The 58-year-old comedian has spoken candidly about how hes always been a bit chunky, but the star successfully slimmed down back in 2016. However, the TV mogul has admitted the weight has started to creep back.

Talking on The Tonight Show with Jimmy Fallon, the After Life writer argued back when the host remarked that he looked well.

Im getting fat again! he admitted, before explaining why he was struggling to keep the weight off.

I didnt want to give up any food or drink, so I worked out, said Ricky, who initially shaped up by taking up exercise.

Now hes finding his age is getting in the way. Because Im old and weak, I cant work out enough to burn off the calories I take in at night, the actor continued.

READ MORE: How to lose weight: Easy meal prep recipe from Aldi for just 20-a-week revealed

In the hilarious clip, the American presenter can barely contain his laughter as The Office star starts ranting about how hard it is to diet as an older man, instead of talking about the series he's been invited on to discuss.

The BAFTA winner said hed already noticed that hes put on weight. Im still eating and drinking too much but I cant work out like Rocky, Ive put about 10 pounds back on.

Sharp-tongued Ricky is well known for his fat jokes and for making light of being overweight, and went on to say theres no such thing as being big-boned.

However, while he knows he needs to watch his weight for health reasons, he said he had no intention of giving up the things he enjoys.

What's the point in living longer if youre sober? the actor quipped as the audience cheered him on. I am just going to get bigger and bigger.

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Gervais is under no illusions about what he needs to do, though, and hit back at a school in the UK which had announced it wanted to ban the word obese. He said of the idea: Dont ban the word, go for a run!

The Golden Globes host, who is estimated to be worth 111.5 million, has previously said he wished people had told him he was fat so that he had done something about it sooner.

Ive never had a problem with weight. I was thin until I was about 29. Then I hit 30 and there was a decade of eating and drinking, he told The People.

Ive just always liked eating. Losing the weight wasnt a problem. I just decided Id work out and slim down because I didnt want to die.

The funnyman said at the time that it was easy as he had a gym in his house, which allowed him to then keep what he loved in his diet - particularly wine and cheese.

Every morning I have red wine coming out of my pores, I feel a bit sick and then I think I have to work out for an hour now to burn off all those calories, the David Brent actor added.

Alcohol is one of the key habits hes not willing to give up, even if it means he cant shed the pounds.

In fact Gervais regularly posts a close-up photo of wine on his Instagram.

Stay well. Take vitamins. Wash your hands. Don't be selfish. Make sure an elderly relative has everything they need. Some are too proud to ask. Be sensible. Drink at home. Everything you love doing you can do in a few weeks. Cheers, he wrote recently in response to the coronavirus lockdown.

Despite his lack of motivation, he doesnt believe in getting surgery and says he wouldnt want to cheat in that way.

However, perhaps the Hampstead-based celebrity is happy to stay a little overweight, as he recently told New York Times magazine that it was the secret to his success in comedy. Before I could do it I had to learn to relate, he said in the interview.Getting fat and old and ugly helped with that.

Its also reported the star is now vegetarian, and he regularly posts anti animal cruelty pictures on Twitter.

Originally posted here:
Ricky Gervais weight loss: After Life star on why he's given up on losing weight - Express.co.uk

COMMENTARY

Despite signing ex-Tampa Bay Buccaneer Beau Allen to a two-year deal after losing Danny Shelton to the Detroit Lions, the Patriots still find themselves shorthanded at the defensive tackle position heading into 2020.

After getting run all over by Derrick Henry and the Tennessee Titans in the playoffs, New England could use another big body or two in the middle of their defensive line to help against the run. This years draft class of defensive linemen isnt outstanding by any means, but has a couple of solid prospects who could help the Patriots upgrade at the position.

Derrick Brown (Auburn) and Javon Kinlaw (South Carolina) are the consensus top two players at the position this year. With Brown expected to go in the top-10, and Kinlaw expected to follow soon thereafter, the Patriots would likely need to move up in order to draft either player. With that being said, here are players who could be options for New England, assuming they dont move up in the draft order for Brown or Kinlaw.

Height/weight: 6-feet-3-inches, 290 pounds

After missing his sophomore year with an Achilles injury, Blacklock shed 25 pounds coming into his redshirt junior year, and returned in 2019 to earn All-Big 12 honors. Blacklock is an elite pass rusher for his position, and has impressive quickness at 290 pounds. He has the power, size, and motor to collapse a pocket quickly, and is light on his feet. He has an NFL-ready frame right now.

With his experience playing over multiple gaps at TCU, Blacklock has versatility that Bill Belichick may find attractive. In addition to his ability to play in different spots along the line, Blacklock also was a team captain as a junior.

Where Blacklock needs to improve is his overall consistency and maintaining his leverage in the run game. Blacklock tends to make himself a bigger target than he needs to and can lose leverage against blockers, allowing them to drive him back in the run game. While he has NFL-caliber physical tools, he needs to improve in using them more consistently to produce. He has some flashy plays on tape, but needs to become a steadier player in order to develop into a starting defensive tackle.

Height/weight: 6-feet-3-inches, 293 pounds

Another undersized tackle who wins with a blend of speed and power in penetrating opposing backfields. Madubuike is an explosive player who wins many matchups with a quick first step and impressive lateral agility. He creates pressure with powerful hands and a quick strike that collapses the point of attack. Madubuike is a violent finisher and strong tackler, and had double-digit tackles for loss in each of his last two seasons. He is best served as a penetrating tackle in a one-gap scheme that allows its tackles to play in space and look to get in the backfield, rather than a two-gap scheme run by teams like New England.

Madubuike is a bit stronger against the run than Blacklock is, but has less experience as a two-gapper, something that the Patriots tend to prefer their defensive linemen be able to do, in order for their linebackers to come in and make plays. Madubuike can have issues holding his own against double teams, in part due to inconsistent pad level, but also due to the fact that his effort can waver at times, something that could be a red flag to some teams.

Height/weight: 6-feet-3-inches, 303 pounds

While not ranked as highly in the draft as his Auburn teammate, Derrick Brown, Davidson is the Auburn DT who led his team in sacks with 6.5, not Brown. He also tied his ex-teammate with 11.5 tackles for a loss, and was named first team All-SEC alongside Brown.

Davidson has more inside/out flexibility than Brown does, having played more on the edge at Auburn. With his large frame though, Davidson is expected to play more on the interior than he did in college, but his experience on the edge makes him a more versatile prospect that could hold more value to some NFL teams like the Patriots.

A four-year starter in college, Davidson is a disruptive player who has long arms that help him shed blocks and make tackles consistently. Hes a high-effort player who knows the game well, and can sniff out plays in the run game better than most.

Davidsons explosiveness is more noticeable in a two-point stance as an edge rusher. When playing in an interior alignment, Davidson tends to pop out of stance rather than drive out of it, ruining his leverage and limiting his ability to win matchups in a phone booth on the inside. Because he lacks the speed and dynamic athleticism to play on the edge in the NFL, he will need to develop a better anchor and refine his technique as a traditional defensive tackle.

Height/weight: 6-feet-2-inches, 304 pounds

Born and raised in Ottawa, Gallimore has a hot motor and never gives up on a play, and his background as a soccer and basketball player shows with his fluid athleticism and solid lateral ability. He has the ability to make some plays that make him look like the best tackle in this draft, but his production in college is unremarkable, with just 18 TFLs and 8.5 sacks over 52 games.

With his quick feet and athletic build, Gallimore projects to be a three-technique DT with the potential to be a starter at some point. He will need to work on keeping his pads low and developing a stronger anchor, but his violent hands and good athleticism make him a player with high potential who could eventually reward whichever team drafts him.

Height/weight: 6-feet-6-inches, 311 pounds

As one of the most physically-imposing players in this draft, and having learned under the tutelage of Belichicks close friend Nick Saban at Alabama, Davis has Patriot written all over him.

With his 34-inch arms and 11-inch hands, Davis has prototypical size to become a 3-4 defensive end in the NFL. However, his poor three-cone and short shuttle times at the draft combine muddy that projection a bit, and lead to some concerns about his quickness and speed.

Because of that, he projects to be a two-down player at the next level, but his power and run-stopping ability would be an immediate help on a Patriots defensive line that lacked those traits in defending the run last year. Daviss enormous wingspan and ability to hold his anchor against anyone make him one of the more NFL-ready prospects at his position, but his lack of a pass rushing skillset and general explosiveness limit his long-term ceiling.

Height/weight: 6-feet-4-inches, 302 pounds

With the speed and explosiveness that is packed into his NFL-ready frame, Elliott has one of the highest ceilings in this years draft class at the defensive lineman position. He has experience playing in several alignments, having played one year at Texas and two at Missouri.

Elliotts strength is as a pass rusher, where he can use his quickness to cross the face of blockers and penetrate through gaps. At 302 pounds, he can hold his own against double teams, but has issues with playing too tall at times. He has the size to be a better run defender, but needs to improve his anticipation and processing of the game in order to allow him to utilize his physical tools more freely.

A strong and slippery player, Elliott can be a scheme-versatile player if he improves against the run, and has a considerably high ceiling thanks to his size and speed.

Height/weight: 6-feet-4-inches, 320 pounds

Hamiltons frame is that of a more traditional defensive lineman in the NFL. A big and powerful player who can take on double teams and hold his position on the line, Hamilton projects to be a two-down, two-gapping defensive tackle in the NFL, and has solid rotational potential thanks to his well-proportioned body and impressive strength.

Hamilton is low on quick-twitch ability, and is an upright rusher who doesnt explode out of his stance often. With an underdeveloped pass rushing skill set, Hamilton still has work to do, but his strength and size make him a good fit as a zero- or one-technique player at the next level.

Height/weight: 6-feet-5-inches, 330 pounds

Another behemoth of a man, Fotu would replace the profile of the kind of defensive tackle that New England lost in Danny Shelton, a physically-imposing player who can occupy multiple blockers in the run game and plug up several gaps.

With 34-inch arms and 10.5-inch hands, Fotu is a classic nose tackle and has an excellent first step with quick penetration and gap control. His closing burst is impressive at his height and weight.

Fotu struggles as a pass rusher, generating only 19 pressures on 298 pass rush snaps at Utah. He can also have issues with his leverage, which he will need to improve on in the NFL.

With a high motor, and a reputation as being a good leader, having been a team captain in 2019, Fotu is a high-character individual with great size for his position, and has potential as a run defender in the NFL.

Height/weight: 6-feet-3-inches, 297 pounds

Murchison spent a lot of time at NC State defending two gaps, making him an ideal fit in New Englands two-gap scheme. A quick player with upside as a pass rusher thanks to his bend and lateral ability, Murchison was a senior captain and started all 25 games of the past two seasons as a member of the Wolfpack. His production has risen steadily each year, indicating he still has room to grow as a prospect.

Despite his quickness, Murchison has inconsistent hands, and is not strong in space. Easily overwhelmed by power, Murchison will need to get stronger and learn better technique so that he can hold his own in the trenches. Because of his lack of length and explosiveness, Murchison is a Day 3 pick with potential to develop into a rotational three-technique defensive tackle in the NFL.

Height/weight: 6-feet-4-inches, 275 pounds

As an undersized lineman, Strowbridge projects to a role as a 3-4 DE in the NFL, but has plenty of experience rushing from an interior position in college and taking on double teams. Hes an agile big man who has a good first step, and uses his big hands and long arms to disengage from blockers and make plays in the backfield. Strowbridge also has experience on special teams, having blocked four kicks over the last three seasons.

Strowbridge impressed at the Senior Bowl, both on the edge and inside. He appears to be an ascending player with some potential to be a versatile rotational defensive tackle as he develops a better range of pass rush moves and learns to play with better pad level.

More:
10 defensive linemen the Patriots could grab at this years NFL Draft - Boston.com

Written by Roger Philby, CEO of The Chemistry Group

Over the past couple of weeks, households across the UK received a letter from the Government outlining important COVID-19 health advice, including rules on leaving the house and social distancing. Yet I can say with confidence that such a letter will fail to elicit any form of meaningful change in the publics behaviour towards minimising the spread of the virus.

A letter in the post will not change behaviour because knowledge is not behaviour. If it were, we wouldnt speed, smoke or fail to keep a 2m social distance from each other when we know that these things are bad for us and everyone around us.

In my time at The Chemistry Group, we have helped many companies create effective organisational change, and in the process have identified some key principles that will be useful for people undergoing the fairly major, enforced changes that are our current reality. These principles will not only help now but will also be vital for those determined to emerge from the current crisis stronger and more successful than before.

Firstly, let me rewind to why and how we developed these principles.

Chemistry has just finished a big piece of insight work for an FTSE 100 multinational organisation. The client was worried that with a huge change of context (post-financial crash) salespeople were struggling with new ways of working

Anticipating this the client had put their 150 managers through rigorous and extensive management training. Chemistrys data clearly showed that most of the managers had the Intellect, Personality, Motivation and Experience to succeed, they just werent. The problem was that the organisation had conflated knowledge with behaviour.

This organisation needed to focus on three behaviours to turn around its revenue gap, only three:

When the client challenged us to help them implement these behaviours, we started gathering information, looking for data-driven insights. What was out there in the world of training/learning & development could help initiate scale behavioural change?

It turns out weight loss is a perfect analogy for what is wrong with training in organisations. Like all of us that have struggled to lose weight, these sales managers knew what to do, they just didnt do it. I know I need to exercise and run a calorie deficit, I even know what to eat and what exercises to doI just dont do it? Why not? Because I dont have time, because I have other pressing things to do, because, because, because. How many times have you run those kinds of thoughts through your head at home and at work? If you are anything like me, too many to count.

Within three weeks we had studied Weight Watchers and Alcoholics Anonymous and within six weeks we had a behavioural change methodology that scaled across an organisation of 1,000+ people. We have illustrated three of them below:

Do one thing at a time, get great at it, be consistent, then do the next thing. In the above example, we worked on one behaviour for 3 months and only when we hit a level of consistency did we introduce the next behaviour.

Finally, focus on managers of people. For our client, just 150 managers caused a wave of behavioural change that turned around an organisations fortunes. 7% behind their target in February, the organisation ended up beating it by 14%, achieving the market-leading position for the first time in 8 years and receiving industry-wide accolades.

Make the behavioural change in groups, at Chemistry we call them Pods. There is a reason all WW classes and AA meetings are groups of people. Behavioural change is hard, you need support from people who are all going through the same change.

Not only does instituting the change in a group encourage support it also adds motivation. Whether people lack rigorous self-discipline or have a competitive streak that means they perform best against others, a group dynamic can motivate people to adopt the behaviours they know they should more quickly, and more effectively.

Behavioural change has to be led by one of the cohort going through the change, not an expert. The person leading the WW class was often not the kind of fitness influencer we see plastered all over social media, thats the point. Managers are far more likely to listen to one of their peers who has achieved the change they are trying to make and accept candid feedback from this person.

Having a peer in the behavioural change process is also likely to result in more effective and accurate feedback, as they will have a more in-depth and immediate experience of the context and process, rather than just a finished idea of what the end result should look like.

See the rest here:
Behavioural Change: Why a letter in the post won't work - Business Leader

What If They dont take The Obvious Receiver?

Every Packer Fan is praying for Rodgers to have another weapon in the passing game. The 2020 draft class might be so deep in wide receiver that the Packers could wait to find LaFleurs new tool. So if the Packers skip on a wide receiver in the first round, who should they target?

Feb 28, 2020; Indianapolis, Indiana, USA; Wisconsin Badgers running back Jonathan Taylor (RB27) participates in a workout drill during the 2020 NFL Combine at Lucas Oil Stadium. Brian Spurlock-USA TODAY Sports

College: University of Wisconsin

Year: Junior

Over Taylors three years in Madison, he ran for over 6,000 yards and averaged almost seven yards per carry. He is one of the fastest running backs in this draft class, clocking a 4.4 40-yard dash time. Taylor is a durable and quick back that can add some juice for the Green Bay backfield coming in when Aaron Jones needs a rest.

Taylor would fit in the passing part of Green Bays offense on all downs eventually. Even though he only had a little over 400 receiving yards in college, he started to show his true receiving skills in his final year as a Badger. Coach LaFleur will be able to recognize how elusive he is when he gets into the open field and how hard it is to bring him down when the ball is in his hands. I can see the Packers splitting him out as a slot receiver and have him run mesh routes on critical downs. He can also be valuable running smash routes, curls, and screens out of the backfield. Jonathan Taylor could thrive in this offense because Lafleur always keeps his running backs active and Rodgers is always best finding a running back on a checkdown letting them make a play in the open field.

Aaron Jones rookie contract will expire after this years season, as well as Jamaal Williams. Jones will most likely be re-signed after this years season proving to be the franchise back. The only question that makes this decision hard is veterans, Kenny Clark, Corey Linsley, and Kevin Kings contracts will expire too.

The Packers could go a different route and re-sign Pro Bowler Kenny Clark and veteran Center Corey Linsley, while also giving the same opportunity to Kevin King(5 INT last season). This would mean that they would have to let Jones walk. Jones will become an expensive target for teams, and if Green Bay doesnt want to go the expensive route, they have to start looking for the future and heavily consider taking a shot at Jonathan Taylor. Even if Aaron Jones does re-sign long term, Taylor could be a great aspect to the offense opening up new challenges for opposing defenses.

Wisconsin Alumni already making him a fan favorite

Able to make a play when the play is already busted (Comparison= Saquon Barkley)

A bruiser in traffic and slippery in the open field

Has talent as a receiver and could make a living in the empty set or in the checkdowngame

Can become a number one RB if Aaron Jones does not re-sign

Feb 29, 2020; Indianapolis, Indiana, USA; Louisiana State Tigers linebacker Patrick Queen (LB32) runs the 40 yard dash during the 2020 NFL Combine at Lucas Oil Stadium. Brian Spurlock-USA TODAY Sports

College: LSU

Year: Junior

The inside linebacker out of Baton Rouge recorded 85 tackles with 12 of them being for a loss of yards. He also added three sacks to the Tigers historical run and an interception off of Tua Tagovailoa (Alabama QB) in the game of the year. The Packers have never had an inside linebacker that would stick around and Queen could finally fill that gap in Pettines defense.

Defensive MVP of The National Championship, Patrick Queen was able to lead his defense by calling every play. What really opens the Packers eyes is his aggressiveness when there is a ball carrier in sight. Also, Queen plays with a different type of swagger that would fit the Packers defense. His biggest impact on the Tigers defense was how well he covered the tight end in deep routes and mesh routes. He was also able to cover running backs in checkdown situations and blew up most screens in sight. Ex Packers Linebacker Blake Martinez struggled to cover tight ends on seam routes and had trouble picking up receivers over the middle. What would make Queen so special is he would be able to pick up on passing situations easily and has the intelligence to call the defense as a rookie. Also, with offensive lines and quarterbacks already focusing on how to contain the Smith brothers, this will give Queen a chance to make big plays in the backfield. The Packers past linebackers have always struggled against tight ends and picking up receivers on broken plays, so making the addition of Queen to Pettines defense will only make them more exciting to watch this season.

Recently the Packers were able to sign former Browns Linebacker Christian Kirksey, filling Blake Martinezs spot temporarily. Kirksey is a veteran who brings a lot of knowledge to the Packers defense. Kirksey is also known to be injury prone, playing only nine games for Cleveland last year. If the Packers draft Queen, he will be able to rotate with Kirksey and be able to gain knowledge from the veteran. Eventually Queen would prove himself and push out Christian Kirksey becoming a leader for the Packers young defense.

Intense hard hitting Linebacker

Able to cover receiving Running Backs and Tight Ends

Recognizes the screen well Plays with the Packers type of Swagger

Has experience being the Play caller already

Will have chances to make big plays with opposing teams fearing the Packers front.

Charlie Neibergall/Associated Press

College: Boise State

Year: Junior

The junior tackle out of Boise is an athletic big man that played every game since 2017 and also ran a 4.93 at the NFL Combine. He is able to move quickly to the block and does the best in pass protection. He does well in the run game when sealing off blocks that open up holes that can provide a spark to the Jones/Williams backfield.

Erza Cleveland is a quick guy who produced a lot of open holes for the run game at Boise State. He has quick feet making him able to seal off fast linebackers and defensive ends. In the run protection he is best on stretch plays because of his quickness and his ability to reach for a block. Cleveland also is able to play both left and right tackles which fits with the Packers history of producing versatile linemen. It seems that Cleveland might be a work in progress forthe first year or so because he would need to put some weight and muscle tone on giving him a stockier build giving him an advantage at being able to protect the inside run. Cleveland may be a bridge at first, but has the athletic ability to soon fill for the loss of Bryan Bulaga.

Recently, the Packers lost long time veteran, Bryan Bulaga, to the Chargers. Bulaga was able to protect Rodgers when All-Pro defensive ends would line up on the other side. He was able to shut down defensive ends Von Miller and Bradley Chubb, who were quick players that easily got after the quarterback. Rick Wagner of the Detroit Lions will be replacing Bulaga and will have to fill a big role. Cleveland would be able to prove himself in the preseason by beating out Wagner and becoming that quick lineman that can keep up with all these fast moving defensive ends and outside linebackers. He will also be successful because the Packers like to run toss/stretch plays where it will be easy for him to get out of his stance and go make a block up the field. The same thing applies for when they run screens with Davante Adams and Aaron Jones.

Agile

Quick feet and able to seal blocks to make holes for the running back

Will thrive in Outside zone runs and screens passes Quick enough to keep up with fast defensive linemen

Will have to put more weight on to be able to have a wide base in the Inside Runprotection

Can be a starter to fill Bulagas role

Related

See the article here:
3 Out of the Box First Round Choices To Improve The Packers - Total Packers

NEWTON, Mass., April 20, 2020 (GLOBE NEWSWIRE) -- Karyopharm Therapeutics Inc. (KPTI) today announced dosing of the first patient in a randomized Phase 2 clinical study evaluating low dose oral selinexor in hospitalized patients with severe COVID-19. This global study is expected to enroll approximately 230 patients at clinical sites in the U.S., Europe, and Israel. Selinexor is an oral selective inhibitor of nuclear export (SINE) compound which blocks the cellular protein XPO1 which is involved in both the replication of SARS-CoV-2, the virus that causes COVID-19, and in the inflammatory response to the virus.

The randomized, multi-center, placebo-controlled Phase 2 study (XPORT-CoV-1001/NCT04349098) of low dose selinexor is designed to assess the activity and safety of 20mg of selinexor given orally three times a week for two weeks. Patients tolerating therapy well and experiencing clinical benefit may be eligible to continue treatment for an additional two weeks at the discretion of the treating physician. The primary endpoint of the study is time to clinical improvement based on improvement in the Ordinal Scale, consistent with the COVID-19 trial recommendations by the World Health Organization and the U.S. Food and Drug Administration (FDA). Additional secondary endpoints in the study include the overall death rate at day 28 as well as the rate of, and time to, mechanical ventilation.

In less than two weeks since announcing our intention to study selinexor in patients with severe COVID-19, we have quickly mobilized our team to activate clinical trial sites across the globe and are proud to announce the dosing of the first patient in our randomized study, said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. This important milestone marks the first study of an XPO1 inhibitor in patients with severe viral infections. We remain highly encouraged by the potential anti-viral and anti-inflammatory activity of XPO1 inhibition with selinexor and look forward to working with the medical community of regulators, treating physicians and patients on advancing this important study as quickly as possible.

SINE compounds have been identified as having the potential to interfere with key host protein interactions with influenza, RSV and other viruses including SARS-CoV-2.1 Furthermore, XPO1 (also called CRM1) was identified as one of the host proteins with the highest number of functional connections with SARS-CoV proteins.2 Finally, SINE compounds, including selinexor, have demonstrated potent anti-inflammatory activity through the inhibition of Nuclear Factor kB (NF-kB), leading to reductions in cytokines such as IL6, IL1, IFNg and others in a variety of models, which may be particularly beneficial to hospitalized patients with COVID-19 and other severe viral infections.

In my laboratory, we have now used two different approaches to investigate selinexors ability to inhibit the viral propagation of the SARS-CoV-2 virus in Vero cells, which are monkey cells commonly used in modeling human viral infections. In our first experiment, with the assistance of Jackelyn Murray in my lab, we demonstrated that selinexor inhibited the production of new virus by 90% at a low concentration (100 nM) from cells that were already infected with SARS-CoV2. This is very exciting as low oral doses of selinexor are expected to deliver levels over 300 nM. In the second experiment, we showed that even lower levels of selinexor, only 10nM, could reduce the ability of the virus to infect new cells by about 99%. I am highly encouraged by these results and thrilled to see how quickly Karyopharm is able to test these scientific findings in patients so dramatically impacted by the current COVID-19 pandemic, said Ralph Tripp, PhD, a Georgia Research Alliance Eminent Scholar and Professor in the Department of Infectious Diseases in the College of Veterinary Medicine at the University of Georgia.

Selinexor, marketed as XPOVIO, is currently approved at higher doses by the FDA as a treatment for patients with relapsed or refractory multiple myeloma. Selinexor is currently the only XPO1 inhibitor approved for commercial use by the FDA and has been extensively tested in clinical trials across numerous cancer indications worldwide since 2012. Karyopharm has sufficient supply of selinexor for current and expected commercial patients with multiple myeloma, for ongoing clinical trials in patients with various cancers, as well as for this study in patients with COVID-19.

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. Karyopharm received accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor. A supplemental New Drug Application was recently accepted by the FDA seeking accelerated approval for selinexor as a new treatment for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), and selinexor has received Fast Track and Orphan designation and Priority Review from the FDA with a scheduled PDUFA date of June 23, 2020 for this patient population. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), for which Karyopharm announced positive top-line results in March 2020. Additional, ongoing trials for selinexor include as a potential backbone therapy in combination with approved myeloma therapies (STOMP), in liposarcoma (SEAL) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharms clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at http://www.clinicaltrials.gov.

For more information about Karyopharms products or clinical trials, please contact the Medical Information department at:

Tel: +1 (888) 209-9326Email: medicalinformation@karyopharm.com

IMPORTANT SAFETY INFORMATION

Thrombocytopenia

XPOVIO can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with XPOVIO. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in <1% of patients.

Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia

XPOVIO can cause neutropenia, potentially increasing the risk of infection. Neutropenia was reported as an adverse reaction in 34% of patients, and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.

Obtain neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity

Gastrointestinal toxicities occurred in patients treated with XPOVIO.

Nausea/Vomiting

Nausea was reported as an adverse reaction in 72% of patients, and Grade 3 nausea occurred in 9% of patients treated with XPOVIO. The median time to onset of the first nausea event was 3 days.

Vomiting was reported in 41% of patients, and Grade 3 vomiting occurred in 4% of patients treated with XPOVIO. The median time to onset of the first vomiting event was 5 days.

Provide prophylactic 5-HT3 antagonists and/or other anti-nausea agents, prior to and during treatment with XPOVIO. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated.

Diarrhea

Diarrhea was reported as an adverse reaction in 44% of patients, and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.Manage diarrhea by dose modifications and/or standard anti-diarrheal agents; administer intravenous fluids to prevent dehydration in patients at risk.

Anorexia/Weight Loss

Anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. The median time to onset of anorexia was 8 days.

Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.

Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support.

Hyponatremia

XPOVIO can cause hyponatremia; 39% of patients treated with XPOVIO experienced hyponatremia, 22% of patients experienced Grade 3 or 4 hyponatremia. The median time to onset of the first event was 8 days.

Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Infections

In patients receiving XPOVIO, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade 3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade 3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms.

Neurological Toxicity

Neurological toxicities occurred in patients treated with XPOVIO.

Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with XPOVIO. Median time to the first event was 15 days.

Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

ADVERSE REACTIONSThe most common adverse reactions (incidence 20%) are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65.3% had the dose of XPOVIO interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.

Please see XPOVIO Full Prescribing Information available atwww.XPOVIO.com.

References

1 Gordon, D. et al. A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug Repurposing. bioRxiv. 2020. 03.22.002386. https://doi.org/10.1101/2020.03.22.002386

2 Zhou, Y. et al. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery. 2020. 6:14. https://doi.org/10.1038/s41421-020-0153-3

About Karyopharm Therapeutics

Karyopharm Therapeutics Inc. (KPTI) is an oncology-focused pharmaceutical company dedicated to the discovery, development, and commercialization of novel first-in-class drugs directed against nuclear export and related targets for the treatment of cancer and other major diseases. Karyopharm's Selective Inhibitor of Nuclear Export (SINE) compounds function by binding with and inhibiting the nuclear export protein XPO1 (or CRM1). Karyopharms lead compound, XPOVIO (selinexor), received accelerated approval from the U.S. Food and Drug Administration (FDA) in July 2019 in combination with dexamethasone as a treatment for patients with heavily pretreated multiple myeloma. A Marketing Authorization Application for selinexor is also currently under review by the European Medicines Agency. A supplemental New Drug Application was recently accepted by the FDA seeking accelerated approval for selinexor as a new treatment for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In addition to single-agent and combination activity against a variety of human cancers, SINE compounds have also shown biological activity in models of neurodegeneration, inflammation, autoimmune disease, certain viruses and wound-healing. Karyopharm has several investigational programs in clinical or preclinical development. For more information, please visit http://www.karyopharm.com.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding Karyopharms expectations and plans relating to selinexor as a potential treatment for hospitalized patients with severe COVID-19; the design and execution of a global randomized clinical trial to study this potential application of selinexor, including the dosing regimen; the potential anti-viral and anti-inflammatory properties of selinexor; submissions to, and the review and potential approval of selinexor in this indication by, regulatory authorities, including the anticipated availability of data to support such submissions, timing of such submissions and actions by regulatory authorities and the potential availability of accelerated approval pathways; the sufficiency of selinexor supply for commercial demand and clinical trial use; and the therapeutic potential of and potential clinical development plans for Karyopharms drug candidates, including the impact of a selinexor clinical trial on the timing or prioritization of other key company milestones, such as its expected submission of a supplemental new drug application in the second quarter of 2020 for XPOVIO in combination with once-weekly Velcade and low dose dexamethasone. Such statements are subject to numerous important factors, risks and uncertainties, many of which are beyond Karyopharm's control, that may cause actual events or results to differ materially from Karyopharm's current expectations. For example, there can be no guarantee that Karyopharm will successfully complete necessary clinical development phases of selinexor in this indication; that data from a clinical trial of selinexor would support its use in treatment of hospitalized patients with severe COVID-19; that regulators will approve the use of selinexor in hospitalized patients with severe COVID-19, or that such approval will be made on an accelerated timeline. Further, there can be no guarantee that any positive developments in the development or commercialization of Karyopharms drug candidate portfolio will result in stock price appreciation. Managements expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other factors, including the following: the risk that the COVID-19 pandemic could disrupt Karyopharms business more severely than it currently anticipates, including by reducing sales of XPOVIO, interrupting or delaying research and development efforts, impacting the ability to procure sufficient supply for the development and commercialization of selinexor or other product candidates, delaying ongoing or planned clinical trials, impeding the execution of business plans, planned regulatory milestones and timelines, or inconveniencing patients; the adoption of selinexor for treatment of COVID-19 in the commercial marketplace, the timing and costs involved in commercializing selinexor for such indication or any of Karyopharms drug candidates that receive regulatory approval; the ability to retain regulatory approval of selinexor for such indication or any of Karyopharms drug candidates that receive regulatory approval; Karyopharm's results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. Food and Drug Administration and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, including with respect to the need for additional clinical studies; the ability of Karyopharm or its third party collaborators or successors in interest to fully perform their respective obligations under the applicable agreement and the potential future financial implications of such agreement; Karyopharm's ability to obtain and maintain requisite regulatory approvals and to enroll patients in its clinical trials; unplanned cash requirements and expenditures; development of drug candidates by Karyopharms competitors for indications in which Karyopharm is currently developing its drug candidates; and Karyopharms ability to obtain, maintain and enforce patent and other intellectual property protection for any drug candidates it is developing. These and other risks are described under the caption "Risk Factors" in Karyopharms Annual Report on Form 10-K for the year ended December 31, 2019, which was filed with the Securities and Exchange Commission (SEC) on February 26, 2020, and in other filings that Karyopharm may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and, except as required by law, Karyopharm expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

Velcade is a registered trademark of Takeda Pharmaceutical Company Limited.

Contacts:

Investors: Karyopharm Therapeutics Inc. Ian Karp, Vice President, Investor and Public Relations857-297-2241 | ikarp@karyopharm.com

Media:

FTI ConsultingSimona Kormanikova or Robert Stanislaro212-850-5600 |Simona.Kormanikova@fticonsulting.com or robert.stanislaro@fticonsulting.com

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Karyopharm Announces Dosing of First Patient in Randomized Study Evaluating Low Dose Selinexor in Patients with Severe COVID-19 - Yahoo Finance

Thor has easily become many people's favorite Avenger, even if he didn't originally start out that way.Thor has changed a lot as a character over the course of the MCU and has gone through significant developments, especially in his last three film appearances alone.

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Some of the changes have been minor and others major. One thing is for certain, he is a much different character than when he first appeared in Thor back in 2011.

Thor has gone through a lot of physical changes in the MCU and one of the most interesting being the loss of his eye. During his battle against Helain Thor: Ragnarok, Thor has his right eye slashed out. At the end ofthe movie,he's sporting an eyepatch making him lookvery similar to his father, Odin. The following year, during Avenger: Infinity War, he receives a replacement eye from Rocket with the only noticeable difference between the two being that his new eye is hazel as opposed to his natural iris color of blue.

One of the saddest and most beautiful moments in the MCU was Frigga's funeral in Thor: The Dark Worldafter she waskilled while attempting to protect Jane Foster. When he lost his mother, Thor was devastated but unfortunately, she was only the first of the many friends and family thathe would lose. Odin faded away in Ragnarok, The Warriors 3 were killed almost instantly by Hela upon her arrival,Thorwas forced to kill his sister in order to save his people,Loki was killed at the hand of Thanos during the opening scene ofInfinity War and to make matters worse during the same scene, he also loses Heimdall. With all the loss he has experienced, it's surprising that he has somehow managed to continue to fight.

Another devastating moment for Thor was when his hammer,Mjolnir, was destroyed by Hela in Ragnarok. Although he learned the lesson that he didn't need a hammer since his power was already apart of him, it is always better to have a weapon of some sort.

RELATED:MCU: 10 People Thor Should Have Been With Other Than Jane Foster

After realizing that he would need a new weapon in order to even stand a chance at defeating Thanos in Infinity War, He,Rocket, and Groot travel to have the ax called "Stormbreaker" forged,leading to the epic scene which sees the God of Thunder take on the full force of a dying star in order to form the metal and thewooden handle being provided by Groot.

Something Ragnarok did better than the other Thor movies was give him a strong arc. Throughout the film hestruggles with his abilities after losing Mjolnir.Aftera touching scene in which Odin comes to him in a vision and asks if he'sthe "God of Hammers",he realizesthat his strength didn't come from hisweapon but from inside him. The display of his true strength comes during the epic fight on the rainbow bridge in which he completely demolishes Hela's army of the dead without anytoolaiding him.

When the Avengers decided in Endgame that they were going to need to put the team back together in order to properly pull off the time heist to retrieve the Infinity Stones from the past, Rocket and Hulk were tasked with traveling to New Asgard to retrieve him. However, they quickly notice that he's gained a significant amount of weight over the 5-year gap likely due to all the beer he had been drinking. Thor's weight gain, despite being the source of some of the film's comedy, was used as a physical representation of the character's depression and guilt that came after feeling the effects of Thanos' snap.

The first and second Thor movies put part of the focus on the relationship between Thor and Jane, so it was surprising that the character was completely absent in Ragnarok, with Thor saying that they've broken up off-screen.It even became a joke during a scene in Endgame in which Thor is discussing during the events of Thor: The Dark World and extracting the Aether from Jane. Jane has been confirmed to return in Thor: Love and Thunder as the Mighty Thor, sothere is a chance we will see the relationship rekindled.

Although the first two Thor movies had their share of comedic moments, lots of the comedy from the first film coming from him being a fish-out-of-water on Earth, trying to adapt and understand human customs and the second had the majority of the comedic beats coming from characters like Darcy and Selvig. After seeing the lackluster fan reception to thosefilms, Marvel decided to take him in a new direction.

RELATED:10 Thor Mannerisms From The Comics Chris Hemsworth Nails

Thanks to Taika Waititi's more improvisational comedic style, the character wasway morehumorous in Ragnarok,making it more similar in tone to Guardians of the Galaxywhich is likely why he blended soseamlessly with those characters in Avengers: Infinity War.

In Ragnarok, Thor realized that the only way to save Asgard from Hela was to destroy it, which meant saying goodbye to the realm forever. In the end, Thor learnsthat the physical location wasn't what was important but rather the people that made it up. The film ends with the citizens boarding a ship in order to escape the destruction and heading off in the direction of Earth.

In Endgame, Thor has established New Asgard on Earth inTnsberg, Norway. Despite the move being unplanned, the new location for the Asgardian's home wasn't chosen at random. Often regarded as the oldest town in Norway,Tnsberg has played a role in the MCU before with it being the location where the Frost Giants arrived centuries agoand is also where Odin spent his final moments before his death.

At the end ofEndgame, after a heartfelt goodbye in which heappointsValkyrie to the mantle on King of New Asgard, Thorboards the Benatar with the rest of the Guardians of the Galaxy. Ever since audiences saw himinteract with theteam in Infinity War, they have been asking for more and the ending of the Endgame, especially Thor referring to them as the Asgardians of the Galaxy, seemingly confirms thatwill be in Phase 4 of the MCU. While it is unclear how long Thor will be a member for, some of Guardians have even been confirmed to show up in his 4th solo movie, Thor: Love and Thunder.

Thor's longgolden hair had become a staple of the character, so it was surprising when, like many things inRagnarok, he was forced to give it up. Before his gladiatorial match on Sakaar, he wasordered by the Grandmaster to have his hair cut in a hilariousscenefeaturing one of Stan Lee's funniest cameos as Thor's barber with a metal hand made of varying blades. While the end result ended up looking pretty good, Thor later allowed his hair to get long again during theBlip, so it is unclear if he would return to the look going forward.

NEXT:MCU: 10 Worst Decisions Thor Has Made

Next10 Obscure (But Awesome) Sci-Fi Movies You can Stream Today On Amazon Prime

Wesley Bell is a writer based out of Silver Spring, MD. He has a passion for film, art, music and all other forms of artistic expression. When he is not spending his time writing, he enjoys watching tv and movies.

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MCU: 10 Ways Thor Changed Throughout The Movies | ScreenRant - Screen Rant