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Wednesday, June 2, 2021

Biogen, up for aducanuamb decision, could be ripe for activist incursion if it's rejected: report

 All eyes are on Biogen as it approaches its date with destiny.

By June 7, the FDA is set to rule on Biogen’s aducanumab. If approved, it would become the first treatment for Alzheimer’s disease to hit the market in more than two decades.     

But if it is rejected, the verdict could have far-reaching implications for the Massachusetts-based company. In fact, it could hasten an activist incursion, according to a report from Insightia.

In its Activitst Insight Vulnerability study, Insightia placed Biogen in the 93rd percentile in a ranking of companies most vulnerable to activist investor pressure over the next nine months. Compared to its peers, Biogen's stock has underperformed, the firm says.

Analyst Iuri Struta contends in the study that Biogen’s lack of preparation for a patent cliff for three key multiple sclerosis drugs—Tysabri, Tecfidera, and Vumerity—has left it exposed.

“Uncertainty over what will be the company’s next revenue driver has dented investor confidence,” Struta wrote.


The numbers Struta cites as reflective of a drop in investor confidence are Biogen's market capitalization trading at just 11 times its profits and 7.7 times its EBITDA (earnings before interest, taxes, depreciation and amortization). The median figures for Biogen’s industry peers are 22.2 and 15.8 respectively. 

Meanwhile, sales figures show a company in free fall. For the first time in decades, Biogen’s annual revenue fell in 2020 and did so in precipitous fashion, dropping from $14.4 billion in 2019 to $13.4 billion. The trend accelerated in the first quarter of this year, with revenue decreasing by 24%, much of it chalked up to a 26% drop in sales of MS drugs, which had begun to decline even before the coronavirus pandemic.

According to Struta, aducanumab is the “only real hope of avoiding a plunge over the patent cliff.”

The drug is designed to break down amyloid plaque buildup that is thought to worsen Alzheimer’s disease. Aside from aducanumab, Biogen and its development partner Eisai are working on another Alzheimer’s treatment, which has finished enrolling patients in a late-stage trial.

Beside these efforts, Insightia says, Biogen hasn’t done enough to sustain sales until 2024, the year CEO Michel Vounatsos targets for Biogen’s early-stage assets to reach the market. 

“An activist investor could question whether the management team is executing poorly or following the wrong strategy,” Struta writes.

Further, an activist could “demand the company spend more money on late-stage assets that could help smooth the upcoming loss of revenues," he added.


Since Vounatsos took over in 2017, Biogen has made just one acquisition, an $800 million purchase of Nightstar Therapeutics, which has brought promising drugs but nothing to address the immediate future, Insightia points out.

But rather than being an acquirer, Insightia sees a potential alternative for Biogen: It could sell itself or merge with a rival. Recent megadeals such as AbbVie’s acquisition of Allergan, Bristol Myers Squibb’s merger with Celgene and AstraZeneca’s buyout of Alexion are examples of the industry’s shifting landscape, the report says.

If an activist stare-down comes about, it won’t be the first time for Biogen. More than a decade ago, billionaire investor Carl Icahn sparred with the company over the same issues, claiming poor management and underperformance relative to peers. 

Icahn first urged Biogen to sell, then argued that it would be better off split in two, with one firm focused on oncology, the other on neurology. Icahn maneuvered to place three of his nominees on the board before abandoning a proxy fight in a 2010 settlement. 

Soon after, Biogen’s fortunes rose with approvals for MS drugs Tecfidera and Vumerity. But 2015 brought a reversal in the momentum, according to Insightia, and Biogen’s failure to respond has again left the company exposed. Tecfidera has now succumbed to U.S. generics, denting sales.


Ahead of the FDA's decision on aducanuamb, Brian Abrahams of RBC Capital Markets has warned investors to be ready, not only for a dramatic move in Biogen stock, but also for moves in the stock of other companies that sell Alzheimer’s treatments and even companies that may be takeover targets for Biogen, including Eisai.

“The FDA’s upcoming decision on aducanumab is not only binary for Biogen but also likely to reverberate throughout the biopharma sector, influencing overall sentiment on the space, perceptions on regulatory flexibility and business development dynamics,” Abrahams wrote. “With sector sentiment negative, the adu decision has potential to rapidly turn perceptions around or conversely, to double down on recent apathy.”

https://www.fiercepharma.com/pharma/aducanumab-biogen-s-future-balance-if-rejected-company-could-be-ripe-for-activist-incursion

Radiation Speeds Up Biological Aging in Head and Neck Cancer

 Patients who underwent radiotherapy for head and neck cancer experienced accelerated biological aging, which contributed to fatigue and inflammation, a prospective longitudinal study found.

Changes in epigenetic age acceleration (EAA) were significant over time, with the biggest increase -- 4.9 years -- seen immediately after the completion of radiotherapy (P<0.001), reported Canhua Xiao, RN, PhD, of Emory University School of Nursing in Atlanta, and colleagues.

The study also demonstrated that EAA was associated with greater inflammation and fatigue, even up to a year after treatment, they noted in Cancer.

While chronological age is a strong risk factor for chronic health problems, Xiao and colleagues said that it often differs from epigenetic age and may be a limited predictor of age-associated disorders. On the other hand, they noted that epigenetic clocks, based on blood DNA methylation measures, have become reliable aging biomarkers.

"Importantly, acceleration of epigenetic age, which is the discordance between epigenetic and chronological age, can be used to quantify the age acceleration process, which most current age markers or chronological age cannot," they wrote.

Xiao's group evaluated EAA in patients with head and neck cancer who underwent radiotherapy with or without chemotherapy, as well as the relationship of EAA with fatigue and inflammation before radiotherapy and up to 1 year after radiotherapy.

The study included 133 patients enrolled at oncology clinics at Emory University's Winship Cancer Institute. Most patients were men (72%) and white (82%), with a mean age of 59 years. Fifty-four percent were diagnosed with oropharyngeal cancer; of these, 90% were human papillomavirus (HPV)-related cancers. All had advanced disease and underwent radiotherapy; 80% underwent concurrent chemotherapy.

Data were collected at four time points -- before radiotherapy, immediately after completing radiotherapy, 6 months after radiotherapy, and 12 months after radiotherapy.

EAA was calculated using the Levine epigenetic clock (DNAm PhenoAge), adjusted for chronological age, while fatigue was measured with the Multidimensional Fatigue Inventory-20 questionnaire. Inflammation was measured using standard laboratory techniques.

Xiao and colleagues found that the magnitude of age acceleration gradually decreased after radiotherapy, with a nonsignificant increase of 0.3 years in EAA persisting 1 year after the completion of treatment (P=0.61) compared with baseline. Post-hoc analyses showed a significant increase in EAA -- 4.7 years -- at the end of radiotherapy among those who also received chemotherapy, but not those who did not receive chemotherapy (P=0.001).

In addition, fatigue scores increased from baseline to the end of radiotherapy, and then gradually decreased over time. Over the course of the study, patients with severe fatigue experienced 3.1 years higher EAA compared with those who reported low fatigue (P<0.001).

EAA was most prominent in patients with HPV-unrelated disease at 12 months after treatment, the authors noted; those with HPV-unrelated tumors who experienced severe fatigue showed an increase of 5.63 years in EAA compared with those who reported low fatigue (P=0.018).

The study also showed that EAA was positively associated with several inflammatory markers over time. For example, patients who had high C-reactive protein levels had an EAA increase of 4.6 years, while those with high levels of interleukin-6 had an increase of 5.9 years, compared with patients who had low levels. Further analysis showed that inflammatory markers significantly mediated the relationship between EAA and fatigue.

The findings "add to the body of evidence suggesting that long-term toxicity and possibly increased mortality incurred from chemoradiation for patients with [head and neck cancer] may be related to increased EAA and its association with inflammation," the authors concluded. "Interventional studies to reduce inflammation, including before chemoradiation, might significantly benefit patients who have cancer in decelerating the aging process and subsequently reducing age-related chronic health problems such as fatigue."

In an accompanying editorial, Kord Kober, PhD, and Sue Yom, MD, PhD, both of the University of California San Francisco, noted that cancer-related fatigue may not be just an ancillary symptom, "but a meaningful physiological phenomenon reflecting a dangerous biology at work in these patients." They further speculated that a chronic inflammatory state that predisposes patients to fatigue and premature aging could be a contributing factor to poor outcomes.

"If there are possibilities that we might be able to combine advances in oncologic aims with improving the overall health and quality of life of our patients who are at highest risk in all of these domains, these deserve concentrated and serious exploration," they wrote.


Disclosures

The study was supported by grants from the National Institute of Nursing Research and the National Cancer Institute .

Xiao reported no disclosures. Co-authors reported relationships with industry.

Kober reported no disclosures.

Yom reported institutional research funding from Genentech, Bristol Myers Squibb, Merck, and BioMimetix; royalties or licenses from Springer and UpToDate; and honoraria from the American Society for Radiation Oncology, all outside the submitted work. She is president of the American Radium Society.

Parkinson's: How Long Do Deep Brain Stimulation Benefits Last?

 Deep brain stimulation remained effective in Parkinson's disease patients more than 15 years after the device was implanted, and patients continued to demonstrate significant improvement in motor symptoms, a retrospective study showed.

Parkinson's patients who had bilateral subthalamic nucleus deep brain stimulation for 15 years or longer spent 75% less time with dyskinesia and 58.7% less time in the off state than pre-surgery baseline (both P<0.001), reported Elena Moro, MD, PhD, of Grenoble Alpes University in France, and co-authors.

These patients also reduced their dopaminergic drugs by 50.6% (P<0.001), they wrote in Neurology. The Parkinson's Disease Quality of Life (PDQL) questionnaire total score, emotional function domain score, and social function domain score improved by 13.8% (P=0.005), 13.6% (P=0.01) and 29.9% (P<0.001), respectively.

"Deep brain stimulation benefits seem to last for several years but not enough data have been available to show that these effects are still present more than 15 years after surgery," Moro said in a statement.

"Our study found that, despite the natural progression of Parkinson's disease and the worsening of some symptoms that become resistant to medications over the years, participants still maintained an overall improvement in quality of life," she added.

"These results (better motor outcomes with less medication) reinforce why subthalamic nucleus deep brain stimulation has revolutionized treatment for advanced Parkinson's disease," observed Kelvin Chou, MD, of the University of Michigan in Ann Arbor, and David Charles, MD, of Vanderbilt University in Nashville, in an accompanying editorial.

Grenoble researchers were the first to report the therapeutic effects of bilateral subthalamic nucleus deep brain stimulation on bradykinesia and rigidity in patients with Parkinson's disease, Chou and Charles noted. The Grenoble group now has the largest number of patients who have lived with deep brain stimulation for 15 years or more.

When patients ask how long benefits of deep brain stimulation last, "we can now reassure them that, at least for subthalamic nucleus deep brain stimulation, improvement in motor complications lasts beyond 15 years and is often accompanied by improvement in quality of life," the editorialists wrote.

In their study, Moro and colleagues evaluated 51 patients with a mean of about 17 years followup after surgery. At surgery, all patients had idiopathic Parkinson's disease, disabling motor complications (motor fluctuations or levodopa-induced dyskinesia), and levodopa responsiveness in all Parkinson's cardinal motor symptoms, including tremor. On average, the group -- 33 men and 18 women -- was about 51 years old at baseline and had Parkinson's disease for 11.35 years.

In 39 patients with complete long-term data, subthalamic nucleus deep brain stimulation improved motor fluctuations and dyskinesia scores on the Unified Parkinson's Disease Rating Scale (UPDRS). Compared with baseline, the time spent with dyskinesia was reduced by 75% (1.64 vs 0.41, P<0.001), and the time spent in the off state diminished by 58.7% (1.85 vs 0.74, P<0.001).

In 27 patients with full long-term followup data, both short-term and long-term PDQL scores improved. Total PDQL score improved by 26.7% at 1 year, while emotional function domain scores rose 21.7%, and social function domain scores increased 33.3%.

In the long-term, 19 patients (37.3%) were completely independent in their activities of daily living, 27 patients (52.9%) needed some help, and five (9.8%) were institutionalized. A total of 18 of 51 patients (35.3%) had dementia.

In contrast to medically managed Parkinson's patients who often lose weight, people in this study gained an average of 9 kg in the first year after surgery, which remained stable during the entire followup period. During long-term followup, five patients needed lead reimplantation due to intracranial infections, lead malfunctions, or lead suboptimal placement.

The study had several limitations, the researchers acknowledged. A high percentage of patients who received deep brain stimulation more than 15 years ago were lost at long-term followup, and the sample presented here may not be representative. Some people in the study did not have long-term motor or quality of life scores.

The editorialists also pointed out that the results are from a highly selected cohort that has been managed by experts in the field of movement disorders and deep brain stimulation. The average age at surgery was 51 and, as a group, these patients already had lived with Parkinson's for 11 years. In contrast, "the average age of onset for Parkinson's disease is between 65-70 years of age," Chou and Charles noted.


Disclosures

The study had no targeted funding.

Researchers reported relationships with Medtronic, Boston Scientific, St Jude, Abbott, and Newronika.

Editorialists reported relationships with NIH, Parkinson Study Group, Michael J. Fox Foundation, Eli Lilly, Voyager Therapeutics, Neuraly, Abbott, Watermark Research Partners, Accordant, CNS Ratings, UpToDate Springer Publishing, Alliance for Patient Access, Newronika, Revance, and US WorldMeds.

AmerisourceBergen Boosts Fiscal Year Earnings Forecast

 AmerisourceBergen Corp. on Wednesday raised its annual earnings forecast following the completion of its purchase of the majority of Walgreens Boots Alliance Inc.'s Alliance Healthcare businesses for $6.275 billion in cash and two million shares.

The drug distributor said it now expects adjusted earnings of between $8.90 and $9.10 a share for fiscal 2021, where it previously anticipated $8.45 to $8.60.

Revenue for the year is expected to be at least $210 billion, compared with earlier guidance for growth in the high-single-digits percent range, AmerisourceBergen said. The company logged revenue of $189.9 billion in fiscal 2020.

AmerisourceBergen said it continues to have a strong performance across its businesses.

With the completion of the sale of its Alliance Healthcare businesses, Walgreens Boots said it would use the proceeds to reduce debt and accelerate growth of its core retail pharmacy and healthcare businesses.

https://www.marketscreener.com/quote/stock/AMERISOURCEBERGEN-CORPORA-9428091/news/AmerisourceBergen-Boosts-Fiscal-Year-Earnings-Forecast-35499215/

Novartis Kisqali: longest median overall survival in postmenopausal HR+/HER2- metastatic breast cancer

 -- MONALEESA-3 median overall survival (OS) results of 53.7 months

      underscore that Kisqali offers more life to postmenopausal women with 
      HR+/HER2- metastatic breast cancer (MBC) in addition to the OS benefit 
      demonstrated for premenopausal women as shown in MONALEESA-71,2 
 
   -- The relative risk reduction of death by 36% in the MONALEESA-3 first-line 
      (1L) postmenopausal population highlights that Kisqali is the only 
      CDK4/6i with proven OS for 1L in combination with fulvestrant1 
 
   -- Time to chemotherapy was delayed to 4 years (48.1 months) in 
      postmenopausal women taking Kisqali in combination with fulvestrant 
      compared to 2.4 years (28.8 months) for women receiving fulvestrant only1 
 
   -- MBC takes a life in the US approximately every 12 minutes, creating an 
      urgent need for treatment proven to extend life while preserving quality 
      of life3-6 
https://www.marketscreener.com/quote/stock/NOVARTIS-AG-9364983/news/Press-Release-nbsp-Novartis-Kisqali-R-reports-longest-median-overall-survival-in-postmenopausal-H-35500199/

Novartis Kymriah trial: strong response rates, safety profile in relapsed or refractory follicular lymphoma

  -- Primary analysis of ELARA trial demonstrated a 66% complete response rate

      and 86% overall response rate with one-time Kymriah infusion1 
 
   -- Robust response observed in heavily pretreated patients in critical need 
      of a potentially definitive treatment option1,2 
 
   -- No patients in ELARA trial experienced grade 3/4 cytokine release 
      syndrome, the most common side effect associated with CAR-T therapy1 
 
   -- Global regulatory submissions based on the ELARA trial on track for later 
      this year
https://www.marketscreener.com/quote/stock/NOVARTIS-AG-9364983/news/Press-Release-nbsp-Novartis-Kymriah-R-pivotal-trial-demonstrates-strong-response-rates-and-a-rema-35500399/

Developed Countries Lock Up Covid-19 Vaccines Through 2023

 The European Union, Canada and other developed countries have signed deals to get hundreds of millions of doses of Covid-19 vaccines and boosters over the next two years, furthering a divide between rich and poor countries.

Under the recent deals, Pfizer Inc. and BioNTech SE agreed to supply the European Union up to 1.8 billion doses of their vaccine through 2023, while agreeing to supply Canada up to 125 million doses.

Australia, Switzerland and Israel, meanwhile, are set to get Moderna Inc.'s shot through next year, and Switzerland has options for doses in 2023.

The agreements will ensure the countries, including some that failed to lock up sufficient supplies of the mRNA vaccines earlier this year, have enough supplies to inoculate residents and protect them against potentially elusive variants, while providing a sales windfall to the manufacturers.

Yet the deals once again leave out developing countries, many of which have fallen behind in vaccinating residents and struggled to contain the spread of the virus.

Moderna sees Covax, the global-health initiative intended to get doses to low-income countries, as its primary means to supply lower- and middle-income countries, a spokesman said. The company said last month it would deliver 34 million doses in the fourth quarter of 2021 to Covax, which has an option to purchase another 466 million doses next year.

Pfizer has pledged to provide 2 billion doses to low- and middle-income countries over the next 18 months, a company spokeswoman said. It also has agreed to provide 40 million doses to Covax this year for distribution, which have begun to reach more than a dozen countries, she said. Pfizer's commitment to ensure access to the vaccine "has never wavered," and it is talking with countries and stakeholders about improving access, she added.

About 6 billion doses have been purchased by more than two dozen rich nations and the European Union, according to the latest figures from the Duke University's Global Health Innovation Center, which tracks vaccine purchases. By comparison, the rest of the world has combined to purchase more than 3 billion doses.

Neither the countries nor the companies disclosed the terms of the recent deals.

Covid-19 vaccine sales are forecast to total $70 billion through next year for Pfizer and more than $27 billion for Moderna, according to Bernstein Research.

Bernstein estimates Pfizer and BioNTech charge between $18 and $19.50 a dose in developed markets, compared with $7.50 in developing markets. Moderna charges between $17 and $20 a dose, compared with $8 in developing markets, according to Bernstein.

The Pfizer-BioNTech vaccine's sales would make it among the top-selling pharmaceuticals of all time. AbbVie Inc.'s anti-inflammatory drug Humira has been the recent top seller, notching nearly $20 billion in 2018 sales.

The U.S. hasn't signed new supply deals, but its agreements with Pfizer and Moderna provide the option for future purchases. In the U.S., each company is slated to deliver 300 million doses by the end of July.

The EU deal would help the bloc resolve the vaccine procurement problems that hurt its vaccination efforts earlier this year.

EU residents and public-health experts criticized the bloc as ordering vaccines too slowly, partly because they didn't want to pay as much as Pfizer and Moderna sought, and favoring older vaccine technologies over new ones.

Limited supplies of the mRNA vaccines hit especially hard after some countries restricted use of shots from AstraZeneca PLC and Johnson & Johnson over safety concerns.

The recent deals suggest the two-dose vaccines from Pfizer and Moderna have become the vaccines of choice in developed nations. They also mean most of the developed world should have enough Covid-19 vaccine supplies for the next couple of years to protect all their residents.

The new EU deal builds on 600 million doses Pfizer agreed to deliver this year. Under the deal, Pfizer agreed to send an initial 900 million doses starting in December, and the EU has the option to buy another 900 million doses.

The new supply will be enough for the bloc's 450 million citizens to get four Pfizer-BioNTech doses, according to Bernstein.

Australia, which has about 25 million residents and recently stopped administering AstraZeneca's shot to people under age 50, said last month that Moderna would provide 10 million doses this year and 15 million booster shot doses next year. Earlier, the country had placed orders for 40 million doses for delivery this year.

Pfizer has said it expects to produce 3 billion doses this year, and at least 4 billion next year. Moderna said it is targeting manufacturing up to 3 billion doses next year.

Some developing nations have reached deals with mRNA vaccine makers for doses, though supplies probably aren't enough to vaccinate all their populations.

Paraguay, which counts more than 7 million residents, said last month it signed a supply deal for 1 million doses of the Pfizer-BioNTech vaccine. Botswana said in April that Moderna is providing the African country, which has more than two million people, 500,000 doses of its shot.

Of the approximate 50 supply deals that Pfizer and BioNTech have with countries and groups like Covax, about half are with low- and middle-income countries, according to Duke's Global Health Innovation Center.

Pfizer has said it would discount its vaccine to middle-income countries, while providing it at cost to poorer countries.

Six of the 19 Moderna deals are for low- and middle-income countries, according to the Duke center. Moderna has said it would price its vaccine in low-income countries at its lowest-tier price.

Many developing nations are still negotiating with Pfizer and Moderna, according to the companies. They also are waiting on doses from Covax and appealing to the U.S. government to provide excess doses.

Covax has been beset by manufacturing and delivery delays.

To access more doses, some developing countries have asked the World Trade Organization to waive patent protection for Covid-19 vaccines. The U.S. said it supports the move, though Germany and some other developed countries have opposed it. The drug industry is lobbying against the proposal, saying waiving patent protection wouldn't provide relief any time soon while straining raw material supplies.

Public-health and vaccine experts say developing countries need more supplies to vaccinate residents to contain the spread of the virus and protect against dangerous new variants that emerge.

Developed countries won't be able to fully reopen, the specialists added, unless developing nations are able to immunize a sufficient number of residents.

With developed countries securing more doses for the next few years, low- and middle-income countries will probably find themselves dependent on rich countries to share or reallocate doses, said Prashant Yadav, a senior fellow at the Center for Global Development who studies supply chains.

He said that, if the divergence persists, more countries will likely sign supply deals with China and Russia, which have been eagerly providing doses made by their manufacturers.

https://www.marketscreener.com/quote/stock/MODERNA-INC-47437573/news/Developed-Countries-Lock-Up-Covid-19-Vaccines-Through-2023-35503918/