Pfizer Xeljanz Gets EU Marketing Authorization for Treatment of Arthritic Conditions

 Pfizer Inc. (NYSE: PFE) announced today that the European Commission (EC) has approved XELJANZ® (tofacitinib) for the treatment of active polyarticular juvenile idiopathic arthritis (JIA) and juvenile psoriatic arthritis (PsA) in patients two years of age and older who have responded inadequately to previous therapy with disease modifying antirheumatic drugs (DMARDs). Two formulations were approved, a tablet and a new oral solution (weight-based dosing). XELJANZ is the first and only Janus kinase (JAK) inhibitor approved in Europe for the treatment of polyarticular JIA and juvenile PsA and has received regulatory approval in four indications in the European Union, the most of any JAK inhibitor.

In addition, the EC has approved XELJANZ prolonged-release 11 mg once-daily tablets for the treatment of adult patients with active PsA who have had an inadequate response or intolerance to methotrexate or other DMARDs. This once-daily treatment is an alternative to the currently approved XELJANZ 5 mg twice-daily treatment of PsA.

https://finance.yahoo.com/news/xeljanz-tofacitinib-citrate-receives-marketing-203100843.html

A natural pandemic is terrible. A synthetic one would be even worse

 In 1988, as Russian scientist Nikolai Ustinov worked in the VECTOR lab, part of a Russian program to develop viral weapons, he accidentally infected himself with the Marburg virus, a deadly pathogen related to Ebola. He died weeks later. During his autopsy, a pathologist accidentally stuck himself with a needle and died as well.

At its peak, the VECTOR lab was thought to be able to produce two tons of Variola virus (the microbe that causes smallpox) per year. The lab was eventually transitioned into a research institute after the Cold War and recently helped develop the Russian Covid-19 vaccine, Sputnik V. It currently holds one of the world’s two official repositories of smallpox.

While recent debates over the origins of SARS-CoV-2 have raised more questions than provided answers, an inescapable reality we need to be considering is that the United States is woefully unprepared for a synthetic pandemic — one purposefully created and deployed to cause mass human harm.

The Covid-19 pandemic has revealed the fragility of the U.S.’s public health preparedness infrastructure when faced with a moderately deadly and moderately transmissible respiratory pathogen. We cannot begin to imagine the devastation — possibly even a threat to civilization — if the country had to face a synthetic pandemic from a virus that had been intentionally engineered to spread as effectively as measles and had the virulence of filoviruses such as Ebola or Marburg.

The Biological Weapons Convention, signed in 1972 and effective since 1975, was the first multilateral disarmament treaty that prohibited developing, producing, and stockpiling weapons of mass destruction, and specifically biological weapons. To date, 182 countries have signed on and ratified this convention. Yet the Biological Weapons Convention has been violated multiple times since its inception: by the Soviet Union through its Biopreparat laboratories (of which VECTOR was one), which developed weaponized anthrax, Ebola, Marburg, plague, smallpox and others; by Iraq, which produced anthrax, botulinum toxin, and aflatoxin during the Gulf War; and by rogue groups such as the Japanese cult Aum Shinrikyo, which attempted to isolate Ebola virus for terrorist activities during a 1992 outbreak in the Democratic Republic of the Congo.

In the U.S., pandemic preparedness efforts are currently housed across a number of institutions, including the Centers for Disease Control and Prevention, the Department of Defense, the Department of Human Health and Services (specifically the Biomedical Advanced Research and Development Authority), the U.S. Department of Agriculture, and the Federal Bureau of Investigation.

This fragmentation is problematic, as identified in 2015 by the Blue Ribbon Study Panel on Biodefense (now the Bipartisan Commission on Biodefense), a group of former high-ranking government officials who analyze U.S. biodefense capabilities. In its seminal report, “A National Blueprint for Biodefense,” the committee said that the “root cause of this continuing vulnerability is the lack of strong centralized leadership at the highest level of government.” The group laid out 33 specific recommendations to address the large gaps in the U.S.’s biodefense infrastructure.

In a follow-up report in March 2021, “Biodefense in Crisis,“ the group rightfully criticized the federal government for failing to follow-through on the majority of the recommendations, aside from the creation of a National Biodefense Strategy in 2018 which was never actually implemented. The group concluded that the U.S. “remains at catastrophic biological risk” from a synthetic pandemic.

Even in the midst of a natural pandemic, the threat of a synthetic pandemic should be at the forefront of the U.S. national security agenda. Here are four steps we believe the country’s leaders need to take.

First, leaders need to recognize that a pandemic driven by a highly virulent synthetic pathogen would be a global threat. The global community must recognize and address this. The single most important step the U.S. government can take to reduce the magnitude of the next pandemic is to provide the essential support and material resources to countries with ongoing Covid-19 epidemic surges, especially with regard to accessing vaccines (including raw materials and technology transfers), and also toward building and strengthening primary health care systems. By creating health infrastructure and new pipelines for access to essential biological materials, the U.S. can help other countries stay prepared if and when they are dealing with any novel disease outbreak.

Only by showing leadership in protecting communities globally can the U.S. engender sufficient trust to secure global support for improving surveillance and response to future threats. U.S. public health leaders must ensure that wherever the next pandemic-prone disease originates, all countries are ready to stop it quickly.

Second, federal leaders must act upon the recommendations laid out in the 2021 “Biodefense in Crisis” report. These include developing a more organized leadership structure within the federal government to coordinate biodefense activities across various sectors and creating a national biodefense hospital system that can be ready for activation in the case of a serious biological attack.

Funding must also be increased for the development of biodetection technologies and medical countermeasures, such as a larger repository of antiviral and antibacterial compounds that can be quickly distributed within cities and hospitals if needed. And the U.S. government must support the Global Health Security Agenda in efforts to strengthen international biosurveillance. Key ways to improve our biosecurity apparatus were laid out six years ago in “A National Blueprint for Biodefense.” The country failed to act on them before Covid-19 and can’t risk doing so again.

Third, the federal government must ensure that states’ hospitals and clinics are adequately equipped to avoid becoming amplifiers of emerging outbreaks. In 2005, a Marburg virus outbreak in Angola was spread primarily through the hospital where patients were being treated. Sick people tend to show up to hospitals and, if it’s unclear what is being treated, inadequate infection control measures may be used.

That was true in 2014 for the first Ebola patient in the U.S., Thomas Eric Duncan, who was initially not asked about his travel history when he arrived at a Dallas hospital, and infected two nurses, one of whom ended up traveling on a domestic flight to and from Ohio. Part of this effort must include wide availability of rapid diagnostic platforms, such as high-throughput genomic sequencing, which can quickly identify organisms of concern. Additionally, we must ensure that ventilation and decontamination practices are functioning effectively.

Fourth, federal and state governments must guarantee that the general public has immediate access to basic safety prevention measures such as high-grade masks that can filter out aerosols in the case of an airborne pathogen, the transmission route that would be of highest concern. The Covid-19 pandemic has made clear that any pandemic response efforts must start with protecting individuals as quickly as possible. Just as many people have fire extinguishers and smoke detectors in their homes, so too should they have adequate personal protection against infectious disease threats.

The emergence of SARS-CoV-2, the virus that causes Covid-19, as a human pathogen may very well have been a natural spillover event. But this pandemic should be a stark reminder that the risk of biological warfare must be taken seriously, and preparations be made for an even worse-case scenario. And the time to do that is now.

Abraar Karan, an infectious disease physician and fellow at Stanford University, worked on the Massachusetts Department of Public Health’s Covid-19 response efforts. Stephen Luby is an internal medicine physician and professor of medicine in infectious diseases at Stanford University.

https://www.statnews.com/2021/08/19/natural-pandemic-terrible-synthetic-one-even-worse/

Why the coronavirus has changed as it has, and what it means going forward

 It’s impossible to say how the coronavirus will continue to evolve. Those changes, after all, are a result of random mutations.

But there are some fundamental principles that explain why the virus has morphed as it has, principles that could guide our understanding of its ongoing evolution — and what that means for our future with the pathogen.

The great fear is that nature could spit out some new variant that completely saps the power of vaccines and upends the progress we’ve made against the pandemic. But to virologists and immunologists, such a possibility seems very unlikely.

That’s not to say variants won’t impair immune protection. Already, it appears Delta is causing breakthrough infections and symptomatic cases at higher rates than other variants. But vaccines have shown they don’t lose much oomph at protecting people from hospitalization and death, no matter the variant they’re up against. The way the vaccines work leaves experts optimistic that mutations won’t suddenly leave everyone vulnerable again.

“I don’t think that we’ll end up with variants that completely escape antibodies or vaccine-induced immunity,” said vaccinologist Florian Krammer of Mount Sinai’s Icahn School of Medicine. Already, Krammer said, we’ve seen the immune system’s ability to neutralize viral variants drop — to the greatest degree with the Beta variant — but it still persists. Because of that, vaccines haven’t lost major steps at protecting people from the worst outcomes of Covid-19.

Something unexpected could happen, scientists caution — another twist in a pandemic full of them. Already, they’ve had to reassess their thinking about the coronavirus’ evolution. This family of viruses proofreads itself as it replicates, which means it picks up mutations more slowly than viruses like influenza. For the first several months of the pandemic, the virus didn’t seem to be changing in dramatic ways. But now, variants are dominating the conversation.

“This virus has been surprising us,” said Ramón Lorenzo-Redondo, a molecular virologist at Northwestern University’s Feinberg School of Medicine.

Below, STAT outlines some of the key questions about the virus’ evolution — and what it means going forward.

Why does the virus keep getting more transmissible? 

When the coronavirus started circulating among people in late 2019, it was already quite the spreader. Cases overwhelmed Wuhan and led China to impose what were then jaw-dropping lockdowns.

But to the virus, people were a new host. A change in its RNA genome had enabled it to infect our cells, replicate inside them, and jump to other people, but the pathogen hadn’t had much of a chance to figure us out yet. It had a lot of room to get better at using us to proliferate.

That meant there were a lot of low-hanging fruit mutations that the virus could pick up and that would give it a competitive advantage over other iterations of the virus. It’s not that the virus was knowingly figuring out which mutations would make it a better spreader. But as the virus made copies of itself, sometimes it made errors. And by chance, some of those errors gave it a boost over its siblings, helping it outcompete them.

It’s happened throughout the pandemic. An early change dubbed D614G led to a strain that was better at spreading than the very first version, enabling that variant to sweep around the world. For a while, that strain was dominant, but then Alpha appeared, and now Delta. Each subsequent iteration was a more effective spreader than the strains before it, so it outran the others. (One note about Alpha: scientists believe it emerged from a person who was immunocompromised and had a rare chronic Covid-19 infection, which allowed the virus to pick up a lot of mutations in a relatively quick period in one host, and then spread from there.)

One way to think about a virus’ transmissibility is on a curve, one that rises fast and tapers off toward some peak ability. It’s going to get better at spreading comparatively quickly, particularly when there’s been uncontrolled transmission for a year and a half. Over time, it could evolve more slowly, with fewer new combinations of mutations that might increase its transmissibility. Some scientists have questioned whether Delta is so transmissible that the virus might be nearing the flatter part of the curve. But to virologist Adam Lauring of the University of Michigan, “We just don’t know where we are in terms of that leveling off.” It’s possible then, that the virus could still stumble upon mutations that help it spread even more efficiently.

The virus could change in other ways too. If there’s one silver lining about Delta, it’s that it’s so transmissible that it’s crowded out other variants that are more worrying from an immune perspective, namely Beta, as well as Gamma. But scientists caution that there’s no fundamental reason why a variant couldn’t emerge that combines Delta’s spreading prowess with Beta’s ability to partially sneak around immune responses.

Such a variant might look different than we would imagine. Sometimes combining mutations that would seem to maximize transmissibility and immune-dodging abilities actually leads to a virus that fizzles out. Variants that can escape the immune response might be inept at hacking into cells to cause infections. But more worrisome variants are possible, and the best way to prevent them, experts say, is cutting transmission.

How will all this change as more people are protected? 

Because basically everyone on the planet was susceptible to Covid-19 at first, the fastest-spreading variant has been able to outrun others. But as the environment changes, the pressures that select for certain characteristics do as well. And instead of a sprinter like Delta, a bulldozer could eventually get the advantage.

Take Beta and Gamma. These variants, which respectively appeared in South Africa and Brazil, emerged in areas that had massive first waves. That’s led to one hypothesis that the variants took off because they could circulate better among people who had previous infections. Viruses that didn’t have those features couldn’t find as many new cells to infect, and fell back.

Scientists can’t say for sure that’s what happened with Beta and Gamma — perhaps they were just more transmissible in other ways. But it still holds that variants that have some ability to get around the immune response will get the upper hand in populations with greater levels of protection. They might not be causing severe disease in people who are protected — whether from vaccination or past infection — but if they can cause infections in at least some of those people and transmit from there, their prevalence will increase over other variants that have a harder time causing infections in protected people. (This appears to be happening with Delta to an extent, given that it’s now known that some vaccinated people transmit the variant.)

When populations have high levels of immunity, “it favors [variants] that have some sort of escape mutation that doesn’t throw a monkey wrench in the transmission side of things,” said Michael Worobey, a professor of evolutionary biology at the University of Arizona.

Now, you may be wondering: If that’s the case, does that mean a population that’s largely vaccinated will actually encourage the virus to evade protection?

Different forces are at play here. But one key factor is that by cutting how much the virus replicates — both through preventing infections and by shortening the infections that do occur — vaccines limit the likelihood of additional, more dangerous variants. People who are protected against the virus can act as evolutionary dead ends.

“The pressure is there, but the opportunity is not,” said Jeremy Kamil, a virologist at Louisiana State University Health Shreveport. “The virus has to replicate in order to mutate, but each virus doesn’t get many lottery tickets in a vaccinated person who’s infected.”

How will the virus’ future evolution affect vaccine protection?

The nightmare scenario is the virus changes in ways that completely escape immune response but that preserve its lethality and transmissibility. But many experts say that a sudden appearance of such a strain seems exceedingly unlikely. Variants could dent some of the defenses vaccines give us, but the immune response should still generally be able to protect us against severe disease.

“A virus just can’t change a couple amino acids and completely evade the totality of the immune response,” said virologist Angela Rasmussen of the University of Saskatchewan’s Vaccine and Infectious Disease Organization, referring to the building blocks that make up the virus.

Our first line of defenders is antibodies, some of which are trained to recognize specific pieces of the virus and prevent it from infecting cells. If mutations change those components — akin to putting on a fake mustache and sunglasses — then perhaps the antibodies geared to identify the virus’ upper lip or eyes might be fooled. The virus could gain a toehold and start an infection. But the vaccines have primed our bodies to recognize other parts of the virus, and to have waves of responders. Antibodies that latch on to other parts of the virus could kick in, and immune cells that help clear out infections before they cause much damage could arrive as reinforcements.

No vaccine is perfect. A small number of people get hospitalized with Covid-19 or even die after being vaccinated, often those with other health conditions. And it’s possible that variants could cause the vaccines to lose some of their effectiveness: perhaps they cause symptomatic disease at higher rates, and even increase the rate of severe disease or death by a hair. Concerns about the immune response waning in general, combined with the partial escape potential of Delta, are driving the debate about boosters, at least for certain groups of people. But overall, the vaccines are so protective that many virologists — while cautioning they can’t guarantee it — don’t see some variant arriving that alone upends the power of the shots.

One future for the virus is that it reaches some stability but then continues to change in small ways. People could become susceptible to an infection over time (whether that’s every year or after several years isn’t known and will likely vary) but will still generally be protected from worse outcomes. And with every exposure to the virus, including exposure-mimicking vaccines, our bodies will get better at warding it off, maybe even without symptoms. In that way, SARS-CoV-2 will eventually become another endemic respiratory virus.

“The indications are that immunity is really protective against hospitalization and death, even if we’re going to be stuck in a groundhog day world where the virus keeps infecting people year after year even after they’ve been exposed,” Worobey said.

A lab study, published as a preprint this month, found that even if a variant emerged that could escape the immune protection people have — a scenario that study author and virologist Paul Bieniasz of Rockefeller University called “extremely unlikely to happen suddenly” — a booster shot could raise antibody levels to the point where people could fend off the evolved virus. Similarly, if the virus continues to evolve and leads to a more gradual erosion of immune protection, an extra jab could handle it, perhaps one that’s tweaked to better suit the changes in the virus.

“Even if the virus acquires those resistance mutations, it’s possible to generate an immune response that’ll cope with that,” Bieniasz said.

https://www.statnews.com/2021/08/20/viral-evolution-101-coronavirus/

Dark side of mechanical ventilators in the ICU

 I walk in to Mr. W’s room to say hello. He is 73 years old and has been in the hospital for three months, ever since he was diagnosed with Covid-19 and developed pneumonia. He smiles at me when I introduce myself but can’t speak because of the tube down his trachea that delivers every breath he receives from the mechanical ventilator at his bedside.

He is no longer contagious, but he is still critically ill, stuck on the ventilator, weak and struggling to take a breath by himself. He doesn’t have the strength in his arm to wave when I say hello, but I note the twitch of movement at his wrist as he tries.

In June 2021, as the third wave of COVID-19 was ebbing in Toronto, I took over the care of patients in one of my hospital’s intensive care units. It was populated by many patients who were technically Covid-19 survivors because they were no longer infected with SARS-CoV-2. Yet weeks to months after their infections had cleared, they were still in the ICU, still dependent on a ventilator for their breathing, and still without any certainty as to whether they would get better.

This condition of chronic organ failure — in this case the lungs — with a weakened immune system leading to recurrent infections and a range of other complications such as kidney failure, low blood pressure, gastrointestinal bleeding, severe weakness, and delirium, is well-known in the ICU. It goes by the name persistent (or chronic) critical illness.

This isn’t the same as long Covid, which features symptoms such as fatigue, shortness of breath, and brain fog that endure for weeks to months after a person has had Covid-19, although some of the symptoms are similar. The big difference is that people with persistent critical illness cannot survive on a regular hospital ward, let alone at home. Theirs is a twilight existence: alive — some are fully alert — but with bodies too fragile to survive outside the cocoon of whirring ventilators and dripping medications providing life support and the attention of a nurse at the bedside 24-7. They are tended to day after day, week after week.

These patients, their families, nurses, doctors, and other care providers all hope their bodies will heal — enough so they can breathe on their own; enough to fight off the next bout of pneumonia. How long can this last? Many hold on for weeks, months, and sometimes even years.

Newspapers have been filled with vivid descriptions of those in the throes of severe acute Covid-19, battling acute respiratory distress syndrome assisted by mechanical ventilators in ICUs around the world. Most of these individuals will be dead or discharged from the hospital within a month. What is less discussed is that the disease is also creating an army of sufferers trapped in the state of persistent critical illness, tucked away in ICU beds around the world. Some have described it as a “state worse than death.”

Throughout most of history, the inability to breathe on one’s own always led to death. Oxygen therapy was introduced at the end of the 19th century. But if the body was too weak to take a breath, there was nothing more to be done except keep someone comfortable.

That changed in 1928 when two individuals at the Harvard School of Public Health, Philip Drinker and Louis Agassiz Shaw, Jr., tackled the problem of respiratory failure due to polio and developed the first machine routinely used for life support. The Drinker and Shaw respirator, dubbed the “iron lung,” meant that respiratory failure was no longer a death sentence. The machine was a revolutionary change, though Drinker grumbled in his later years that the “damn machine,” and not his other accomplishments, would be what he was known for.

Before the iron lung was deployed, however, doctors worried about its use. What happened, they wondered, if someone couldn’t live without it? The idea of the iron lung was that it would provide temporary support while the nerves and muscles regenerated after acute polio, and would eventually allow people to breathe again on their own. But what if that didn’t happen and someone could no longer breathe on his or her own — ever? In a taped interview archived at the U.S. Library of Congress, Drinker described the possibility of patients living permanently in iron lungs as “disquieting.” The concept of dependence on a machine to breathe, which was something out of science fiction, suddenly became a reality.

As the use of mechanical ventilators broadened over the decades, from supporting those who had polio to aiding those with many other forms of critical illness, such as bacterial pneumonia, stroke, trauma, meningitis, and now Covid-19, the aftermath of such diseases leaves individuals not just dependent on a machine for breathing but with a suppressed immune system, multiple organ failure, skin breakdown, bleeding stomach ulcers, blood clots, and a host of other medical problems.

It is a precarious existence that is even more complicated than dependence on just a machine to breathe — it is a dependence on the ICU itself.

In countries such as the U.S. or Canada, decisions regarding life support rest primarily with patients or their families, and those decisions vary widely. For some, any time spent on life support is too much, while for others it is a religious imperative that life, in any form, be continued. 

For many patients and/or families, the choice is to transition away from aggressive treatments and the use of machines after some period of time. Others continue to hope that with more time and more treatment the body will recover sufficiently to allow them to be weaned from the ventilator and regain independence — or at least the ability to leave the ICU and the hospital and spend time at home. 

But there is a group of patients who understand there is no possibility of recovery, and they must choose between existence in the ICU and death.

That is fundamentally a cruel choice. Life in an ICU is not a normal existence. It is a state of limbo and invariably involves painful procedures — needle sticks, cleaning of wounds, suctioning of the airway, and the like. Patients experience this daily distress, but so do family members who visit day after day (when Covid-19 regulations don’t forbid it) and those providing care at the bedside. This buying a bit more life is a Faustian bargain.

At times, care provided to people with persistent critical illness prolongs dying rather than saves life. Medicine has no tools to heal an entire body when it is so irreparably broken. Clinicians offer time, nutrition, ventilation, and supportive care. The magic bullet that takes dying bodies and makes them live again has not yet been invented.

Almost a century ago, Drinker and Shaw fundamentally changed the relationship between human and machine and made possible a symbiosis that has saved the lives of hundreds of millions of people. But they also unleashed new technology that creates agonizing choices for patients, families, and clinicians — and a tortured existence for some.

We cannot and should not forget about this additional impact of Covid-19: a new wave of people dealing with the uncertainty and challenges of persistent critical illness.

Philip Drinker understood from the very beginning the potential dark side of his machine, and we are still grappling with its legacy.

Hannah Wunsch is an intensive care physician at Sunnybrook Health Sciences Centre in Toronto, a professor of anesthesiology and critical care medicine at the University of Toronto, and holds a Canada Research Chair in critical care organization and outcomes. This essay is adapted from a longer version that details the development of the iron lung.

https://www.statnews.com/2021/08/20/that-damn-machine-the-dark-side-of-mechanical-ventilators-in-the-icu/

Roxadustat shows the latest regulatory fault line split

 The reception roxadustat received from drug regulators on the two sides of the Atlantic could not have been much different. In the US Fibrogen’s novel anaemia pill was savaged by an advisory committee and then sent back for more trials by the FDA, while Europe’s CHMP has recommended use in a surprisingly broad patient population.

The EU backing was rubber-stamped by the European Commission this week, although the full label and prescribing information have yet to emerge. While it is fairly rare for the FDA and EMA to take such stridently different positions this does happen, a look back at diverging decisions shows.

Other notable examples include Viviant, an osteoporosis product that the FDA rejected three times on the grounds of stroke and clotting risks, but one that Wyeth and then Pfizer have been selling in Europe for more than a decade.

Replagal, a treatment for the rare enzyme deficiency disease Fabry disease, never satisfied the US regulator, despite repeated attempts by the therapy’s originator, Tranksaryotic Therapies, and then Shire, which bought TKT in 2005. EU regulators approved the drug in 2001, and Shire gave up trying to appease the FDA in around 2012.

Galapagos’s Jyseleca could yet join this club, with the FDA  last year refusing to approve a dose high enough to be commercially competitive in rheumatoid arthritis. The company and its partner Gilead are still exploring options in ulcerative colitis and Crohn’s disease, but with ongoing FDA scrutiny of the Jak class, to which Jyseleca belongs, it would not be too surprising if this product never makes it to the US market.

The cross-Atlantic regulatory fault lines
Product	Company	EMA approval	US status	2026e sales
Leqvio	Novartis	2020	Pdufa date Jan 2022 (delayed by manufacturing concerns)	$2bn (assumes US approval)
Zynteglo	Bluebird	2019	Clinical hold lifted Jun 2021; BLA in beta-thal to complete Q3 2021	$723m (consensus predates decision to exit Europe)
Viviant	Pfizer	2009	Abandoned after three rejections	$638m
Jyseleca	Galapagos/Gilead	2020	Abandoned in arthritic conditions, inflammatory bowel diseases under review	$623m
Zynquista	Lexicon	2019	Filing in type 2 diabetes with heart failure planned in 2021 (EU approval is in type 1 diabetes)	$476m
Priorix	Glaxosmithkline	1997	Filed Aug 2021	$387m
Replagal	Takeda	2001	Abandoned	$385m
Hepcludex	Gilead	2020	Filing planned 2021	$364m
Libmeldy	Orchard Therapeutics	2020	Filing planned 2022/23	$360m
Source: Evaluate Pharma.

Bluebird’s ability to win speedy EU approval for Zynteglo, also known as Lentiglobin, turns out not to have mattered much. The company failed to negotiate an acceptable price with reimbursement gatekeepers and last month said it would wind down operations on the continent.

The US had always wanted to see longer-term data on the gene therapy for beta-thalassemia, evidence that could well have helped the company in its talks with EU payers.  

Others still hoping to convince the FDA include PTC Therapeutics, which has been trying to get its Duchenne muscular dystrophy project Translarna to the US market for almost a decade, having been turned down three times already.

A small study designed to support accelerated approval yielded disappointing results earlier this year, and it seems likely that the regulator will want to see data from an ongoing placebo-controlled trial. That is unlikely to yield results until late 2023 at the earliest, however, meaning that PTC’s wait looks set to continue.  

One of the most curious examples here is Glaxosmithkline’s MMR vaccine Priorix, which protects children against mumps, measles and rubella in one shot, but which has never been filed in the US. This live vaccine was first registered in Germany in 1997 and is authorised in more than 100 countries worldwide.            

Glaxo filed Priorix with the FDA a few weeks back, and approval would make the jab only the second measles-containing vaccine available in the US, where currently Merck’s MMR II is the only option.

Several projects highlighted here seem likely to receive FDA approval at some point, including Gilead's recently acquired hepatitis D treatment Hepcludex and Novartis's cholesterol-lower Leqvio. But should Fibrogen’s US partner, Astrazeneca, decide to walk away from roxadustat it seems likely that the drug will join the small group of products destined never to reach the US market.

https://www.evaluate.com/vantage/articles/news/policy-and-regulation/roxadustat-shows-latest-regulatory-fault-line-split

EU expects key data on Novavax vaccine around October

 The European Union expects Novavax to submit data needed for the possible approval of its COVID-19 vaccine around October, an EU official told Reuters on Friday, in what could be another delay for the U.S. biotech firm.

Novavax signed a deal with the EU this month to supply up to 200 million doses and said it would complete the submission of data to the European Medicines Agency (EMA) for the vaccine’s approval in Europe as early as the end of September.

“We expect data around October, but we are not sure about the precise timing,” an EU official familiar with the process said under condition of anonymity as the matter is confidential.

“It’s all very uncertain,” the official said, noting that further delays were possible. However, the source said a decision on the vaccine approval was still possible this year, “as long as there are no more delays”.

Novavax said in its most recent earnings announcement that it planned to submit its data to the EU “within weeks” of its filing to British regulators, setting the likely timeline between late September and early October, a spokesperson said.

“We are confident in this timeline and the progress that’s underway,” the spokesperson said in an email to Reuters on Friday.

EMA declined to comment on the matter because it said its assessment of the vaccine was still under way.

Novavax’s protein-based vaccine uses alternative technology to the four shots already approved in the EU. The Pfizer/BioNTech and Moderna vaccines use messenger RNA (mRNA) technology while the AstraZeneca and Johnson & Johnson shots are based on viral vectors.

That makes the Novavax jab more interesting to the EU, which is seeking to diversify its portfolio of vaccines.

U.S. DELAYS

Earlier in August, Novavax delayed its timeline for seeking U.S. authorisation for its two-dose vaccine, pushing it back to the last quarter of this year from the third. The company has filed for regulatory authorisation for its shot in India, Indonesia and the Philippines.

The EU official said Novavax needed to submit information on so-called chemistry, manufacturing and controls (CMC) and that had been delayed because Novavax has changed its production strategy. Those changes have complicated the clearing by regulators of its manufacturing sites which need authorisation before the vaccine is placed on the market, the official said.

The source said it was now harder to demonstrate that the vaccine used in clinical trials was the same as the one that would be produced for mass consumption.

EMA is also still assessing the vaccine’s clinical data under a rolling review that was launched in February.

Novavax and the EU reached a preliminary deal in December for the supply of the vaccine but due to regulatory and production issues the final contract was only signed this month.

The EU Commission, which coordinates talks with vaccine makers together with EU governments, has said it expected the first Novavax doses to arrive this year.

https://whbl.com/2021/08/20/eu-expects-key-data-on-novavax-vaccine-around-october-source/

Fate Collapses As Investors Question Durability Of Cancer 'Killers'

Fate Therapeutics (FATE) delivered mixed results for its lymphoma treatments, which caused Fate stock to crumble on Friday.

The company said late Thursday it is working on a treatment for a blood cancer called B-cell lymphoma. After treatment with a drug called FT516, six patients achieved a complete response — meaning they showed no signs of cancer. However, the cancer returned and worsened in two patients roughly four to five months later. Another patient with a partial response later needed an additional anti-cancer treatment.

Still, analysts were bullish on the results, which they say prove the concept of Fate's technology. Fate is working to activate so-called natural killer cells. As their name suggests, these cells find, bind to and destroy cancer cells.

"Overall, we found the event to be positive for Fate with the first indication of iNK (induced natural killer) response durability," SVB Leerink analyst Daina Graybosch said in a report to clients.

But in morning trading on the stock market today, Fate stock tumbled 19.4% near 69.

Fate Stock: Anti-Cancer Mechanism

Investors were spooked Friday on the potential for waning durability in lymphoma. The company is working on two treatments called FT516 and FT596.

Researchers evaluated 14 patients treated with FT596. In that group, 10 patients responded, including seven that had complete responses. The company also evaluated 11 patients who received FT516. Of those, a total of eight patients responded. That included the six complete responses.

Among the latter eight patients, five maintained their responses without additional treatment. But investors in Fate stock focused on the two patients that progressed after having been deemed complete responders. Their cancer returned and worsened at 4.2 months and 5.1 months following treatment.

Another patient who experienced a partial response required an additional treatment at 4.1 months.

It's important to note, most patients in both groups were heavily pretreated. In the study of FT596, patients had undergone a median of four prior treatments. In the FT516 group, patients had received and worsened while on a median of three prior treatments.

Complete Responses Questioned

Fate's technology could offer a lower-cost competitor to other cancer drugs called CAR-T therapy, short for chimeric antigen receptor T-cell therapy.

Fate is using engineered cells, while first-generation CAR-T drugs from Gilead Sciences (GILD) and Novartis (NVS) harvest cells from sick patients. Second-generation competitors aim to use donor cells, a process called allogeneic CAR-T. Fate is trying to leapfrog both with a master line of cells that can be cloned.

But the company remained sunny on its opportunity in B-cell lymphoma.

The data demonstrate the products "can uniquely deliver substantial therapeutic benefit and expand patient access to cell-based cancer immunotherapies," Chief Executive Scott Wolchko said in a written statement.

https://www.investors.com/news/technology/fate-stock-collapses-as-investors-question-its-cancer-drug-durability/