No!
Oof...
*Sniff Sniff*
It smells funny down here.
What are you doing down there?
Excuse me young man, but I shouldn't be talking to strangers.
Although, it appears you cut your face.
You should put some ointment on that.
Can I have my boat back?
Oh is this yours?
Of course...
You know... cuts can lead to infections.
Did you have your tetanus shot?
I... I don't know-
Immunization shots are very important to...
*Sniff*
...very important to curb the spread of infectious diseases.
Mischief: It's a myth that vaccines cause autism.
Kid: Thanks mister... I'm going now-
Mischief: Make sure you tell that to your mother!
We can't have another epidemic on our hands!
For more infomation >> Stranger Danger - Duration: 1:01.-------------------------------------------
Open Wide Up - Duration: 1:01.
(piano chord sound)
I'm not one to be played with.
(tool falling, metal banging, splash)
You shopuld probably get that out.
(breathes in, crunch)
Look at me, I'm the dentist now.
Let's take a closer look.
Hmmm....
That looks like trouble!
Yep.
That's a cavity.
-------------------------------------------
เด็กมันมีของ!! แฟนหงส์เรียกร้องผลักดัน "แฮร์รี่ วิลสัน" เสียบแทน "ลัลลาน่า" ในซีซั่นใหม่ - Duration: 1:41.
For more infomation >> เด็กมันมีของ!! แฟนหงส์เรียกร้องผลักดัน "แฮร์รี่ วิลสัน" เสียบแทน "ลัลลาน่า" ในซีซั่นใหม่ - Duration: 1:41. -------------------------------------------
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Caique Aguiar discute com Evandro e faz acusação: "Você tenta, mas não sou manipulável" - Duration: 4:12.
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Kumbayá - Eu, ela e o cosmos - Duration: 3:32.
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Así es la decoración navideña de la Casa Blanca | Al Rojo Vivo | Telemundo - Duration: 1:09.
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Discoteca ofreció vino a mujeres que se quitaran la ropa | Al Rojo Vivo | Telemundo - Duration: 0:58.
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Los Tucanes de Tijuana conmovidos con caravana migrante | Al Rojo Vivo | Telemundo - Duration: 1:03.
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Últimas notícia de hoje : RENAN REBATE ACUSAÇÃO DA PF REPASSADA AO GLOBO - Duration: 2:46.
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Famosos Al Rojo Vivo: resumen de farándula de hoy | Al Rojo Vivo | Telemundo - Duration: 2:51.
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Tekashi 6ix9ine se declaró no culpable | Al Rojo Vivo | Telemundo - Duration: 0:52.
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Actores conviven con supuestos fantasmas en vieja casona | Al Rojo Vivo | Telemundo - Duration: 2:14.
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Cyber Monday rompe récord de ventas en EE.UU. | Al Rojo Vivo | Telemundo - Duration: 2:40.
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300 novias compitieron por ganarse la boda de sus sueños | Al Rojo Vivo | Telemundo - Duration: 0:46.
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Julión Álvarez bautizó a su bebita | Al Rojo Vivo | Telemundo - Duration: 0:39.
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Gemelas idénticas gastan millones para parecerse más | Al Rojo Vivo | Telemundo - Duration: 0:51.
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Sirena urbana navegó el Río Támesis por esta campaña | Al Rojo Vivo | Telemundo - Duration: 1:04.
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El príncipe Harry y Meghan Markle se mudarán | Al Rojo Vivo | Telemundo - Duration: 0:48.
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Stranger Danger - Duration: 1:01.
No!
Oof...
*Sniff Sniff*
It smells funny down here.
What are you doing down there?
Excuse me young man, but I shouldn't be talking to strangers.
Although, it appears you cut your face.
You should put some ointment on that.
Can I have my boat back?
Oh is this yours?
Of course...
You know... cuts can lead to infections.
Did you have your tetanus shot?
I... I don't know-
Immunization shots are very important to...
*Sniff*
...very important to curb the spread of infectious diseases.
Mischief: It's a myth that vaccines cause autism.
Kid: Thanks mister... I'm going now-
Mischief: Make sure you tell that to your mother!
We can't have another epidemic on our hands!
-------------------------------------------
Open Wide Up - Duration: 1:01.(piano chord sound)
I'm not one to be played with.
(tool falling, metal banging, splash)
You shopuld probably get that out.
(breathes in, crunch)
Look at me, I'm the dentist now.
Let's take a closer look.
Hmmm....
That looks like trouble!
Yep.
That's a cavity.
-------------------------------------------
เด็กมันมีของ!! แฟนหงส์เรียกร้องผลักดัน "แฮร์รี่ วิลสัน" เสียบแทน "ลัลลาน่า" ในซีซั่นใหม่ - Duration: 1:41. For more infomation >> เด็กมันมีของ!! แฟนหงส์เรียกร้องผลักดัน "แฮร์รี่ วิลสัน" เสียบแทน "ลัลลาน่า" ในซีซั่นใหม่ - Duration: 1:41. -------------------------------------------
The Five reacts to Streisand's attack on female Trump voters - Duration: 4:38.
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Financial Aid at Stanford: Cameron - Duration: 3:38.
For more infomation >> Financial Aid at Stanford: Cameron - Duration: 3:38. -------------------------------------------
Stocks to Buy When the Market Crashes: The Trade Desk - Duration: 2:57.
David Gardner: Stock No. 4: the company is, the fourth T, it's The Trade Desk, ticker TTD.
The Trade Desk, on September 26th, two days shy of the end of September, was trading at $156 a share.
Right now, it's about $111, down $45 a share. That equates to a 29% drop.
This has been a wonderful stock. Like the others, it's a big-time winner.
In the case of The Trade Desk, I first picked it in February 2017, that's almost two years ago, at $34.
I just mentioned to you, it's dropped from $156 to $111.
We're still pretty happy with that $34 cost basis.
And three months later, in May of last year, it had risen to $52.
I re-recommended it right there.
In both cases, it's up, on the one hand, 250%; on the other, 138%, in less than two years.
This has been a great winner. What are two things that I like about The Trade Desk?
The first is, I really like the CEO.
Jeff Green is one of those classic visionary founder types.
Highly eloquent, feels like the smartest guy in the room for his industry.
If you've never heard of The Trade Desk before, you might be wondering, "What's being traded?"
The answer is, The Trade Desk offers a platform where people who want to advertise
come on and bid for where they're going to locate their ads.
It's kind of like eBay, where you have buyers and sellers.
But in this case, it's called programmatic ad buying.
Instead of doing it the old way, let's say through an agency, where you would find out,
what are the rates and where are you guys going to put me?
You actually go right into the platform and you bid against others to have your ad seen
in this or that site.
It's a brilliant use of the internet where there's already so much advertising,
so it makes a lot of sense to me.
And it makes a lot of sense when you have someone like Jeff Green steering this company, the founder.
It makes a lot of sense to me that it's been such a winner, and I expect that it will be
a winner going forward. Again, the stock is down 29% in less than two months.
The second thing I like about The Trade Desk is, I'm not going to go through my six traits
of a Rule Breaker stock, but it is a true Rule Breaker.
The six traits that I've written about for years, that help me find stocks, one of them is
top dog and first mover in an important emerging industry.
This is kind of that type of a company.
This is the top dog and first mover in a very relevant industry, ad buying around the internet,
doing it through a programmatic platform. This is the leader. It's kind of like eBay,
for what it was doing back in the day.
This is a true Rule Breaker, and I like that a lot about The Trade Desk,
including its outstanding performance overall.
-------------------------------------------
2 Big Telemedicine Stocks You Can't Buy Yet - Duration: 3:57.
Shannon Jones: Todd, with the time we have left, let's switch gears just a bit and talk
about two privately-held companies, the first of which is a company called MDLIVE.
It started back in 2006. It sounds very similar, to me, to Teladoc.
But, it's attracted the likes of some big-name healthcare backers and partners.
Todd Campbell: What's interesting for investors to keep an eye on, I mentioned early on when
we were talking about Teladoc that of the big three, Teladoc is the only one that's publicly-traded.
Two more, these other two that you should be keeping your eye on. MDLIVE is one of them.
They have about 30 million consumers that are enrolled as members because of relationships
that they have with different healthcare payers.
They expect to do about 500,000 virtual visits, that's the run rate right now, per year. Smaller.
That's less than what Teladoc did last quarter. Still, a big player.
And, as you mentioned, big investors in the healthcare area, especially as of this year,
through a new capital raise that they did, include Cigna, which is a major insurer,
and Novo Holdings, which is the venture capital arm of Novo Nordisk, a major biopharma company.
Jones: The other company is actually the company that's been behind Apple's health study,
a company called American Well.
For those of our listeners who aren't familiar with the Apple heart study, Apple has been
using an app using the Apple Watch -- wearable devices -- to identify irregular heart rhythms,
including those from potentially serious heart conditions like atrial fibrillation.
The Apple heart study is basically utilizing this video consultation to connect participants
in the study to physicians 24 hours a day, seven days a week.
Let's talk a little bit more about American Well, one that I didn't even realize was a
part of this study. It's gotten so much press.
I didn't realize just how connected they were to Apple.
Campbell: This another company that you can't buy yourself, necessarily, unless you're one
of the lucky few. It's a private equity, private venture.
But they're raising a truckload of money -- just shows how much interest there is out there
in telemedicine companies. They just raised $366 million this summer alone.
Participating in that capital raise was Philips, which is one of the global leaders in telemedicine technology.
They're actually going to be joining American Well's board.
Anthem Health is also an investor in this company.
One of the things that's interesting when you look at MDLIVE and American Well is to
see that these insurance companies are taking these equity stakes within these telemedicine providers.
I think that's incredibly encouraging for what their view is of telemedicine in the future,
and how it could change how people get low-cost care.
Jones: Absolutely. Definitely a positive there.
In closing, Todd, it sounds like telemedicine, intriguing opportunity for investors if you're
not already in the space. An even more intriguing value proposition for patients.
Everyone can agree that healthcare costs here in the U.S. are out of control and need to be reined in.
Sounds like telemedicine could be just what the doctor ordered to help with that, Todd.
Campbell: Absolutely. And like most things, don't go crazy with it in your portfolio.
But keep an eye on it. I think it's really exciting.
In ten years from now, these companies are going to be a lot bigger than they are today.
-------------------------------------------
Why This is The Last Onething Conference | Mike and Diane Bickle Share - Duration: 1:33.
We are in a remarkable season in the IHOPKC family and ministry.
The Lord has been speaking to us about the need
to be very intentional about resetting our heart in ways that line up with His heart,
And the phrase we've been using is the phrase that Jesus spoke to Martha,
And He says, "Your sister Mary, she has chosen the good thing.
She has chosen the one thing,
and it's necessary. It's the good thing."
It is an hour to reset with a connection of His heart,
and you have to reset in connection with one another as a family.
Yeah. I am so excited for this season that we find ourselves in.
It's a time to look one another in the eyes
and just celebrate what the Lord has done in one another.
The Lord celebrates us, right,
so we get to celebrate one another.
I believe that John 17,
the way that prayer of Jesus gets answered is by us
loving one another and receiving His love in that same way
It's passion for Jesus and compassion for people
that the Lord is speaking on. Well said.
We're asking the Lord to confirm this in your own heart,
and multiply it and increase it in your own spiritual family back home
That's where we're going by the grace of God
and that's where so many of you are going too
We're in it together.
Amen.
-------------------------------------------
GM to close 5 plants in North America, cut 15% of salaried workers - Duration: 2:21.
General Motors is set to close five plants in the US and Canada and lay off
15 percent of its workers in a bid to slash costs
the automaker also plans to end production of several models to reflect
the shifting consumer sentiment for certain types of cars using je with this
report in a shattering announcement Monday General Motors announced a major
restructuring of its global business that will see it cease production at
five facilities in North America plants will be shut in Detroit Ohio Maryland
Michigan and Ontario Canada explaining its decision GM said the plants produced
sedans that have seen a slump in sales adding will no longer produce the
Chevrolet Volt Impala and four other models to other plants made engines and
parts for those models GM also said it would close three plants outside North
America by the end of next year one of those being its kunsan plant in South
Korea GM's decision will mean layoffs for up to eight thousand salaried
workers and six thousand hourly workers the affected workers will either be made
redundant or reassigned to other plants a quarter of the company's executives
are among those affected GM's union has vowed to fight but observers say the
plants will likely be closed for good president Trump didn't hide his
displeasure over GM's decision saying the automaker CEO Mary Barra must open
new plants in the future well we don't like it I believe they'll be opening up
something else and I was very tough I spoke with her when I heard they were
closing and I said you know this country's done a lot for General Motors
you better get back in there soon that's Ohio and you better get back in there
soon GM's massive restructuring plans comes as its said to reinvest money into
new technology the company's new motto zero crashes zero missions zero
congestions signals it's shifting to self-driving electric vehicles but
watchers say the restructuring is also about making cars that consumers want
now with more and more drivers favoring SUVs
and hash bags over sedans Eason J Arirang news
-------------------------------------------
Absolutely Stunning Tiny House on Wheels - for sale in Arvada, Colorado 80005 - Duration: 2:01.
Absolutely Stunning Tiny House on Wheels - for sale in Arvada, Colorado 80005
-------------------------------------------
How To Train Your Dog To Wait Before Eating - Professional Dog Training Tips - Duration: 7:06.
- Teaching your dog to wait for their food
isn't just a great way to keep from getting dive bombed
when you put their meal down,
it's actually a great way
to build in some impulse control.
I mean, personally, I hate waiting for things,
but sometimes it's really important.
(microwave dinging) Yes!
Ow, it's like a buttery blast furnace in here.
In this video, I'm gonna show you two methods
to teach your dog to wait before they eat.
The first one's gonna be simple and fast,
you've probably seen it before,
but the second one I'm gonna teach you
how to level up your training with your wait command
so that you can use it anywhere.
I'm Ken Steepe and welcome back to McCann Dogs.
(gentle guitar chord)
(dog barking)
Now, you might recognize this little guy.
This is Levi from our First Day Home with a Puppy
video with instructor Kim,
and I thought he'd be a great demonstration dog
for this exercise.
So what I'm gonna do is I'm gonna lower the food bowl down,
and when Levi chooses to remain in position,
I will reward him for that
at a couple steps along the way.
Now if he decides he wants to dive bomb in
and take hold of that food,
I'll just lift the bowl up again.
Oops.
Yes, he saw that, what a great choice he made.
He knew he really wanted the food.
Oops, and there.
Yes, good boy.
Yes, good.
Good boy.
Yes, good.
Good boy.
Yes, good choice, pal.
Good sit.
Yes, good.
Good boy.
Yes, good choice.
What a nice job.
Good boy.
And then we'll end with our release word
so he can get his dinner.
Okay, get your dinner, okay.
Okay, (claps) get your dinner.
That's a boy, good boy.
Now this is the method that we're gonna try to level up
your wait training.
So this is the kind of wait that you're gonna use
to keep your dog from barging through doors
or maybe in the parking lot,
you're gonna ask your dog to wait
before you let them out of a car,
or, you know, at any point in your walk,
you can ask your dog to wait while you pick up something.
And this is what you're about to learn next.
I talked a little bit about the sit and start position
in one of our earlier videos, and I'll link that above.
But for this exercise, you're gonna start
with your dog in at your side.
And we really want to build this wait for,
on a foundation of success.
We want to, in the early stages,
we want lots of successful repetitions.
You want to make it easy for Funkee.
So here's what we're gonna do.
I'm gonna tell her to wait,
and then I'm just gonna wave my hand
in front of her face.
I'm gonna step in front of her, toe to toe,
so that she can't be wrong
and she can't go anywhere.
And I'm gonna yes and reward her, good girl.
Maybe I'll even move back while I remind her to wait.
Good girl, yes.
And I can reward her again for not moving.
Now what's really important about using this wait
is that your dog has a definitive ending,
so when I'm done practicing my wait,
after this first repetition, before Funkee decides to move,
I'm gonna use her release word, which is okay.
And that way Funkee knows when her job is over,
and I want you to be using that every single time
you're working on this wait exercise with your dog.
After you've practiced that a couple of times,
you can make it a little bit more challenging for your dog.
So with Funkee Monkee, maybe I'll tell her to wait,
and I'll step out a little bit farther.
I can praise her from here.
Good girl, good wait.
And then step in, yes, good girl.
And reward her for a job well done.
Other things you might be able to do,
wait, is wiggle your leash,
provide a little bit of distraction,
yes, and then I can step back in and reward Funkee
for remaining in that wait position.
And then when we're done, as I mentioned earlier,
I'm just gonna tell her, okay,
so that she knows she can move.
So now we've got a few repetitions in
where I've returned back to Funkee's side
and she knows how valuable it is
to remain there in that waiting position.
Now with our wait, using the McCann Method,
we'll use a stay if we want our dog to not move ever
until we get back to them.
But with our wait, we want to be able
to release our dogs remotely.
So I'll ask Funkee in this case to wait,
and then I'll step away from her a little bit.
And now, at any point, if she's made a great choice,
a tough distraction goes by, I can yes,
step back in, and reward her.
But ultimately, I want her to know that if I step out here,
that I can release her at any point in time.
Okay, and she comes to me,
she gets very excited when she hears that release word.
Now as we start to increase the challenges
in the real world for our dogs,
it's really likely that they're going to make mistakes.
So this time, I'm gonna ask Funkee Monkee to wait,
but then I'm secretly lure her out of that waiting position.
What's really important is that if she makes that mistake,
I don't pull food out right away
and lure her back to where she was sitting.
Remember, we've spent so much time teaching our dogs
that them making the right choice gets them a food reward.
So I'll show you what happens
when Funkee Monkee makes a mistake.
Wait.
Good girl, good.
So I'll just lure her out, ah ah.
So I marked that moment with my voice,
and I'm just gonna guide her back to exactly where she was.
I'll show her how to be right.
What a good sit, good girl, wait.
And the next time, I'm gonna make it a little bit easier.
So I have a moment to reinforce that good behavior.
Good wait, yes, good girl.
And now I can step in and use my food.
It's really important,
the two elements of that that you need to keep in mind
are marking that moment with your voice,
especially as you're getting farther away,
and that you show them how to be right.
Rather than pulling out a piece of food
and guiding them back to where you think they were,
you show them exactly where to be,
and then you can reward them
after they've spent a couple of seconds in that position.
Now at the top of the video,
you saw us have the dogs lined up
a few feet away from their food bowls,
and they were all sitting in a wait,
and maybe that's a tough distraction for your dog,
so we're gonna set that up.
And while you're training all of these exercises,
whatever you think is a tough challenge for your dog,
make sure you hang onto the leash.
The last thing we want to do is ask Funkee to wait,
put a bowl of food down,
and then she breaks the wait
and then goes and gobbles down most of the food
before we have a chance to interrupt that behavior.
So let's try this one.
Wait, and I'll go put the food down.
I'll try to make it as enticing as I can.
Wait, good girl.
Good, and again, I talked about that timing of our yes,
good girl, and then I can step in.
Remember, with those dogs
who really, really love something like food
or love to barge through the door,
you want to reward them in that stationary position
more often then you let them out.
I'll show you what I mean.
Okay, Fun, can you sit?
Wait, good girl.
And at the beginning, you might even make it really easy.
Yes, good girl.
Just take one foot out the door.
Good, wait.
Yes, what a good girl, good job, buddy.
But it's really important that Funkee finds it
just as valuable for her to remain, wait,
on the inside of the doorway
as it is when she comes out.
Okay, good girl.
Now I think the wait is one of the most functional skills
that you can teach your dog.
I use it probably every single day with our dogs.
And I hope you find the same value in this exercise.
Now, if this is your first time on the channel,
make sure you hit that Subscribe button.
We publish new videos every single week
to help you to have a well-behaved
four-legged family member.
On that note, I'm Ken.
This is Funkee Monkee.
Happy training.
(upbeat music)
-------------------------------------------
Verify: Will Arizona taxpayers pay more individual income tax? - Duration: 2:10.
For more infomation >> Verify: Will Arizona taxpayers pay more individual income tax? - Duration: 2:10. -------------------------------------------
Trump threatens to permanently close border with Mexico after weekend of unrest - Duration: 0:42.
in other news president Trump has threatened to closed the US border with
Mexico if the southern neighbor does not act to stop a migrant caravan the threat
came in a tweet on Monday in which he called many of the migrants quote
stone-cold criminals and appealed to Congress to fund his border wall it also
came a day after American authorities closed the country's busiest southern
border crossing and fired tear gas into crowds Mexican Mexican authorities said
hundreds of those who were detained after Sunday's incident would be
deported to their home countries Mexico City however did not immediately respond
to Trump's tweet
-------------------------------------------
That Time I Got Reincarnated as a Slime - "Nameless Story" (OP) 「転生したらスライムだった件」 Shayne Orok 【歌ってみた】 - Duration: 2:01.
For more infomation >> That Time I Got Reincarnated as a Slime - "Nameless Story" (OP) 「転生したらスライムだった件」 Shayne Orok 【歌ってみた】 - Duration: 2:01. -------------------------------------------
I LOVED Trinidad!! // Trinidad Walking Tour // Trinidad, Cuba - Duration: 5:14.
Hello.
I am in Trinidad, Cuba with Tropical Tours.
We're gonna be doing a walking tour around the city
so that you can get to know it a little better.
This city was founded in 1514.
Trinidad's monastery has been turned into a museum,
but one of the reasons you might want to visit this monastery
is because it has a overlook tower,
so, we're gonna go check that out now.
Wow, look at that.
That is nice.
I just bought a fan,
it's made out of wood and it has this Ford Cargo look,
it says, Ford 1932.
You can also go ziplining right on the outskirt up Trinidad
here in the Valle de Ingenios.
We're now going to drive to Playa Ancon to take a dip in the ocean.
It gets really hot here, especially today, it was extremely hot,
so, taking a quick dip into the ocean feels really nice,
and the water is pretty warm, it feels good.
I'll see you in a bit.
Now, I am back at my casa particular, I have showered,
the beach was really great,
and I am going to head out to dinner now
and check out the nightlife here in Trinidad.
I just sat down at the restaurant where I'm gonna have dinner,
Quince Catorce, also known as 1514,
and it is really beautifully decorated.
Tonight they're actually having this special festival with chefs,
and they're doing this whole competition thing.
So, there's a lot of people out and a lot of music,
so, this is kind of like a special night that's happening.
So, this restaurant is a little bit quieter on side street,
so, it's gonna be really nice.
That food was really good.
I had a light dinner, so, it didn't really look like much
but it was exactly what I needed.
I just got back to my Airbnb or casa particular here in Trinidad.
The night is still very much alive but I am really tired,
so, I'm ready to go to sleep.
That concludes this video.
I hope that you enjoyed this tour of Trinidad here in Cuba.
Thanks to Tropical Tours for putting this together.
Don't forget to check out their website nowgotocuba.Com
Don't forget to use my code
if you end up booking any of their tours.
And very important,
subscribe so that you see more videos like this from me.
The links for everything are gonna be in the description.
Hit the subscribe button, hit the bell next to subscribe button
so that you can get notifications every time I make a video or go live.
But for now I'm gonna go.
So, I will see you when I see you, bye!
This video was made possible by my patrons over at PATREON.COM/REDROMINA
If you like what I do, become a patron and be a part of the exploration.
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Arsenal news: Mesut Ozil revelation made about Unai Emery by Ian Wright… he's very HAPPY - Duration: 2:49.
Emery replaced Arsene Wenger last summer and after a shaky start, has steadied the ship and got Arsenal playing some stunning football
The change in style has helped the Gunners hit their stride and their 2-1 win away to Bournemouth on Sunday in the Premier League extended their unbeaten run in all competitions to 17
However, Emery made a bold decision in dropping German midfield maestro Mesut Ozil to the bench
Ozil - who is the club's highest earner on a £350,000-a-week contract - played no part in the victory against the Cherries
And Wright thinks dropping Ozil proved that Emery is prepared to take risks and he has no qualms about that
"He makes decisions because they are best for the team," Wright said on BBC Radio 5 live's Monday Night Club
"He's not afraid to say 'you know something, I don't think I'm getting enough out of you' and against a Bournemouth side he's got the nerve to drop him
It's up to Ozil to kick on." Explaining in more detail the significance of that decision, Wright added: "He [Emery] is very, very good for Arsenal
"You can say Ozil is on X amount, but he is a professional footballer and he has got to get on board, he has got to kick himself on
"But I want to focus on Emery, as, as a team Arsenal players know that 'if I'm doing well the manager will pick me, it doesn't matter who you are, he will stick by me'
" Although Ozil didn't feature against Bournemouth, the Gunners coped fine in his absence
The winner from Pierre-Emerick Aubameyang took him to double figures (10) for the league campaign so far
Arsenal turn their attentions to the Europa League on Thursday (5.55pm) when they travel to the Ukraine to face Vorskla Poltava
After that, there is the small matter of the north London derby on Sunday (2.05pm) when they host Tottenham
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Woman Seen In Viral Photo Escaping Tear Gas At Border Speaks Out | NBC Nightly News - Duration: 1:10.
For more infomation >> Woman Seen In Viral Photo Escaping Tear Gas At Border Speaks Out | NBC Nightly News - Duration: 1:10. -------------------------------------------
Just How Bad Is Alkermes' FDA Depression Drug Setback? - Duration: 12:46.
Shannon Jones: Let's dig into Alkermes.
For our listeners, on November 1st, Alkermes, ticker ALKS, had the opportunity to make its
case for its depression drug, ALKS 5461 -- we'll just call it 5461 -- in front of an FDA advisory panel of experts.
5461 has been studied, is still being studied, in treatment-resistant major depressive disorder.
But this drug in and of itself has had quite the roller coaster history.
Looking at earlier this year, in April, at one point, you had the FDA issuing a refuse to file letter.
In the grand scheme of things, a complete response letter is terrible.
When the FDA refuses to even look at your drug, because they say it's not complete enough,
that is red flag of red flags.
But, two weeks later, all of a sudden, the FDA did an about face.
Alkermes came out and said that they were able to "clarify" some things with the FDA.
Todd, what is all the fuss with this drug, 5461?
Todd Campbell: It makes you wonder whether they really clarified things, or if they basically
just strong-armed them and said, "We're filing it anyway!"
And the FDA said, "Hey, do it at your own risk."
I urge everybody to go out and check out the background that that was put together by the
FDA for the members of the Advisory Committee.
As a refresher, what ends up happening with many of these drugs that go through the FDA
process of approval is that the company will make a presentation in front of a panel of
experts in that field and try to convince that panel of experts that their drug is both efficacious,
it works, and that it's safe, it doesn't harm anybody relative to the efficacy that it delivers.
That's what we're talking about.
The FDA Advisory Committee panel meeting met to weigh in on 5461.
And they voted overwhelmingly against its approval. The vote was 21-2 overall against approving it.
20-3 said that Alkermes did not provide substantial evidence of the drug's effectiveness.
That's crazy, they only convinced three people that the drug was approvable for efficacy.
And on safety, it squeaked by with safety barely, 13 votes in favor on safety versus 10.
And if you read the background that was put together by the FDA for these committee members,
you certainly feel a slant against this drug by the FDA.
You'd assume that probably factored into the committee members' decision.
Jones: There were so many interesting things.
I would encourage any healthcare investor, if you are investing in the biotech space,
I would say this is just as important as reviewing SEC filings -- reviewing the advisory committee
briefing documents, to your point, Todd, is crucial.
Oftentimes, a company may issue a press release, or they'll say, "We had very successful talks
with the FDA and we're both on the same page."
Really, I think what this panel demonstrated and highlighted is that that's not always the case.
Looking at this drug, it was novel, not just the drug itself, but even from a study design perspective.
Todd, what can you tell us about the drug itself? This is not your typical antidepressant.
Campbell: Alkermes, I think, was thinking that because there's such a big need for new
therapies that can address depression, they could push this over the finish line.
There are about 15 million people in America who suffer from major depression.
About 3 million new cases of major depression are diagnosed per year.
Unfortunately, 60-70% of people with depression fail to respond to the existing antidepressant
therapies that are on the market, and less than 30% achieve remission in depression on
the first line of therapy that they try.
So, what ends up happening is that they go through multiple lines of trying and failing
on different antidepressants, hoping to find the right one that will work for them.
Part of that is because we don't fully understand the cause of depression.
We can make some assumptions about biology.
We know that the environment can factor into causing it, as well.
Most of the antidepressants, what they try to do manipulate the amount of chemicals that
are in your brain, things like serotonin, to try and improve mood.
This was going to be an entirely novel approach, an entirely new approach.
What they were doing at Alkermes was combining together an opiate and a second compound that
was designed to prevent you from becoming addicted to the opiate.
You had buprenorphine, which is the opiate part of 5461, and samidorphan, which was the
new entity that was trying to counteract the risks associated with taking buprenorphine.
The idea here was "We know that opiates can improve mood.
Is there a way that we can make them less addictive?"
We look at the trial design, the way that Alkermes set up the trials to try and win
approval ... again, reading this background, wow.
They actually said in the background at one point, the FDA wrote that there was a
"lack of alignment between the applicant and the FDA on this new drug application."
A lack of alignment.
It's really weird when you're being told by the FDA, "Hey, these are the things that you
should probably do if you want to come in front of us and win approval," and you're
basically ignoring them and saying,
"No. We're going to do these things. We're just going to hope that you give us approval."
Jones: Yeah. That's what's been the big head scratcher here.
You sometimes expect to see this with really small, very early-stage biotechs.
You don't expect to see it with a company like Alkermes.
They're about a $6 billion market cap company, with approved products already on the market.
That was a bit of a head scratcher.
Going back to that trial design, it's something called sequential parallel comparison design, or SPCD.
The reason that Alkermes was attempting to use this novel study design that the FDA didn't
think had much merit was trying to get after one of the major problems that they see with
depression trials, and that's the placebo effect.
You see this consistently with drug companies that attempt to go after this depression indication.
Oftentimes, when a patient is exposed to placebo, they have improvements.
It makes it much harder to see the actual effect of the drug in the trial.
Alkermes was attempting to mitigate this with this study design.
Uh ... basically, they failed. I'm trying to think of a nice way to say it.
They failed! [laughs] Campbell: Downright failed!
I mean, you think about the people who will enroll in a trial, it's going to be the ones
who are most motivated to want to see an improvement.
I think that's probably why you see the placebo effect typically being high in these trials.
Historically, that's been a big problem for drug developers.
Failure rates in depression and related disorders are much higher than they are in other disorders
where maybe you can connect the dots little bit more easily to treatment versus outcome.
This two-stage trial design approach, basically what they did is they randomized for the drug
and for placebo, then they took the non-responders, and that's from that stage one that were in
the placebo group, and then randomized again into either the placebo or the drug.
And the FDA basically said, "We've never really considered this for any trial.
We would need to see a lot more evidence to be convinced that this is a good way to design it."
And, apparently, obviously, Alkermes did not deliver that.
That wasn't the only problem.
They also designed the trial to take an average of outcomes over multiple weeks.
Historically, when trials are designed for this indication, they use a fixed endpoint, so,
the improvement at the six-week mark or the four-week mark or the five-week mark, whatever.
In this case, Alkermes was trying to convince them, "No, use an average."
They actually wrote in this background, "The division did not prospectively agree on this approach."
[laughs] So, they already had told Alkermes, "Listen, we're not really comfortable with this."
And the third problem that Alkermes had, the third decision that they made that went against
what the FDA was hoping that they would do, is that they used entirely new rating scale
that they crafted.
The Montgomery-Asberg Depression Scale rating is commonly used, but it's a ten-item questionnaire.
And they cherry picked it.
They created their own six-item version of it that excluded some pretty important stuff
like suicidal thoughts.
Jones: The actual important things, and particularly more so, the things that really have not just
a long-term impact, but, to your point, suicide, concentration difficulties, reduced appetite,
reduced sleep, these are all things that are important for someone who suffers from depression.
In terms of what's next for the company…
To back up a little for our listeners the FDA Advisory Committee makes a recommendation
to the FDA whether or not to approve a drug.
The FDA doesn't have to follow those recommendations.
Sometimes, you've even seen the FDA be a little more lenient when it comes to psychotic therapies.
But, right now, Alkermes is still running a Phase IIIb study.
Not a lot of hope, especially given the trial results that we've already seen,
but they have an approval date of January 31st.
We could find out before then whether or not the FDA gives the green light.
Thankfully, it sounds like this isn't the only thing that Alkermes has in the pipeline. Right, Todd?
Campbell: Yeah, it's not a one trick pony. It already generates about $250 million in sales per quarter.
If you look at last quarter, sales were up about 14%.
It markets a drug, Vivitrol, that's used to help prevent relapses for people who are addicted
to alcohol or that use drugs.
Sales of that drug were $80 million last quarter, up 15% year over year.
It also has an atypical anti-psychotic drug, Aristada, that's approved and generating revenue
growth for the company.
It also collects royalties on a bunch of different anti-psychotic drugs that are on the market
already and marketed by some of the largest companies in the world.
This is definitely a company that generates revenue on an adjusted basis. It turns a profit.
But this is obviously a disappointing failure because it's a multibillion dollar marketplace,
and it could have turned this 5461 into a billion-dollar blockbuster for them.
Their next thing that investors are going to want to keep an eye out for is results
from a drug called 3831 that's being evaluated in schizophrenia.
Basically, it's a version of Zyprexa, which is commonly used but its patent expired,
so they can manipulate it if they want, and they are.
They're manipulating it so that it doesn't result in weight gain, which has been a big
drawback of Zyprexa. Phase III results are expected before the end of this year.
If they're positive, they could file for FDA approval next year.
Zyprexa's peak sales were above $2 billion, so theoretically, this could add nicely to
its sales in the future. Jones: Absolutely.
Also, what's really interesting is, Alkermes also has an early immuno oncology asset in their pipeline now.
It'll be interesting to see this traditionally CNS-focused company pivot into immuno oncology.
Certainly something to keep an eye on.
-------------------------------------------
Rustic Beautiful The Tiny House on Wheels | Lovely Tiny House - Duration: 3:05.
For more infomation >> Rustic Beautiful The Tiny House on Wheels | Lovely Tiny House - Duration: 3:05. -------------------------------------------
Bitchin' Rides - The Snowball Episode - Duration: 43:35.
For more infomation >> Bitchin' Rides - The Snowball Episode - Duration: 43:35. -------------------------------------------
Beware of Being Precious - Duration: 1:07.
Don't be precious and force your creative ideas on a client
G'day folks Den here. I had a situation recently what I needed a short sting created.
A little graphic it had to be less than three seconds. When I talked to this
supplier, they were very adamant that I should create a 5 to 10 to 15 seconds
thing with all this music and all these animations. And one of the challenges was
they just weren't really listening to me and I felt quite pissed off actually
that they weren't really listening and that made me start to think about how
often does that happen when the intention of this supplier was all good
and well-meaning. But they weren't listening to what I needed so be really
careful when discussing an idea with a client not to get too excited, not to get
too precious and force a creative idea which is really just your ego talking
into their situation. Listen to what they need, give them what they want, offer a
little polish on top and you'll find yourself being very successful.
That's it for me today folks, speak to you again soon
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