapt attention. Streamlining R&D and improving the odds of success finding high impact therapies are considered keys to longterm profitability. But now the focus is on which outfits can actually deliver.

There will be plenty of people watching to see if Koller and the team she’s now recruiting can perform. And she knows it won’t be easy. She writes:

There is a lot of hype today around machine learning, with hyperbolic promises that it will magically solve all of humankind’s problems (and dire warnings that it will lead to the destruction of humankind). We at insitro don’t expect ML to be the solution to all of the problems in drug development, nor to be the magic bullet that helps find a treatment for every disease. However, we do believe that the time is right to rethink the drug design process using a different and more modern toolkit, in the hope that a new paradigm may help us cure more people, sooner, and at a much lower cost.

I’d queried Koller recently after hearing word about insitro. For now, she tells me in a message, her blog post goes about as deep into this as she wants to go right now. But more is coming.

https://bit.ly/2JMGO4j

Mallinckrodt jaundice drug snubbed by FDA advisory committee

Mallinckrodt got a big thumbs down from the FDA’s advisors who say data on the company’s newly-acquired jaundice drug isn’t convincing a majority of the group that it’s safe and effective.

The England-based drugmaker just bought the drug — called stannsoporfin — from InfaCare last year. It paid $80 million upfront in a deal that could add up to $425 million if milestones were reached. But the drug’s future is now cast in shadow, as the FDA’s advisory committee voted a strong no, with a clear majority (21 to 3) voting against an OK.

Stannsoporfin is a heme oxygenase inhibitor designed to prevent jaundice by turning down the dial on the formation of bilirubin, an orange-yellow pigment formed in the liver by the breakdown of hemoglobin and excreted bile.

Mallinckrodt was angling for an approval after InfaCare engineered a deal with the FDA to seek an approval based on a confirmatory Phase IIb study. But it looks like Mallinckrodt might have to add more data to the case for stannsoporfin before the drug moves forward.

The company released a statement Thursday evening.

“Mallinckrodt appreciates the committees’ review and discussion of stannsoporfin, and will work closely with the FDA as the review process continues. Given the outcome of today’s meeting, the company is evaluating alternatives for this development program.”

https://bit.ly/2rm6ME2