Inside Sanofi's $3.2B Translate Bio Buyout

 

• Before the $3.2 billion acquisition of mRNA player Translate Bio Inc TBIO 0.21% earlier this month, Sanofi SA SNY 0.21% expressed interest in selling off around 25% of its shares in the company, which it had been working with since 2018.
• Translate Bio filed SEC document to give an inside look at how the buyout negotiations played out. Translate agreed to that plan, but it didn’t last long. 
• Sanofi CEO Paul Hudson reached out to Translate CEO Ron Renaud in late May, indicating that Sanofi was now interested in buying Translate outright. The initial offer came in at $28 per share.
• Translate asked its consultants to test the waters for other potential suitors as part of its due diligence on a possible deal. Feelers put out to three companies that turned up duds, with all three showing no interest in engaging.
• On June 4, Translate told Sanofi that its initial offer was “insufficient” and undervalued the company. Sanofi responded with a 55% premium offer, but Translate asked for $40 per share as a final offer. 
• In response, Translate asked Sanofi an offer of $37 to $38 per share with milestones baked in to get shareholders $40 per share. 
• Sanofi countered with an offer of $35 and eventually agreed to come up to $38.
• The acquisition also makes sense in Sanofi’s plans to make mRNA a centerpiece of its business plan moving ahead. 
• In June 2020, Sanofi laid out $425 million in cash upfront and up to $1.9 billion in milestones payments to accelerate its partnership with Translate, signed initially in mid-2018.

https://www.benzinga.com/general/biotech/21/08/22517496/inside-sanofis-3-2b-translate-bio-buyout

Less passive screen time, more structure better for kids' mental health in pandemic

 There are a number of simple, practical steps that families can take -- including reducing passive screen time and news consumption, having a structured daily schedule and getting enough sleep -- that can promote resilience against mental health problems in youth during the COVID-19 pandemic, according to a new study published this week in the open-access journal PLOS ONE by Maya Rosen of Harvard University, US, and colleagues.

The COVID-19 pandemic has introduced unprecedented change into the lives of children and adolescents. Many of these disruptions, coupled with pandemic-related stressors, are likely to increase risk for depression, anxiety and behavioral problems in youth.

In the new study, researchers recruited participants from two ongoing longitudinal studies of children and adolescents in the greater Seattle area. 224 youth and their caregivers completed an initial questionnaire assessing social behaviors, psychopathology and pandemic-related stressors in April and May 2020; 184 of these youth and their caregivers completed a similar battery of assessments six months later, in November 2020 through January 2021. Since data on each youth was available from prior to the pandemic, results at each time point could be controlled for pre-pandemic symptoms. The youth ranged in age from 7 to 15 years old, were 47.8% female, and their racial and ethnic background reflected the Seattle are, with 66% of participants White, 11% Black, 11% Asian and 8% Hispanic or Latino.

The number of pandemic-related stressors was strongly associated with increases in both internalizing (β=0.345, p<0.001) and externalizing (β=0.297, p<0.001) symptoms during the pandemic after controlling for pre-pandemic symptoms. Early in the pandemic, youths who spent less time on digital devices (β=0.272, p=.0004) as well as those who consumed less than 2 hours of news per day (β=0.193, p=.010) had lower externalizing symptoms, while greater time spend in nature was marginally associated with lower internalizing symptoms (β=-0.124, p=.074). Getting the recommended amount of sleep (β=0.-0.158, p=.080) and having a more structured daily routine during stay-at-home orders (β=-0.164, p=.049) was associated with lower levels of externalizing psychopathology six months later. Finally, the strong association between pandemic-related stressors and psychopathology was absent among children with lower amounts of screen time and news media consumption. The authors write that the study identifies a set of strategies that can be beneficial to families when considering how to support the mental health of their children during the ongoing COVID-19 pandemic.

The authors add: "Mental health problems increased dramatically among children and adolescents during the COVID-19 pandemic, particularly among those who experienced high levels of pandemic-related stressors including serious illness or death of a family member, significant financial loss, and social isolation. A number of simple strategies families engaged in appeared to promote better mental health during the pandemic including having a structured daily routine, limiting passive screen time use, limiting exposure to news media about the pandemic, and to a lesser extent spending more time in nature, and getting the recommended amount of sleep."

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Materials provided by PLOS. Note: Content may be edited for style and length.

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Journal Reference:

1. Maya L. Rosen, Alexandra M. Rodman, Steven W. Kasparek, Makeda Mayes, Malila M. Freeman, Liliana J. Lengua, Andrew N. Meltzoff, Katie A. McLaughlin. Promoting youth mental health during the COVID-19 pandemic: A longitudinal study. PLOS ONE, 2021; 16 (8): e0255294 DOI: 10.1371/journal.pone.0255294

https://www.sciencedaily.com/releases/2021/08/210816102542.htm

Blood clotting may be root cause of Long COVID syndrome

 New evidence shows that patients with Long COVID syndrome continue to have higher measures of blood clotting, which may help explain their persistent symptoms, such as reduced physical fitness and fatigue.

The study, led by researchers from RCSI University of Medicine and Health Sciences, is published in the Journal of Thrombosis and Haemostasis.

Previous work by the same group studied the dangerous clotting observed in patients with severe acute COVID-19. However, far less is known about Long COVID syndrome, where symptoms can last weeks to months after the initial infection has resolved and is estimated to affect millions of people worldwide.

The researchers examined 50 patients with symptoms of Long COVID syndrome to better understand if abnormal blood clotting is involved.

They discovered that clotting markers were significantly elevated in the blood of patients with Long COVID syndrome compared with healthy controls. These clotting markers were higher in patients who required hospitalisation with their initial COVID-19 infection, but they also found that even those who were able to manage their illness at home still had persistently high clotting markers.

The researchers observed that higher clotting was directly related to other symptoms of Long COVID syndrome, such as reduced physical fitness and fatigue. Even though markers of inflammation had all returned to normal levels, this increased clotting potential was still present in Long COVID patients.

"Because clotting markers were elevated while inflammation markers had returned to normal, our results suggest that the clotting system may be involved in the root cause of Long COVID syndrome," said Dr Helen Fogarty, the study's lead author, ICAT Fellow and PhD student at the Irish Centre for Vascular Biology in the RCSI School of Pharmacy and Biomolecular Sciences.

This work was funded by the Welcome Trust, the Health Research Board (HRB) Irish Clinical Academic Training (ICAT) programme as well as the HRB-funded Irish COVID-19 Vasculopathy Study (ICVS). The work was also supported by a philanthropic grant from the 3M Foundation to RCSI University of Medicine and Health Sciences in support of COVID-19 research.

"Understanding the root cause of a disease is the first step toward developing effective treatments," said Professor James O'Donnell, Director of the Irish Centre for Vascular Biology, RCSI and Consultant Haematologist in the National Coagulation Centre in St James's Hospital, Dublin.

"Millions of people are already dealing with the symptoms of Long COVID syndrome, and more people will develop Long COVID as the infections among the unvaccinated continue to occur. It is imperative that we continue to study this condition and develop effective treatments."

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Story Source:

Materials provided by RCSI. Note: Content may be edited for style and length.

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Journal Reference:

1. Helen Fogarty, Liam Townsend, Hannah Morrin, Azaz Ahmad, Claire Comerford, Ellie Karampini, Hanna Englert, Mary Byrne, Colm Bergin, Jamie M. O’Sullivan, Ignacio Martin‐Loeches, Parthiban Nadarajan, Ciaran Bannan, Patrick W. Mallon, Gerard F. Curley, Roger J.S. Preston, Aisling M. Rehill, Dennis McGonagle, Cliona Ni Cheallaigh, Ross I. Baker, Thomas Renné, Soracha E. Ward, James S. O’ Donnell. Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome. Journal of Thrombosis and Haemostasis, 2021; DOI: 10.1111/jth.15490

https://www.sciencedaily.com/releases/2021/08/210816125717.htm

Robust T-cell response to mRNA COVID-19 vaccines: more durable protection

 Messenger-RNA (mRNA) vaccines against the coronavirus that causes COVID-19 provoke a swift and strong response by the immune system's T cells—the heavy armor of the immune system—according to a study from researchers in the Perelman School of Medicine at the University of Pennsylvania. Although recent studies of vaccines tend to focus on the antibody response, the T-cell response is also an important and potentially more durable source of protection—yet little has been reported so far on the T-cell response to COVID-19 vaccines.

In the new study, which appears in the journal Immunity, the Penn Medicine researchers analyzed the T-cell responses in 47 healthy people who received two doses of the Moderna and Pfizer/BioNTech mRNA vaccines.

The results reveal the complex details of how the T-cell response to these vaccines unfolds, and underline the importance of a second dose for people with no history of COVID-19. The findings showed, however, that in people with a history of COVID-19, the T-cell response was already robust after the first vaccine dose, with no significant increase after the second dose, which may have implications for potential future booster shots.

"Our findings underscore the fact that we need to look at T cells, not just antibodies, if we want a complete picture of the vaccine response for those who have not had COIVD-19 and for those who have recovered from the disease," said senior author E. John Wherry, PhD, chair of the department of Systems Pharmacology and Translational Therapeutics and director of the Penn Institute of Immunology in the Perelman School of Medicine at the University of Pennsylvania.

Antibodies are forked proteins secreted by immune cells called B cells; they can bind tightly to specific viral structures on virus-infected cells. T cells also have antibody-like receptors that enable tight binding to specific viral structures, but they are whole cells, some of which—called "killer" T-cells—are capable of directly killing virus-infected cells they encounter. T cells therefore have long been regarded as the heavy armor of the immune system. Their responses to vaccines are harder to study than antibody responses, though, so less is known about those responses, including in the case of COVID-19.

Researchers examined in detail the T-cell responses to mRNA vaccination in 36 healthy people who had no history of COVID-19, and 11 people who had previously recovered from COVID-19.

In the group of participants who did not previously have COVID-19, they found that the first vaccine dose elicited a rapid and strong response from helper T cells called CD4 T cells—some of which help marshal an antibody response, while others stimulate the proliferation of CD8 killer T cells. The strengths of those initial CD4 T cell responses generally predicted the later strengths of antibody and killer T-cell responses. However, the killer T cells tended not to appear in large numbers until after the second vaccine dose—confirming the importance of that second dose for people with no COVID-19 history.

By contrast, in the prior-COVID-19 group, helper and killer T cells specific for the COVID-19 coronavirus were already substantially present before the first dose. After that first dose, T cell numbers rose somewhat, but did not significantly increase after the second dose.

"For people who haven't had COVID-19, the first dose powerfully primes the pump, and the second dose turns on the whole engine—but having had COVID-19 is like having had that first vaccine dose already," Wherry said. "It is important to point out, however, that a complete understanding of the relative importance of these T cell responses, compared to antibody, in protection from future infections will require larger clinical studies."

The results also showed that the T-cell response in the weeks after mRNA vaccination includes T-cell types normally elicited by natural infection—and in general, natural viral infection is known to be capable of inducing T-cell protection that lasts years and even decades.

"We need to do follow-up studies to confirm the longevity of the T-cell response to vaccination, but our results here support the idea that that response can be long-lasting," Wherry said.

More information: Mark M. Painter et al, Rapid induction of antigen-specific CD4+ T cells is associated with coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination, Immunity (2021). DOI: 10.1016/j.immuni.2021.08.001

https://medicalxpress.com/news/2021-08-robust-t-cell-response-mrna-covid-.html

After FibroGen FDA rejection, Akebia CEO aims to seize first-in-class opening with vadadustat

 In the race for novel oral drugs to treat anemia of chronic kidney disease, AstraZeneca and FibroGen’s roxadustat held the front-runner position for quite some time. But as that program has now stumbled, rival Akebia Therapeutics sees a first-in-class opportunity for its underdog vadadustat.

Despite roxadustat’s recent FDA rejection, Akebia remains confident its Otsuka-partnered vadadustat can at least get an FDA approval in patients who aren't dependent on dialysis, CEO John Butler said in an interview.

Still, after roxa’s FDA rejection, Akebia has some convincing to do. As the company’s stock performance suggests, investors seem to believe that vada will follow a similar path to roxa and ultimately be turned away by U.S. drug regulators. Akebia’s stock price was nearly halved in July and hasn’t recovered since.

Akebia's vadadustat has already won approval in Japan for anemia from chronic kidney disease in both dialysis-dependent and nondialysis-dependent patients. The company’s local partner Mitsubishi Tanabe Pharma is selling the drug there under the brand name Vafseo. If eventually approved by the FDA, vadadustat would be the first in the HIF-PH inhibitor to enter the U.S. market.

HIF-PHIs, a drug class that includes roxa and vada, leverage the body’s natural response to a reduction in the level of oxygen to induce red blood cell production. Scientists hope this novel mechanism of action can help patients avoid the dangerous heart-related side effects seen in the current standard-of-care injectable erythropoiesis-stimulating agents (ESAs), such as Amgen’s Epogen and Johnson & Johnson’s Procrit.

But in a stunning revelation earlier this year, the FDA linked roxa to increased risk of blood clots, death, serious infections and other complications compared with erythropoietin therapy in the dialysis population and with placebo in nondialysis-dependent patients. The safety concerns prompted a key FDA advisory committee to vote against a potential approval, and the FDA rejected the drug last week.

About a year ago, vada also failed on a safety marker of a composite of heart-related events when compared with Amgen’s ESA Aranesp in healthier, nondialysis-dependent patients in the phase 3 Pro2tect trial. That flop, paired with roxa’s safety signal, made many market watchers believe HIF-PHIs share the same heart safety problem.

Akebia begs to differ.

“We obviously don’t think that there’s a class-wide issue here,” Butler said. As the CEO pointed out, vada matched up to Aranesp in the dialysis-dependent population in the phase 3 Inno2vate study on the major adverse cardiovascular event (MACE) marker, which includes death, heart attack and stroke. Some of the safety problems that cropped up in roxa’s trial, including thromboembolic events, seizures and serious infections, weren’t seen in vada’s program, Butler noted.

For roxa, the FDA and FibroGen suspect that the blood clots might be related to a hemoglobin overshoot. While the hemoglobin overreaction could theoretically be managed by lowering the drug’s dose, the FDA still need hard data to show that doing so could solve the cardiovascular safety problem. In vada’s phase 3 trials, the drug instead showed a more “gradual increase” in hemoglobin, Butler pointed out. 

Butler’s confidence in vada’s approval also comes from the fact that the company designed vada’s registrational trials while in dialogue with the FDA. As the agency expressed concerns about hemoglobin overdrive and its potential risks, Akebia lowered vada’s starting dose to 300 mg once daily from the 450 mg strength used in its phase 2 trial.

Still, even though Akebia may have run vada’s clinical program under the FDA’s advice, the agency lately has become somewhat unpredictable. Just a few days ago, the FDA rejected Adrelyx's chronic kidney disease prospect tenapanor even though the drug hit all of the clinical endpoints agreed upon by the FDA. Plus, the agency convened roxa’s advisory committee meeting late into its review, surprising industry watchers.

Butler noted that vada’s application is under consideration at the FDA’s non-malignant hematology division, which is different team than the tenapanor review group. On a potential advisory committee meeting, the CEO said the company is preparing for that possibility even though the agency said it didn’t expect one. The drug is set for an FDA decision by March 29, 2022.

As for the nondialysis population, Butler said Akebia is “more cautious” about its drug’s approvability in those patients given the negative phase 3 data. Still, the eight-year Akebia veteran sees a window for vada to score a go-ahead in that use.

In the Pro2tect trial, vada matched up to Aranesp on the MACE endpoint in nondialysis patients in the U.S., who made up about half of the trial participants, the CEO pointed out. The different outcome in ex-U.S. patients might be caused by inconsistent clinical practices for managing nondialysis patients in different parts of the world, he said.

An FDA approval based on subgroup analysis is never a certainty at the FDA. Analysts at BTIG, Cantor Fitzgerald, Mizuho and Piper Sandler all figured vada can win over the FDA in the dialysis population but that it’s not likely in nondialysis patients.  

Even so, a limited nod would crown vada the first HIF-PHI to land on the U.S. market. That’s good enough to get analysts excited over vada’s commercial potential, especially since the drug was once thought to not stand a chance against then first-in-class candidate roxa.

After roxa’s thumbs-down at the advisory committee in July, Cantor’s Alethia Young said vada’s peak sales in U.S. dialysis patients could reach $1.2 billion, assuming a market penetration of 40%. Piper Sandler’s Christopher Raymond has put the drug’s 2025 sales at $629 million worldwide. BTIG’s Bert Hazlett has calculated nearly $500 million U.S. dialysis sales for that year.

Although roxa isn’t getting to the U.S. market in the foreseeable future—if ever—AZ and Daiichi are exploring next steps after the rebuff. And a third player isn’t far off.

GlaxoSmithKline last June snatched a Japanese nod for its HIF-PHI candidate daprodustat under the brand name Duvroq for patients regardless of their dialysis status. In July, the British pharma touted topline data from its global phase 3 program dubbed Ascend. In the study, dapro was non-inferior to ESAs on MACE for both dialysis and nondialysis groups.

GSK’s topline message at least refuted the notion that heart safety represents a class concern for all HIF-PHIs, Butler said. As for the potential threat from this fast follow-up, the Akebia CEO said he looked forward to seeing detailed data to make a judgment.

In the U.S. and EU, Akebia has partnered with Otsuka. The two firms are currently working through the details of the marketing strategy and the split of responsibilities, Butler said.

In addition, Akebia in 2019 expanded a licensing deal with Vifor Pharma to provide vada to the Fresenius Medical Care dialysis clinics and other third-party dialysis organizations in the U.S. The collaboration gives vada access to up to 60% of U.S. dialysis patients, Akebia says.

https://www.fiercepharma.com/pharma/as-roxadustat-lost-fda-s-favor-akebia-ceo-touts-first-class-opening-for-its-anemia-contender

Philip Morris enters tender for Vectura

 The Vectura board have unanimously recommended PMI's 165p-per-share offer to shareholders

- The board cited PMI’s superior cash price offered to Vectura shareholders, and the benefit to stakeholders from PMI's significant financial resources, commitment to enhanced research and development, and autonomy as factors contributing to their decision

Philip Morris International Inc. (PMI) (NYSE: PM) today announced it has published an offer document with U.K.-based Vectura Group plc (Vectura) (LSE: VEC) in connection with the recommended cash offer to acquire the inhaled therapeutics company. Under the terms of the acquisition, Vectura shareholders would be entitled to receive 165 pence per share, a 60% premium to the ex-dividend closing price of 103 pence per Vectura share on May 25, 2021.1

"PMI’s acquisition of Vectura is part of our long-term strategy to transform PMI by investing in scientific excellence and leveraging its capabilities and expertise," said PMI’s Chief Executive Officer, Jacek Olczak. "Our investment will accelerate the development and delivery of inhaled therapeutics to address many of today’s unmet medical needs. We look forward to working with Vectura’s great people as we embark on the next stage of our transformation."

PMI’s proposed acquisition of Vectura is part of its long-term strategy, as outlined in its 2020 Integrated Report and will provide support for Vectura’s continued growth as:

- PMI will build on its leading scientific capabilities to develop products and services that go Beyond Nicotine. PMI aims to achieve at least $1 billion in annual net revenues from Beyond Nicotine sources in 2025.

- PMI’s business model and strategy are driven by a long-term commitment to the transformation of its business and not a search for short-term gains and efficiency. Since 2008, PMI has invested $8.1 billion in the research, development, and commercialization of new smoke-free products for adults who would otherwise continue to smoke. PMI’s track record of investing in innovation exemplifies its commitment to invest the time and resources it takes to allow for scientific innovation of better products. In a 2017 letter to shareholders, PMI reaffirmed its commitment to fundamentally change its business.

The transaction value represents a multiple of around 15 times Vectura’s 2020 EBITDA.

The Offer will initially remain open for acceptance until 1:00 p.m. (London time) on September 15, 2021.

https://finance.yahoo.com/news/philip-morris-international-enters-tender-170100360.html

Determining how safe vaccinated people are from Covid-19

 Imagine peering into people’s blood and being able to pick up a simple marker of exactly how well protected they are from Covid-19.

It’s a pressing goal for scientists who are still trying to understand what immunity to the coronavirus looks like, how robustly vaccines protect us over time, and how protected people are who’ve had and recovered from Covid-19.

Now, a year and a half into the pandemic, researchers are starting to flesh out exactly what these “correlates of protection” look like, a step that could help track the durability of immunity and speed the development of additional vaccines. In a preprint paper last week, a group of researchers from both academia and U.S. health agencies reported their findings of the immune correlates for Moderna’s Covid-19 vaccine. The study demonstrated the link between the level of antibodies in a person’s system and how protected they are against Covid-19, validating the hypothesis that antibodies could be used as a measure that signifies overall protection.

“We saw a very clear correlation that the higher the level of antibody produced by vaccines, the less likely you were to become sick with Covid-19,” said Christopher Houchens, one of the authors of the paper and a biologist at the U.S. Biomedical Advanced Research and Development Authority.

The team is working on similar studies for the other vaccines that received support from Operation Warp Speed, including Johnson & Johnson’s and AstraZeneca’s, while other research groups are investigating other vaccines used around the world. Additional recent studies have also pointed to using antibody levels as correlates of protection.

A key advantage of knowing the correlates of protection is potentially enabling the approval of future vaccines. The vaccines that are available now went through a slog of clinical trials involving tens of thousands of people. But with vaccines increasingly available, it’s harder to enlist volunteers to participate in a study in which they might receive a placebo. Most people would instead choose to get a shot they know works.

Going forward, depending on what sort of evidence regulatory agencies decide to require, vaccine makers could instead study their shots in a few hundred people. Scientists could settle on a particular antibody threshold that shots would have to induce in people to get the green light — if someone has enough antibodies to hit that level, they’re protected, while anything below it portends infection risk.

With some other infections, researchers haven’t determined the exact correlates, but have a rough estimate of how much antibody a person needs to be protected, and they use that level for regulatory decisions. Flu shots, for example, don’t have to go through clinical trials every year, but are instead authorized based in part on the quality of immune response they generate in much smaller studies.

“Knowing the correlates of protection is incredibly useful,” said virologist Angela Rasmussen of the University of Saskatchewan’s Vaccine and Infectious Disease Organization, who is not part of the research group studying immune correlates in Covid-19 vaccines. “It really helps us develop vaccine policies that maximize keeping people as safe as possible.”

The Food and Drug Administration did not respond to a question about the agency’s views on using correlates of protection to authorize future Covid-19 vaccines.

Establishing the immune correlates for a certain pathogen can help predict whether a vaccine will be effective or not, but really, protection isn’t binary. As biostatistician David Benkeser of Emory University and another of the study authors put it, people don’t go “from sitting duck to someone who’s completely protected from Covid.”

Rather, protection exists on a gradual scale, with people being more or less vulnerable to disease depending on their immune landscape. And indeed, the study focused on Moderna’s shot didn’t narrow in on a particular cliff where protection fell off entirely, but rather found that the higher level of antibodies someone had, the more protected they were. Put another way, the lower their antibody levels, or titers, the more likely they were to get a symptomatic breakthrough case of Covid-19.

Knowing that, researchers wouldn’t just be able to look at antibody titers and determine whether a vaccine is effective overall. Rather, they could use the titers produced in a group of vaccine recipients to extrapolate an estimated level of effectiveness of a particular vaccine, a measurement that’s normally established during clinical trials.

The new study also underscored the variability in people’s responses to vaccines. There are only a handful of authorized vaccines being put into arms around the world, but a range of factors, from age to body mass to genetics and beyond, can influence how our individual immune systems kick in when primed. Some people will simply have more robust responses than others.

Scientists generally caution against individuals relying on antibody tests to determine their own protection against Covid-19. The tests can be faulty at such a granular level, and, as the researchers behind the new correlates study acknowledged, only look at antibodies, not the other parts of the immune response — like B cells and T cells — that are also involved in keeping people protected from disease.

Still, the immune correlate studies could more broadly inform the discussion about when and whether people — or at least certain groups of people — should get a booster shot. The research groups are continuing to follow the study volunteers and will track their antibody levels. If they drop over time, and in turn there’s an increase in Covid-19 cases among those people, it could point to the level at which people should receive another shot.

“We can track these individuals and look at if their antibody titers start to go down, but we don’t know how far they have to go down at this point to say, ‘Well your risk of infection is significant enough that we would recommend a third vaccine,’” Houchens said.

https://www.statnews.com/2021/08/16/scientists-clues-how-safe-vaccinated-people-are-from-covid-19/