June 9, 2023 • 44 mins
After years of frustration and despair, scientists finally make a breakthrough. You can find a list of books, articles, and documentaries we used in our research at bit.ly/fiascopod
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:00):
Hey, this is Leon Napok. I'm the host of Fiasco,
but you may also know me from the podcasts Slowburn,
Think Twice, Michael Jackson, and Backfired the Vaping Wars. I'm
excited to be sharing with you the next season of Backfired,
titled Attention Deficit, which is now available exclusively on Audible.
Backfired is a podcast about the business of unintended consequences.
(00:20):
In the first season, my co host ri L Pardess
and I dove deep into the world of vaping and
how the well intentioned quest for a safer cigarette went awry.
Now we're tackling ADHD and how the push to destigmatize
this hard to define childhood diagnosis has led to an
explosion of stimulant use in kids as well as adults.
It's a story about the promise of psychiatry to fix
(00:41):
our brains and the power of the pharmaceutical industry to
shape how we and our doctors think about what's wrong
with us. To hear both seasons of Backfired, go to
audible dot com slash Backfired and start a free trial
that's audible dot com slash backfired. Previously on Fiasco.
Speaker 2 (01:00):
My main job was to try and develop drugs that
could treat this devastating disease.
Speaker 3 (01:07):
The FDA announced today it would formerly streamline it's drug
approval process.
Speaker 4 (01:12):
This thing of hoping for like a magic bullet, that
you know, we would all be activists for two or
three years, and then the cure would come, the vaccine
would come, and we would all go back to our
lives wasn't going to happen.
Speaker 5 (01:22):
People need medication now, ten years from now, they'll be dead.
Speaker 1 (01:33):
When the virus that causes AIDS was isolated in nineteen
eighty three, it looked kind of like a time bomb.
HIV could eat away at someone's immune system for months
or years before they experienced any serious symptoms. Then one day,
pretty much any infection could become fatal. In nineteen eighty seven,
(01:54):
a young chemist at the pharmaceutical company Murk came up
with an idea for how to disable the bomb. His
name was Irving Siegel.
Speaker 6 (02:03):
What Siegel took on was really an impossible task. No
pharmaceutical scientist had ever really taken on such a challenge
as this.
Speaker 1 (02:12):
David France is the author of the book How to
Survive a Plague and the director of the documentary film
by the same name. During the height of the epidemic
France was an activist and a journalist who covered the
search for AIDS treatments. He says that after the release
of the first AIDS drug, AZT, many drug companies scrambled
to produce knockoffs.
Speaker 6 (02:34):
When AZT had come out in eighty seven, it immediately
proved that there was a massive and very of financially
rewarding market for drug companies to exploit.
Speaker 1 (02:46):
But as you've heard, AZT was not a miracle drug.
Even when AZT seemed to make someone better at first,
the virus rapidly mutated inside their body, which meant that
eventually almost everyone who took it still developed AIDS. Irving Seagull,
the scientist at MERK, was convinced he could build something
(03:07):
better than AZT, a new class of drug that would
attack HIV in a totally different way.
Speaker 6 (03:14):
Irving Siegel, he was young, he was charismatic. He pulled
together a team of very excited researchers, and the very
first thing that he focused on was a very novel approach.
No one else was taking it, and that was an
approach to look at protease inhibitors.
Speaker 1 (03:35):
Maybe you've heard that phrase before protease inhibitors. I definitely had,
but I also did not know what a protease was
or what it meant to inhibit it. So as I've learned,
the HIV one protease is an enzyme that plays a
critical role in allowing the virus to replicate in the body.
Siegel believed that the key to treating HIV was stopping
(03:59):
the protease from doing its job. After getting some initial
buy in from the higher ups at MERK, Siegel and
his colleague Nancy Cole started working on it, and just
a few months later they completed a paper reporting a
promising result. By inhibiting the HIV protease, it was possible
to stop the virus from replicating, at least in the
(04:20):
confines of a lab experiment. The quick turnaround was typical
of Siegel. His wife Catherine told me he was someone
who took the stairs two steps at a time when
he came into work, and was often moving so fast
that he would forget to button his shirts all the way.
Speaker 2 (04:34):
Can remember very clearly saying to myself, I have to
keep up with this guy, because he's just he did.
That's how rapidly he moved, That's how rapidly his brain
worked too.
Speaker 1 (04:43):
Emilio Emini is a virologist who worked with Siegel as
the head of Murk's efforts on HIV. He was a
co author on that first paper about the HIV protease.
Speaker 2 (04:53):
So you can imagine, you know, a very you know,
thin individual who is constantly moving and whose brain is
constantly functioning, absolutely extraordinary.
Speaker 1 (05:02):
By December of nineteen eighty eight, Siegel and his team
were on the cusp of a major advance, producing the
first three D image of the protease. After more than
a year of intensive work, they finally had a clear
understanding of its unique cellular structure. Emilio Emini sometimes compares
(05:22):
the HIV protease to a pac man, introducing it has
a wedge like mouth which it uses to chomp down
on HIV proteins and slice them into smaller pieces. These
smaller pieces then spawn new HIV proteins throughout the body. Siegel, Emini,
(05:45):
and their colleagues at MURK wanted to jam the pac
man's mouth and render it incapable of doing any chomping
or slicing. They believed that once this happened, the virus
would stop replicating.
Speaker 2 (06:01):
So if the protease is not functional, or if it's
rendered non functional and cannot perform this cutting activity, then
the viral proteins that are produced won't be assembled into
new viral particles right, and therefore the viral infection cycle
is terminated.
Speaker 1 (06:23):
The three D image of the protease gave Segel and
his colleagues a precise map of the enzyme, showing them
where exactly they had to jam it. Now they could
move on to the next step developing a drug, a
protease inhibitor that could be digested by human beings. Siegel
was confident that it could be done, but then shortly
(06:44):
before Christmas, Siegel had to travel to London to deliver
a long scheduled lecture. After three days away from his lab,
he was eager to get back, so at the last
minute he decided to change his flight to a red eye.
Pan Am flight one oh three left London on the
night of December twenty first, nineteen eighty eight. Less than
(07:06):
an hour after takeoff, the plane exploded over Lockerby, Scotland,
killing everyone on board.
Speaker 7 (07:13):
Just after seven this evening, a jumbo jet crashed onto
the town of locker Bit in the Scottish borders. It
was a Pan American Boeing seven four seventh.
Speaker 2 (07:21):
I remember very clearly where I was when I got
the news. I was at home. Actually it was right
before Christmas. It was right before Christmas in nineteen eighty eight.
Speaker 7 (07:29):
We now know there were two hundred and forty four
people on board, including three children.
Speaker 1 (07:34):
Irving Seagull was just thirty five years old when he
died in the locker be bombing.
Speaker 2 (07:39):
It was absolutely devastating, as you can imagine. It was
devastating for what we were doing collectively, was devastating for
the science. It was devastating for the whole field. But
more importantly, it was devastating personally for Irving and for
his family.
Speaker 1 (07:53):
Seagull's vision of a protease inhibitor would eventually lead to
a massive paradigm shift in AIDS treatment as part of
the so called triple cocktail. It would unlock the first
effective therapy for HIV and AIDS, and it would finally
make it possible for people who had the disease to survive.
But none of that would happen until nineteen ninety six,
(08:15):
nine years after Segel first saw promise in the HIV protease,
and fifteen years after the first cases of AIDS were
observed in America. It's impossible to say whether an effective
treatment might have come sooner if Irving Siegel hadn't changed
his flight from London. What's clear enough is that his
(08:39):
death was a major setback, one of many in science's
long and grueling campaign against AIDS. I'm Leon Napak from
Audible Originals and Prologue projects. This is fiasco.
Speaker 3 (08:54):
Typically, the stronger the drug, the faster HIV adapts to
resist it.
Speaker 4 (08:59):
It seemed that everything we had done up to that
point hadn't been enough.
Speaker 8 (09:02):
Researchers say a new class of drugs are working.
Speaker 9 (09:05):
Where once there was only desperation, there is now genuine hope.
Speaker 10 (09:09):
I'm looking falling through a future, the Lazarus effect that
people described it felt like a miracle.
Speaker 1 (09:17):
In this episode, the darkest days of the AIDS crisis
in America followed at long last by a glimpse of light.
By the nineteen nineties, HIV had spread all over the globe.
Speaker 11 (09:37):
Fourteen million people in the world are now HIV positive.
The number grows dramatically every year.
Speaker 1 (09:41):
And affected just about every demographic.
Speaker 11 (09:44):
Still, no cure still no vaccine to prevent it.
Speaker 1 (09:48):
In the US, cases among women and people of color
were climbing at a particularly alarming rate, and as the
time bomb went off and more and more people, the
death totals were rising.
Speaker 3 (10:00):
Every year in this country, four hundred thousand have gotten AIDS,
two hundred and forty thousand have died.
Speaker 2 (10:05):
Whatever we've been doing has not been enough.
Speaker 6 (10:08):
It wasn't until we hit nineteen ninety three and nineteen
ninety four and nineteen ninety five that the body counts
became extreme.
Speaker 1 (10:16):
David France again, these were.
Speaker 6 (10:18):
Mass dying events each year. Forty three thousand Americans died
in nineteen ninety three, fifty thousand Americans in nineteen ninety four.
So we entered a period of real despair.
Speaker 1 (10:34):
For many AIDS activists, the tragedy wasn't just about how
many people were dying during this period. It was also
that many of the dead had been leaders in the movement.
Speaker 6 (10:43):
Nineteen ninety three opened with the death of Bob Ravski,
who was a key member of Act UP, one of
its kind of poet warriors.
Speaker 12 (10:52):
Questions, what does a decent society do with people who
hurt themselves because they're human? Who smoke too much, we
too much, you drive carelessly, who don't have safe sex?
And the answer, I think the answer is at a
decent society does not put people out to pastor and
let them die because they've done a human thing.
Speaker 6 (11:08):
His death was a trauma for the movement and the community,
and then by the end of the year, Michael Callen died.
Speaker 1 (11:16):
You met Michael Callen in our second episode. He was
the singer, an early AIDS activist who spearheaded a safe
sex campaign in New York and helped create a Bill
of Rights for people with AIDS.
Speaker 13 (11:28):
It's hard to believe Michael Callen is no longer with us.
For more than a decade, he made beautiful music and
worked tirelessly to improve the quality of life for people
with AIDS, all the while fighting the disease himself.
Speaker 10 (11:40):
We won.
Speaker 6 (11:40):
Michael Callen was the author of a book on surviving
HIV and if the guy who was a self proclaimed
long term survivor couldn't survive, then it seemed we were
all lost.
Speaker 14 (11:55):
I realized that some people could look at my life
and say, oh, it was so sad when he died
of AIDS, And isn't that tragic? But what I want
to come through is that even after all the pain
and all the torture, and even having AIDS, I can
honestly say being gay is the greatest gift I was
ever given. I wouldn't change it.
Speaker 2 (12:17):
For the worlds.
Speaker 1 (12:27):
Amid all of this death, more and more activists started
to burn out Garantz. Frankie Ruda, who had joined Act
Up as a teenager in the late eighties, was one
of them.
Speaker 10 (12:38):
I think people have just had a lot of unprocessed
grief and we're just really like unraveling.
Speaker 1 (12:43):
Honestly, Like many in the movement, Frankie Ruda was exhausted
by the lack of progress on medical treatment and by
infighting among her fellow activists.
Speaker 10 (12:54):
All activist organizations have kind of a half life. They
burst onto the scene, they're incredibly viral, and then they
start to sort of change.
Speaker 1 (13:04):
The changes Act UP was going through might have been
easier to take if Frankie Ruda wasn't also losing friends
to AIDS on a routine basis.
Speaker 10 (13:13):
A lot of people had been infected around the same
period of time, and there was a sense amongst a
lot of people that they were not getting out of
this alive. Some people were very pessimistic about whether or
not they were going to see the end of the pandemic.
Speaker 1 (13:33):
The sense of despair deepened in June of nineteen ninety
three when scientists made a crushing announcement about AZT at
the International AIDS Conference in Berlin.
Speaker 11 (13:43):
Discouraging news Today about the effectiveness in some cases of AZT.
Speaker 1 (13:48):
French and British researchers had conducted the largest study ever
on AZT. Their conclusion was that in the long term
the drug simply did not work well.
Speaker 4 (13:58):
The T yes it was, there no significant benefit in
terms of survival or profession to AIDS.
Speaker 3 (14:05):
Reading from slides on a big overhead screen, the head
of the European study told the delegates patients inspected with
HIV who take AZT before they develop symptoms of AIDS
are no better off than patients who take it after
they come down with the disease.
Speaker 1 (14:20):
The limits of AZT were already well known, but according
to the new study, the drug didn't extend life for
people with AIDS by a single day. In fact, patients
in the placebo group actually lived a little longer. After
the conference, the Washington Post described it as the most
depressing moment in aid's treatment history. Mark Harrington, the act
(14:44):
UP member you first met in our previous episode, was
in Berlin at the time of the AZT announcement.
Speaker 4 (14:50):
I think at that point it was pretty universally felt
that we were all doomed and anybody that had HIV
was going to die. We're not going to be changing
the field fast enough to to save our lives or
the lives of most of our friends that had HIV
and most of the other millions and millions of people
that had HIV. So it seemed that everything we had
done up to that point hadn't been enough.
Speaker 1 (15:11):
Three weeks after the conference in Berlin, a group of
AIDS activists channeled their sorrow into a protest in Washington, Free.
Speaker 3 (15:20):
The deaths of years we are taking any harm.
Speaker 1 (15:24):
It was a new kind of protest known as a
political funeral.
Speaker 6 (15:29):
It got to the point where the community started this
campaign to show our deaths, to show what AIDS looked like,
and the most dramatic way that that happened was through
political funerals, in which the corpses of the fallen comrades
were taken out into the streets and displayed in these
(15:52):
these really heartbreaking expressions of anger and rage.
Speaker 1 (16:00):
The point of political funerals was to force an awareness
of the death toll from AIDS onto those who might
otherwise find it easy to look away. Mark Harrington says
that activists didn't want AIDS to be a private epidemic.
Speaker 4 (16:14):
We wanted the American people to see the cost, to
see the lives that were being lost, and to be
made aware by us putting it into their faces that
the people that were dying were loved and were valued
members of our society. And so this was a sign
of desperation, of despair, but also a beautiful sign of solidarity.
Speaker 1 (16:40):
It was the summer of nineteen ninety three when an
act UP member with AIDS named Tim Bailey took a
turn for the worse. As he lay dying, Bailey told
his friends that he wanted his body thrown over the
White House gate. It would be a nod to an
act UP protest held the previous year when more than
a dozen activists poured out the ashes of their loved
(17:01):
ones onto the White House lawn.
Speaker 5 (17:03):
And we're here today to bring home to George Brush
the results of this murders in action.
Speaker 1 (17:11):
Tim Bailey's idea to have people throw his actual body
onto the lawn was a little more extreme, and his
friends demurred, but they promised him they would do something
in front of the White House.
Speaker 5 (17:27):
True Love.
Speaker 1 (17:33):
On July first, nineteen ninety three, a few days after
Bailey died, his friends drove his body from a funeral
home in New Jersey to Washington, d C.
Speaker 6 (17:43):
This was carried out like a military operation. They rented
a van and they called upon Act Up members around
the country to meet them in Washington.
Speaker 1 (17:52):
The plan was to meet up at the Capital reflecting pool,
then marched down Pennsylvania Avenue in a procession, But by
the time the activist van pulled into a parking lot
near the Capitol, the authorities were already there. Some were
wearing riot gear.
Speaker 10 (18:07):
This is this is the last whistles, It's in the will.
Speaker 2 (18:10):
There are legal permits, there are family members here.
Speaker 5 (18:13):
You're going to You're going to interfere with a funeral
procession in front of.
Speaker 15 (18:18):
All this press.
Speaker 6 (18:19):
It was a showdown of remarkable tension and anger. There
was rage and tears coming from the protesters, who felt
that they owed it to Tim Bailey to be able
to accomplish what he had asked for and yet they
were being blocked.
Speaker 1 (18:50):
According to one witness, a federal agent at one point
reached into the van holding Bailey's casket and snatched the
keys from the driver. Activists surrounded van and sat down
so it couldn't be driven away. After a tense standoff
that lasted several hours, they flung open the back doors
and forced the casket.
Speaker 6 (19:09):
Out, But the pushback from this phalanx of police officers
was such that the whole casket nearly fell over and
nearly emptied itself in the parking lot. Everything you wanted
to do, and now you're fucking hell.
Speaker 1 (19:32):
You have to god damn more. Eventually, the activists regained
control of Bailey's casket and managed to get it back
into the van. The police then surrounded the van and
escorted it onto the highway back towards New Jersey.
Speaker 6 (19:46):
The escort lasted into Maryland to Baltimore, and Tim's body
was returned ultimately to the funeral home and he was
given a regular burial after that.
Speaker 1 (20:04):
By nineteen ninety three, activists weren't the only ones losing hope.
Scientists were also beginning to doubt whether an effective treatment
for HIV was possible AZT like drugs had proven ineffective,
and while MIRK was putting its energy behind protease inhibitors,
there was no guarantee that those would work either. Here
(20:25):
again is Emilio Emini, the virologist who ran Merk's HIV efforts.
Speaker 2 (20:31):
What was in everyone's back of everyone's mind was, well,
maybe every single drug we develop against this virus, or
even an inhibit of the protease, maybe the virus can
very quickly defeat it by simply becoming resistant quickly.
Speaker 1 (20:44):
Thanks to Irving Siegel and his colleagues, MIRK had been
early on protease research, but in the years after Siegel's death,
progress had been slow. It wasn't just because Siegel wasn't
there to help. Everyone I spoke to said his team
continued working on protease inhibitors with the same urgency as before.
It was just that making a functional drug out of
(21:06):
Siegel's idea was extremely hard. Here's David Franz again.
Speaker 6 (21:11):
It was the most complex pharmaceutical production ever undertaken. To
create this molecule took fourteen painstaking steps, each one very
time consuming. Each one depended on the one before it.
The idea that this would work was certainly far from
(21:32):
but reliable.
Speaker 1 (21:34):
The drug that Merk was working on would eventually be
called krick Savan. The scientist in charge of producing it
happened to also be a chef, and in an interview
with the Philadelphia Inquirer, he explained that making krick savan
was like cooking an intricate, multi course meal for a
thousand people. If you wrote the recipe for krick savan,
he said, each of the fourteen steps would cover sixty pages.
(22:00):
The effort seemed to be paying off. Kricks Evan worked
extremely well in lab trials, so well that, according to
David France, the team at Merk did something pretty unusual.
Speaker 6 (22:12):
As Merk and the HIV team were getting more and
more excited about kricks evan from what they saw in laboratories,
they wanted to push the thing into human trials very quickly,
and they had such faith that it would work that
they did something that is not done in pharmaceutical research.
Speaker 1 (22:34):
Typically, after successful lab trials, pharma companies test their drugs
on healthy animals to make sure the drugs aren't toxic
and can be absorbed into the bloodstream. According to France's reporting,
Merk skipped the animal trial.
Speaker 6 (22:49):
Sort of What they did instead was they tested it
among the scientists. They took it themselves, and so they
knew that it was safe because they all survived the
exposure to it. And it's something that has often joked
about in the pharmaceutical world as a big chimp study,
in which the big chimp is the scientist himself.
Speaker 1 (23:14):
We asked Emilio Amini about the big chimp trial. He
declined to comment. I told you a bit ago about
the devastating AZT announcement in Berlin. It was about six
months later that Merk ran a trial of krick Savan
and a group of people who were all HIV positive.
A week into the study, each patient's viral load fell dramatically.
(23:39):
Krick Savan appeared to work, at least in the short run.
Speaker 2 (23:43):
What we initially saw was that there was in fact,
very clear and rapid decline a virus load in those individuals.
And this was the first time that was seen with
any drug, you know, for HIV. So it gave us
a sort of a glimmer of hope that you know,
we have, you know, something potentially useful here, right, you know,
we felt, well, maybe there's something special about the proteuse.
(24:03):
Maybe there's something special that the virus cannot rapidly become
resistant to this class of drugs, and so we were encouraged.
Speaker 1 (24:12):
The question was would the virus find a way to
mutate around the drug like it had with AZT. The
researchers at MERK were optimistic enough that they had shared
their preliminary results with other AIDS researchers, but soon their
hopes were dashed. Once again, HIV had mutated and effectively
(24:34):
become resistant to the new drug.
Speaker 2 (24:38):
So if if we go back to the pac man analogy,
and you consider the protease inhibitor has been a something
a ball of rock, whatever you want to call it,
that gets in the mouth of the pac mand so
that the pac man can no longer, you know, close
its mouth and chump up the viral proteins. What the
mutation does is that the mutation alters the structure of
(24:59):
the pac man mouth just ever so slightly, but ald
is it enough so that the inhibitor can't bind into
that mouth anymore.
Speaker 12 (25:12):
The one.
Speaker 1 (25:15):
Just to make sure you got that, the mutation occurred
right in the pac man's mouth. Now, the protease inhibitor
that Murk had spent years developing and fine tuning didn't
fit properly, and so the pac man the protease went
right back to chomping and slicing HIV proteins and enabling
them to replicate in patient's bodies. HIV was rebounding in
(25:39):
Murk's study participants, and it was happening extremely fast. By
that time, we had a good feel for this.
Speaker 2 (25:45):
We already knew that what we were looking at here
was resistant selection.
Speaker 1 (25:49):
It was harder.
Speaker 2 (25:50):
It was harder for the virus to become resistant against
the protease inhibitor, but it wasn't that hard.
Speaker 1 (25:55):
HIV was the ultimate Darwinian nightmare. It seemed to evolve
around every obstacle put in its path. After years of
effort and hundreds of millions of dollars spent, Merk's new
drug appeared to be meeting the fate of every other
HIV treatment. The disappointment of krick Savan didn't mean that
(26:17):
protease inhibitors in general would never work, or that a
different drug based on the same idea wouldn't produce different results.
In fact, in the early nineties, several pharmaceutical companies other
than Merk were attempting to develop their own protease inhibitors.
In May of nineteen ninety four, a company called Hoffman
Laroche became the first of Mrk's rivals to put a
(26:40):
protease inhibitor in front of the FDA.
Speaker 11 (26:42):
But new drug called the most important advance since AZT.
Speaker 1 (26:47):
The drug was called sequineverr.
Speaker 11 (26:49):
Sha quivnaire, the first of a new generation of AIDS
fighting drugs.
Speaker 1 (26:53):
Hoffman Laroche was asking the FDA for accelerated approval, which
was exciting news for AIDS activists patients across the country.
Merk's protease inhibitor hadn't panned out, but maybe Hoffman the
Rosch's version would turn out to be the real deal.
Speaker 3 (27:08):
Researchers caution against too much optimism, but it is the
most powerful weapon yet developed against the AIDS virus.
Speaker 1 (27:15):
There was, however, a surprising hitch in the company's plan
to get sequinevere to market quickly. A small but influential
group of former act UP members was standing in the way.
They called themselves the Treatment Action Group or TAG for short.
(27:36):
TAG included many of the science oriented activists from act UP,
including Mark Harrington. As you heard in our previous episode,
Harrington and some of his colleagues had split off from
act UP, in part because they wanted to work with
government officials, not just antagonize them. By nineteen ninety four,
TAG was in regular contact with the FDA, and one
(27:57):
of its members served on the Agencies of FI Advisory Board.
As the FDA considered the possibility of early approval for sequinivere,
the activists in TAG made it known that they were
against it. I asked Harrington to explain their thinking. So
TAG opposed fast tracking the drug, and I think as
we tell our listeners about that, that their first instinct
(28:20):
will be to say, wait a second. I thought these
guys wanted to fast trike the drugs.
Speaker 4 (28:24):
What happened Berlin happened.
Speaker 1 (28:26):
After the conference in Berlin, where it was revealed just
how much of a failure AZT was. Harrington had come
to view the drug as a cautionary tale. Years earlier,
AZT had been fast tracked and given the benefit of
the doubt. Now the pitfalls of moving too fast were
all too clear.
Speaker 4 (28:45):
We recognized that some of the things that we'd done
to change clinical trials had led to false answers that
weren't accurate. We found out that the fast tracking for
drugs resulted in some drugs that didn't work being released
onto the market.
Speaker 1 (29:00):
Harrington felt that he and his fellow activists had been
naive for years. They had agitated for drugs to be
released as quickly as possible to people with AIDS on
the theory that anything was better than nothing, and.
Speaker 4 (29:13):
We had gotten a scientist in the regulators to also
be naive. But everyone was tired of all the deaths
and all the sick people and the lack of hope.
Everyone wanted these drugs to work, but just wishing.
Speaker 1 (29:24):
Doesn't make it so sequinevere. The protease inhibitor developed by
Merk's rival Hoff and Laroche struck the members of TAG
as yet another source of false hope. Among other things,
Harrington was alarmed by the way Hoff and Laroche had
conducted its trials.
Speaker 4 (29:42):
They did a little study in fewer than three hundred people,
and in summer of ninety four they wanted to FDA
to give it accelerated approval, and we said, no, this
is three hundred people. You want to do the first
of a new generation of AIDS drugs with a shitty
inadequate sample size. That's far too load to tell us
even if there's a side effects, let alone whether the
(30:02):
drug works, and you need to redraw your whole clinical
development plan from scratch.
Speaker 1 (30:09):
From tag's perspective, if sequinavere were approved hastily, it had
a good chance of dominating the market for protease inhibitors.
That was what had happened with AZT after the FDA
fast tracked approval of that drug back in nineteen eighty seven.
David Franz explains.
Speaker 6 (30:26):
They did not want an AZT like scenario to take place.
If sequinavere was probably the least promising of the protease inhibitors,
and yet if it had gotten to market before anybody else,
they worried that it would you take all the oxygen
out of the air for the other developed compounds.
Speaker 1 (30:47):
TAG demanded that Hoffman Laroche go back to the drawing
board and dramatically expand the trial size for sequinavier. They
proposed eighteen thousand participants, a sixtyfold increase from the original study.
Hoffman Laroche executives weren't exactly pleased to hear this, and
to gin up support for their fast track application, they
(31:08):
faxed tag's proposal to a bunch of other AIDS activist
groups across the country. When those activists learned about tag's opposition,
many of them were outraged.
Speaker 6 (31:19):
When TAG went their own way, they stepped on a
lot of feet. In fact, they stepped on just about
every foot in the movement. AIDS activists had never before
this point tried to slow down a drug to market,
and it created an amazing shit storm in the activist community.
Speaker 1 (31:37):
Dozens of AIDS groups signed a statement registering their disagreement
with TAG over sequinivir, but TAG by this point had
built up a lot of sway with the FDA, and
Hoffman Laroche's application was rejected.
Speaker 4 (31:50):
The controversy was fast and furious between libertarian activists who
really thought people should just take anything they want, and
then kind of more rigorous activists who thought we needed
better data before approving drugs that were going to be
taken by hundreds of thousands of Americans and millions of
people around the world. People from the community were yelling
at each other and calling each other killers and murderers
(32:12):
and so on.
Speaker 1 (32:13):
TAG made it clear that they were not just singling
out Hoffman Laroche. They wanted every drug company working on
protease inhibitors to take their time to run large, rigorous
trials that would yield rich, clean data. Other activists stuck
with what they had been saying for years, and people
with AIDS didn't have time to wait. Back at Murk,
(32:43):
Emilio Emini and his colleagues were continuing to track the
participants of their protease inhibitor trial. Remember, they had seen
their virus levels plummet in the first week of using
crick savan, and then like clockwork, the numbers had shot
back up in all of them, all of them except
one patient, number one hundred and forty two. For some reason,
(33:09):
that patient's viral load remained nearly undetectable, not just at
first but for months afterwards.
Speaker 2 (33:16):
And that one patient, for reasons that to this day
are never never been really understood, that one patient, the
virus level came down but never came back up again.
Speaker 3 (33:30):
And this was.
Speaker 2 (33:31):
The first time any patient, as far as we knew,
that had been treated with an HIV inhibitor, had actually
demonstrated the ability for prolonged virus suppression. And we kept
following that patient and never came back up, and just
stayed down.
Speaker 1 (33:48):
Amini and his colleagues didn't just write this off as
an anomaly. The data was real, and patient one hundred
and forty two wasn't some kind of superhuman And.
Speaker 2 (33:58):
What we said to ourselves was, well, the fact that
it happened in one patient doesn't tell us that, you know,
we have a high probability that we're going to be
able to do this, you know and everybody. But you
know what it does tell us. It tells us for
the first time that it's actually possible to do it.
Speaker 1 (34:16):
Patient one hundred and forty two became Mrk's north star.
Speaker 2 (34:20):
In fact, various members of the team had mouse pads
actually made up that actually showed the virus load in
this one individual. It was a way of saying to ourselves, look,
we actually did it. Now what we now need to
figure out is how do we do it in everybody.
Speaker 1 (34:38):
Emini and his colleagues followed their small phase one study
with a much bigger Phase two trial that would track
thousands of subjects over many months. Even just producing enough
drugs for a study that big was a challenge.
Speaker 2 (34:50):
The process of making the drug was not trivial. It
would require the establishment of literally a brand new chemical
manufacturing facility. One of the steps was an extreme exotherm,
which is a way of saying that it was an
explosive step that if you didn't do it carefully, it
would blow up your factory literally.
Speaker 1 (35:08):
While the trial got underway, Amini and his colleagues began
testing out different doses of cricksivan on patients. They also
tested the drug in combination with other kinds of drugs,
including AZT. That was a relatively new idea meant to
address HIV's ability to rapidly mutate around pretty much every
(35:28):
drug researchers had thrown at it.
Speaker 6 (35:31):
A thought occurred to scientists, and it was simultaneously in
multiple labs that it's simply a matter of math that
two drugs is better at preventing the virus from mutating
in ways that will escape the drug treatment.
Speaker 1 (35:47):
Emilio Emini was one of the scientists who'd helped make
this discovery. It's so called combination therapy was more effective
than using a single drug. Before protease inhibitors were developed,
there had only been in two classes of drugs to
try in combination with each other, AZT and one other.
Now there were three each one would attack HIV in
(36:10):
its own way and essentially back the virus into a
corner until it could no longer mutate its way out.
Speaker 6 (36:18):
People wanted to try a third drug and to see
if attacking the HIV virus in three different ways would
indeed flummix the HIV to the point of being able
to actually produce lasting results.
Speaker 1 (36:33):
A group of patients were given cricksavan along with AZT
and the other drug. The early results were remarkable, and
by the end of nineteen ninety five, Amini and his
colleagues at MURK were ready to tell the world about
what they were seeing.
Speaker 8 (36:52):
There's a major new reason for hope in the fight
against age. Tonight, researchers at an age conference in Washington
say a new class of drugs were working.
Speaker 1 (37:01):
On January thirtieth, nineteen ninety six, Amini was in Washington,
d c. To address the annual Conference on Retroviruses and
Opportunistic Infections. There, he delivered some major news.
Speaker 9 (37:14):
Studies presented at the conference show that over a six
month period, the drug sharply reduced the level of virus
in the body. Also, over a six month period, people
taking the drugs died at half the rate of people
not taking the drugs.
Speaker 1 (37:27):
Crick Savan, combined with the two other drugs, had made
HIV undetectable in most patients, and the effect didn't appear
to be temporary. At the time of the conference, it
had persisted for six whole months. Audience members gasped at
the data. For the first time since the AIDS epidemic began,
a treatment was having a lasting impact. The three drug
(37:50):
combination was working. After all those years of disappointment. AZT
did end up being part of an effective therapy, but
the development of proteus inhibitors had made the crucial difference.
By March, crick Savan and two other protease inhibitors have
been approved by the FDA. They were the fastest approved
drugs in the agency's history.
Speaker 2 (38:11):
I'd be lying if I didn't say it wasn't emotionally
and personally very satisfying. And what was most gratifying was
not just looking at the virus load. But it was
clear that as soon as the drugs became available and
started to be used appropriately as a combination from the
very beginning, that the impact it was having on progression
to as was us extraordinary.
Speaker 1 (38:35):
The three drug combination became known as the Triple Cocktail.
It came with difficult side effects at a huge price
tag upwards of fifteen thousand dollars a year. Still, many
people were able to obtain it through their health insurance
or through the federally funded AIDS Drug Assistance program. That summer,
Mark Harrington began taking the Triple Cocktail and experienced an
(38:58):
almost immediate change.
Speaker 4 (39:00):
My fire load went from over two hundred thousand to
nothing over the next three months, and it's been either
very low or undetectable in the twenty five years since.
And none of us could really believe it at first.
It was too good to be true, But the truth
was that these drugs really did stop the progression of HIV.
Speaker 9 (39:21):
Nobody is proclaiming a cure for AIDS yet, but based
on the results with a new drug combination, many people
are starting to believe it may soon be a possibility.
Speaker 1 (39:31):
Harrington's friend and fellow activist Garantz. Frankie Ruda had joined
the movement at the tail end of the Reagan administration.
By nineteen ninety six, she had scaled back her involvement
and had enrolled in college hoping to become a doctor.
She still remembers where she was when she heard the
triple cocktail was working.
Speaker 10 (39:49):
I was in New York that summer, and I remember
talking to folks and sort of getting the news and
just like being in this elevator to this crappy little
apartment I was sharing with some friends in college.
Speaker 2 (40:00):
Like.
Speaker 10 (40:02):
Feeling like, even though I knew it was the work
of men and science, it felt like some grand act
of mercy made manifest. And I think the Lazarus effect
that people described for these medications on people sort of
coming off their deathbeds and coming back to life gives
(40:25):
you a sense also that even the scientists and the
doctors had to take a recourse in biblical and religious
language to describe what happened, because it felt like a miracle.
Speaker 9 (40:38):
Where once there was only desperation, there is now genuine hope.
Speaker 13 (40:42):
Started getting weight, and little lakers and pains and problems
that I had in my body started resolving, and sort
of like everything went back to normal.
Speaker 15 (40:51):
And now I feel that I have a great potential
to live a much longer lifespan than was originally fought
when I was diagnosed in nineteen eighty seven, and I
look forward.
Speaker 3 (41:02):
To being here for my daughter's graduation next year from college.
Speaker 1 (41:06):
I have a fourteen month old grand.
Speaker 2 (41:08):
Baby that I you know, so I'm looking forward to
a future.
Speaker 1 (41:13):
The opportunistic infections disappeared, a ma seated people began gaining
weight again. The so called AIDS wards in America's hospitals
emptied out and closed down.
Speaker 9 (41:23):
In New York City, which has the most AIDS cases
in the country, the death rate from AIDS dropped almost
half from nineteen to day last January to eleven a
day in July. Across the country, hospitals are seeing fewer
AIDS patients and fewer deaths.
Speaker 4 (41:38):
When I found out that they were working for me,
and they were also working for other people that had
started them, I could exhale, you know, I could say, okay, okay,
we can move on now. We have got to this point.
Speaker 9 (41:57):
Nineteen ninety six was a watershed year in AIDS.
Speaker 13 (42:01):
It was the first year, the first time that treatment
actually outpaced the virus.
Speaker 4 (42:07):
And the first time in fifteen years of the pandemic,
we had something that we could offer to anybody with
HIV or AIDS that could keep them healthy if they
had HIV OR, that could reverse their AIDS and save
their life if they had AIDS, and that was truly unbelievable,
and yet it was true.
Speaker 1 (42:26):
With that, a new era in the history of AIDS began.
But the nightmare wasn't over yet, not even close. On
(42:55):
next week's season finale, why the HIV AIDS epidemic persists
after the development of the Triple Cocktail, and why it
continues to this day.
Speaker 13 (43:06):
Anytime you're talking about sex and drugs, it's a moral
issue rather than a public health issue.
Speaker 1 (43:14):
Fiasco is presented by Audible Originals and Prologue Projects. The
show is produced by Andrew Parsons, Sam Graham Felsen, Madelin
kaplan Ula Cualpa, and me Leon Nafock. Our researcher is
Francis Carr. Editorial support from Jessica Miller and Norah waswas
archival research by Michelle Sullivan. This season's music is composed
(43:37):
by Edith Mudge. Additional music by Nick Silvester of God Mode,
Joel Saint, Julian and Dan English, Noah Hect and Joe Valley.
Our theme song is by Spatial Relations. Our credits song
this week is Philosophers by Peter Sandberg. Music licensing courtesy
of Anthony Roman audio mixed by Erica Wong with additional
(43:57):
support from Selina Rabbe. Our artwork is designed by Teddy
Blanks at Chips and Y. David Blum is the editor
in chief of Audible Originals. Mike Charzak is the vice
president of Audible Studios. Zach Ross is head of acquisition
and development for Audible. Thanks to Peter Yasse, Nancy Cole,
Elliott Siegel, and Catherine Siegel. Thanks to you for listening.
(44:22):
Come back next week for the final episode of our season.
Hey, this is Leon Napok. I'm the host of Fiasco,
but you may also know me from the podcasts Slowburn,
Think Twice, Michael Jackson, and Backfired the Vaping Wars. I'm
excited to be sharing with you the next season of Backfired,
titled Attention Deficit, which is now available exclusively on Audible.
Backfired is a podcast about the business of unintended consequences.
(00:20):
In the first season, my co host ri L Pardess
and I dove deep into the world of vaping and
how the well intentioned quest for a safer cigarette went awry.
Now we're tackling ADHD and how the push to destigmatize
this hard to define childhood diagnosis has led to an
explosion of stimulant use in kids as well as adults.
It's a story about the promise of psychiatry to fix
(00:41):
our brains and the power of the pharmaceutical industry to
shape how we and our doctors think about what's wrong
with us. To hear both seasons of Backfired, go to
audible dot com slash Backfired and start a free trial
that's audible dot com slash backfired. Previously on Fiasco.
Speaker 2 (01:00):
My main job was to try and develop drugs that
could treat this devastating disease.
Speaker 3 (01:07):
The FDA announced today it would formerly streamline it's drug
approval process.
Speaker 4 (01:12):
This thing of hoping for like a magic bullet, that
you know, we would all be activists for two or
three years, and then the cure would come, the vaccine
would come, and we would all go back to our
lives wasn't going to happen.
Speaker 5 (01:22):
People need medication now, ten years from now, they'll be dead.
Speaker 1 (01:33):
When the virus that causes AIDS was isolated in nineteen
eighty three, it looked kind of like a time bomb.
HIV could eat away at someone's immune system for months
or years before they experienced any serious symptoms. Then one day,
pretty much any infection could become fatal. In nineteen eighty seven,
(01:54):
a young chemist at the pharmaceutical company Murk came up
with an idea for how to disable the bomb. His
name was Irving Siegel.
Speaker 6 (02:03):
What Siegel took on was really an impossible task. No
pharmaceutical scientist had ever really taken on such a challenge
as this.
Speaker 1 (02:12):
David France is the author of the book How to
Survive a Plague and the director of the documentary film
by the same name. During the height of the epidemic
France was an activist and a journalist who covered the
search for AIDS treatments. He says that after the release
of the first AIDS drug, AZT, many drug companies scrambled
to produce knockoffs.
Speaker 6 (02:34):
When AZT had come out in eighty seven, it immediately
proved that there was a massive and very of financially
rewarding market for drug companies to exploit.
Speaker 1 (02:46):
But as you've heard, AZT was not a miracle drug.
Even when AZT seemed to make someone better at first,
the virus rapidly mutated inside their body, which meant that
eventually almost everyone who took it still developed AIDS. Irving Seagull,
the scientist at MERK, was convinced he could build something
(03:07):
better than AZT, a new class of drug that would
attack HIV in a totally different way.
Speaker 6 (03:14):
Irving Siegel, he was young, he was charismatic. He pulled
together a team of very excited researchers, and the very
first thing that he focused on was a very novel approach.
No one else was taking it, and that was an
approach to look at protease inhibitors.
Speaker 1 (03:35):
Maybe you've heard that phrase before protease inhibitors. I definitely had,
but I also did not know what a protease was
or what it meant to inhibit it. So as I've learned,
the HIV one protease is an enzyme that plays a
critical role in allowing the virus to replicate in the body.
Siegel believed that the key to treating HIV was stopping
(03:59):
the protease from doing its job. After getting some initial
buy in from the higher ups at MERK, Siegel and
his colleague Nancy Cole started working on it, and just
a few months later they completed a paper reporting a
promising result. By inhibiting the HIV protease, it was possible
to stop the virus from replicating, at least in the
(04:20):
confines of a lab experiment. The quick turnaround was typical
of Siegel. His wife Catherine told me he was someone
who took the stairs two steps at a time when
he came into work, and was often moving so fast
that he would forget to button his shirts all the way.
Speaker 2 (04:34):
Can remember very clearly saying to myself, I have to
keep up with this guy, because he's just he did.
That's how rapidly he moved, That's how rapidly his brain
worked too.
Speaker 1 (04:43):
Emilio Emini is a virologist who worked with Siegel as
the head of Murk's efforts on HIV. He was a
co author on that first paper about the HIV protease.
Speaker 2 (04:53):
So you can imagine, you know, a very you know,
thin individual who is constantly moving and whose brain is
constantly functioning, absolutely extraordinary.
Speaker 1 (05:02):
By December of nineteen eighty eight, Siegel and his team
were on the cusp of a major advance, producing the
first three D image of the protease. After more than
a year of intensive work, they finally had a clear
understanding of its unique cellular structure. Emilio Emini sometimes compares
(05:22):
the HIV protease to a pac man, introducing it has
a wedge like mouth which it uses to chomp down
on HIV proteins and slice them into smaller pieces. These
smaller pieces then spawn new HIV proteins throughout the body. Siegel, Emini,
(05:45):
and their colleagues at MURK wanted to jam the pac
man's mouth and render it incapable of doing any chomping
or slicing. They believed that once this happened, the virus
would stop replicating.
Speaker 2 (06:01):
So if the protease is not functional, or if it's
rendered non functional and cannot perform this cutting activity, then
the viral proteins that are produced won't be assembled into
new viral particles right, and therefore the viral infection cycle
is terminated.
Speaker 1 (06:23):
The three D image of the protease gave Segel and
his colleagues a precise map of the enzyme, showing them
where exactly they had to jam it. Now they could
move on to the next step developing a drug, a
protease inhibitor that could be digested by human beings. Siegel
was confident that it could be done, but then shortly
(06:44):
before Christmas, Siegel had to travel to London to deliver
a long scheduled lecture. After three days away from his lab,
he was eager to get back, so at the last
minute he decided to change his flight to a red eye.
Pan Am flight one oh three left London on the
night of December twenty first, nineteen eighty eight. Less than
(07:06):
an hour after takeoff, the plane exploded over Lockerby, Scotland,
killing everyone on board.
Speaker 7 (07:13):
Just after seven this evening, a jumbo jet crashed onto
the town of locker Bit in the Scottish borders. It
was a Pan American Boeing seven four seventh.
Speaker 2 (07:21):
I remember very clearly where I was when I got
the news. I was at home. Actually it was right
before Christmas. It was right before Christmas in nineteen eighty eight.
Speaker 7 (07:29):
We now know there were two hundred and forty four
people on board, including three children.
Speaker 1 (07:34):
Irving Seagull was just thirty five years old when he
died in the locker be bombing.
Speaker 2 (07:39):
It was absolutely devastating, as you can imagine. It was
devastating for what we were doing collectively, was devastating for
the science. It was devastating for the whole field. But
more importantly, it was devastating personally for Irving and for
his family.
Speaker 1 (07:53):
Seagull's vision of a protease inhibitor would eventually lead to
a massive paradigm shift in AIDS treatment as part of
the so called triple cocktail. It would unlock the first
effective therapy for HIV and AIDS, and it would finally
make it possible for people who had the disease to survive.
But none of that would happen until nineteen ninety six,
(08:15):
nine years after Segel first saw promise in the HIV protease,
and fifteen years after the first cases of AIDS were
observed in America. It's impossible to say whether an effective
treatment might have come sooner if Irving Siegel hadn't changed
his flight from London. What's clear enough is that his
(08:39):
death was a major setback, one of many in science's
long and grueling campaign against AIDS. I'm Leon Napak from
Audible Originals and Prologue projects. This is fiasco.
Speaker 3 (08:54):
Typically, the stronger the drug, the faster HIV adapts to
resist it.
Speaker 4 (08:59):
It seemed that everything we had done up to that
point hadn't been enough.
Speaker 8 (09:02):
Researchers say a new class of drugs are working.
Speaker 9 (09:05):
Where once there was only desperation, there is now genuine hope.
Speaker 10 (09:09):
I'm looking falling through a future, the Lazarus effect that
people described it felt like a miracle.
Speaker 1 (09:17):
In this episode, the darkest days of the AIDS crisis
in America followed at long last by a glimpse of light.
By the nineteen nineties, HIV had spread all over the globe.
Speaker 11 (09:37):
Fourteen million people in the world are now HIV positive.
The number grows dramatically every year.
Speaker 1 (09:41):
And affected just about every demographic.
Speaker 11 (09:44):
Still, no cure still no vaccine to prevent it.
Speaker 1 (09:48):
In the US, cases among women and people of color
were climbing at a particularly alarming rate, and as the
time bomb went off and more and more people, the
death totals were rising.
Speaker 3 (10:00):
Every year in this country, four hundred thousand have gotten AIDS,
two hundred and forty thousand have died.
Speaker 2 (10:05):
Whatever we've been doing has not been enough.
Speaker 6 (10:08):
It wasn't until we hit nineteen ninety three and nineteen
ninety four and nineteen ninety five that the body counts
became extreme.
Speaker 1 (10:16):
David France again, these were.
Speaker 6 (10:18):
Mass dying events each year. Forty three thousand Americans died
in nineteen ninety three, fifty thousand Americans in nineteen ninety four.
So we entered a period of real despair.
Speaker 1 (10:34):
For many AIDS activists, the tragedy wasn't just about how
many people were dying during this period. It was also
that many of the dead had been leaders in the movement.
Speaker 6 (10:43):
Nineteen ninety three opened with the death of Bob Ravski,
who was a key member of Act UP, one of
its kind of poet warriors.
Speaker 12 (10:52):
Questions, what does a decent society do with people who
hurt themselves because they're human? Who smoke too much, we
too much, you drive carelessly, who don't have safe sex?
And the answer, I think the answer is at a
decent society does not put people out to pastor and
let them die because they've done a human thing.
Speaker 6 (11:08):
His death was a trauma for the movement and the community,
and then by the end of the year, Michael Callen died.
Speaker 1 (11:16):
You met Michael Callen in our second episode. He was
the singer, an early AIDS activist who spearheaded a safe
sex campaign in New York and helped create a Bill
of Rights for people with AIDS.
Speaker 13 (11:28):
It's hard to believe Michael Callen is no longer with us.
For more than a decade, he made beautiful music and
worked tirelessly to improve the quality of life for people
with AIDS, all the while fighting the disease himself.
Speaker 10 (11:40):
We won.
Speaker 6 (11:40):
Michael Callen was the author of a book on surviving
HIV and if the guy who was a self proclaimed
long term survivor couldn't survive, then it seemed we were
all lost.
Speaker 14 (11:55):
I realized that some people could look at my life
and say, oh, it was so sad when he died
of AIDS, And isn't that tragic? But what I want
to come through is that even after all the pain
and all the torture, and even having AIDS, I can
honestly say being gay is the greatest gift I was
ever given. I wouldn't change it.
Speaker 2 (12:17):
For the worlds.
Speaker 1 (12:27):
Amid all of this death, more and more activists started
to burn out Garantz. Frankie Ruda, who had joined Act
Up as a teenager in the late eighties, was one
of them.
Speaker 10 (12:38):
I think people have just had a lot of unprocessed
grief and we're just really like unraveling.
Speaker 1 (12:43):
Honestly, Like many in the movement, Frankie Ruda was exhausted
by the lack of progress on medical treatment and by
infighting among her fellow activists.
Speaker 10 (12:54):
All activist organizations have kind of a half life. They
burst onto the scene, they're incredibly viral, and then they
start to sort of change.
Speaker 1 (13:04):
The changes Act UP was going through might have been
easier to take if Frankie Ruda wasn't also losing friends
to AIDS on a routine basis.
Speaker 10 (13:13):
A lot of people had been infected around the same
period of time, and there was a sense amongst a
lot of people that they were not getting out of
this alive. Some people were very pessimistic about whether or
not they were going to see the end of the pandemic.
Speaker 1 (13:33):
The sense of despair deepened in June of nineteen ninety
three when scientists made a crushing announcement about AZT at
the International AIDS Conference in Berlin.
Speaker 11 (13:43):
Discouraging news Today about the effectiveness in some cases of AZT.
Speaker 1 (13:48):
French and British researchers had conducted the largest study ever
on AZT. Their conclusion was that in the long term
the drug simply did not work well.
Speaker 4 (13:58):
The T yes it was, there no significant benefit in
terms of survival or profession to AIDS.
Speaker 3 (14:05):
Reading from slides on a big overhead screen, the head
of the European study told the delegates patients inspected with
HIV who take AZT before they develop symptoms of AIDS
are no better off than patients who take it after
they come down with the disease.
Speaker 1 (14:20):
The limits of AZT were already well known, but according
to the new study, the drug didn't extend life for
people with AIDS by a single day. In fact, patients
in the placebo group actually lived a little longer. After
the conference, the Washington Post described it as the most
depressing moment in aid's treatment history. Mark Harrington, the act
(14:44):
UP member you first met in our previous episode, was
in Berlin at the time of the AZT announcement.
Speaker 4 (14:50):
I think at that point it was pretty universally felt
that we were all doomed and anybody that had HIV
was going to die. We're not going to be changing
the field fast enough to to save our lives or
the lives of most of our friends that had HIV
and most of the other millions and millions of people
that had HIV. So it seemed that everything we had
done up to that point hadn't been enough.
Speaker 1 (15:11):
Three weeks after the conference in Berlin, a group of
AIDS activists channeled their sorrow into a protest in Washington, Free.
Speaker 3 (15:20):
The deaths of years we are taking any harm.
Speaker 1 (15:24):
It was a new kind of protest known as a
political funeral.
Speaker 6 (15:29):
It got to the point where the community started this
campaign to show our deaths, to show what AIDS looked like,
and the most dramatic way that that happened was through
political funerals, in which the corpses of the fallen comrades
were taken out into the streets and displayed in these
(15:52):
these really heartbreaking expressions of anger and rage.
Speaker 1 (16:00):
The point of political funerals was to force an awareness
of the death toll from AIDS onto those who might
otherwise find it easy to look away. Mark Harrington says
that activists didn't want AIDS to be a private epidemic.
Speaker 4 (16:14):
We wanted the American people to see the cost, to
see the lives that were being lost, and to be
made aware by us putting it into their faces that
the people that were dying were loved and were valued
members of our society. And so this was a sign
of desperation, of despair, but also a beautiful sign of solidarity.
Speaker 1 (16:40):
It was the summer of nineteen ninety three when an
act UP member with AIDS named Tim Bailey took a
turn for the worse. As he lay dying, Bailey told
his friends that he wanted his body thrown over the
White House gate. It would be a nod to an
act UP protest held the previous year when more than
a dozen activists poured out the ashes of their loved
(17:01):
ones onto the White House lawn.
Speaker 5 (17:03):
And we're here today to bring home to George Brush
the results of this murders in action.
Speaker 1 (17:11):
Tim Bailey's idea to have people throw his actual body
onto the lawn was a little more extreme, and his
friends demurred, but they promised him they would do something
in front of the White House.
Speaker 5 (17:27):
True Love.
Speaker 1 (17:33):
On July first, nineteen ninety three, a few days after
Bailey died, his friends drove his body from a funeral
home in New Jersey to Washington, d C.
Speaker 6 (17:43):
This was carried out like a military operation. They rented
a van and they called upon Act Up members around
the country to meet them in Washington.
Speaker 1 (17:52):
The plan was to meet up at the Capital reflecting pool,
then marched down Pennsylvania Avenue in a procession, But by
the time the activist van pulled into a parking lot
near the Capitol, the authorities were already there. Some were
wearing riot gear.
Speaker 10 (18:07):
This is this is the last whistles, It's in the will.
Speaker 2 (18:10):
There are legal permits, there are family members here.
Speaker 5 (18:13):
You're going to You're going to interfere with a funeral
procession in front of.
Speaker 15 (18:18):
All this press.
Speaker 6 (18:19):
It was a showdown of remarkable tension and anger. There
was rage and tears coming from the protesters, who felt
that they owed it to Tim Bailey to be able
to accomplish what he had asked for and yet they
were being blocked.
Speaker 1 (18:50):
According to one witness, a federal agent at one point
reached into the van holding Bailey's casket and snatched the
keys from the driver. Activists surrounded van and sat down
so it couldn't be driven away. After a tense standoff
that lasted several hours, they flung open the back doors
and forced the casket.
Speaker 6 (19:09):
Out, But the pushback from this phalanx of police officers
was such that the whole casket nearly fell over and
nearly emptied itself in the parking lot. Everything you wanted
to do, and now you're fucking hell.
Speaker 1 (19:32):
You have to god damn more. Eventually, the activists regained
control of Bailey's casket and managed to get it back
into the van. The police then surrounded the van and
escorted it onto the highway back towards New Jersey.
Speaker 6 (19:46):
The escort lasted into Maryland to Baltimore, and Tim's body
was returned ultimately to the funeral home and he was
given a regular burial after that.
Speaker 1 (20:04):
By nineteen ninety three, activists weren't the only ones losing hope.
Scientists were also beginning to doubt whether an effective treatment
for HIV was possible AZT like drugs had proven ineffective,
and while MIRK was putting its energy behind protease inhibitors,
there was no guarantee that those would work either. Here
(20:25):
again is Emilio Emini, the virologist who ran Merk's HIV efforts.
Speaker 2 (20:31):
What was in everyone's back of everyone's mind was, well,
maybe every single drug we develop against this virus, or
even an inhibit of the protease, maybe the virus can
very quickly defeat it by simply becoming resistant quickly.
Speaker 1 (20:44):
Thanks to Irving Siegel and his colleagues, MIRK had been
early on protease research, but in the years after Siegel's death,
progress had been slow. It wasn't just because Siegel wasn't
there to help. Everyone I spoke to said his team
continued working on protease inhibitors with the same urgency as before.
It was just that making a functional drug out of
(21:06):
Siegel's idea was extremely hard. Here's David Franz again.
Speaker 6 (21:11):
It was the most complex pharmaceutical production ever undertaken. To
create this molecule took fourteen painstaking steps, each one very
time consuming. Each one depended on the one before it.
The idea that this would work was certainly far from
(21:32):
but reliable.
Speaker 1 (21:34):
The drug that Merk was working on would eventually be
called krick Savan. The scientist in charge of producing it
happened to also be a chef, and in an interview
with the Philadelphia Inquirer, he explained that making krick savan
was like cooking an intricate, multi course meal for a
thousand people. If you wrote the recipe for krick savan,
he said, each of the fourteen steps would cover sixty pages.
(22:00):
The effort seemed to be paying off. Kricks Evan worked
extremely well in lab trials, so well that, according to
David France, the team at Merk did something pretty unusual.
Speaker 6 (22:12):
As Merk and the HIV team were getting more and
more excited about kricks evan from what they saw in laboratories,
they wanted to push the thing into human trials very quickly,
and they had such faith that it would work that
they did something that is not done in pharmaceutical research.
Speaker 1 (22:34):
Typically, after successful lab trials, pharma companies test their drugs
on healthy animals to make sure the drugs aren't toxic
and can be absorbed into the bloodstream. According to France's reporting,
Merk skipped the animal trial.
Speaker 6 (22:49):
Sort of What they did instead was they tested it
among the scientists. They took it themselves, and so they
knew that it was safe because they all survived the
exposure to it. And it's something that has often joked
about in the pharmaceutical world as a big chimp study,
in which the big chimp is the scientist himself.
Speaker 1 (23:14):
We asked Emilio Amini about the big chimp trial. He
declined to comment. I told you a bit ago about
the devastating AZT announcement in Berlin. It was about six
months later that Merk ran a trial of krick Savan
and a group of people who were all HIV positive.
A week into the study, each patient's viral load fell dramatically.
(23:39):
Krick Savan appeared to work, at least in the short run.
Speaker 2 (23:43):
What we initially saw was that there was in fact,
very clear and rapid decline a virus load in those individuals.
And this was the first time that was seen with
any drug, you know, for HIV. So it gave us
a sort of a glimmer of hope that you know,
we have, you know, something potentially useful here, right, you know,
we felt, well, maybe there's something special about the proteuse.
(24:03):
Maybe there's something special that the virus cannot rapidly become
resistant to this class of drugs, and so we were encouraged.
Speaker 1 (24:12):
The question was would the virus find a way to
mutate around the drug like it had with AZT. The
researchers at MERK were optimistic enough that they had shared
their preliminary results with other AIDS researchers, but soon their
hopes were dashed. Once again, HIV had mutated and effectively
(24:34):
become resistant to the new drug.
Speaker 2 (24:38):
So if if we go back to the pac man analogy,
and you consider the protease inhibitor has been a something
a ball of rock, whatever you want to call it,
that gets in the mouth of the pac mand so
that the pac man can no longer, you know, close
its mouth and chump up the viral proteins. What the
mutation does is that the mutation alters the structure of
(24:59):
the pac man mouth just ever so slightly, but ald
is it enough so that the inhibitor can't bind into
that mouth anymore.
Speaker 12 (25:12):
The one.
Speaker 1 (25:15):
Just to make sure you got that, the mutation occurred
right in the pac man's mouth. Now, the protease inhibitor
that Murk had spent years developing and fine tuning didn't
fit properly, and so the pac man the protease went
right back to chomping and slicing HIV proteins and enabling
them to replicate in patient's bodies. HIV was rebounding in
(25:39):
Murk's study participants, and it was happening extremely fast. By
that time, we had a good feel for this.
Speaker 2 (25:45):
We already knew that what we were looking at here
was resistant selection.
Speaker 1 (25:49):
It was harder.
Speaker 2 (25:50):
It was harder for the virus to become resistant against
the protease inhibitor, but it wasn't that hard.
Speaker 1 (25:55):
HIV was the ultimate Darwinian nightmare. It seemed to evolve
around every obstacle put in its path. After years of
effort and hundreds of millions of dollars spent, Merk's new
drug appeared to be meeting the fate of every other
HIV treatment. The disappointment of krick Savan didn't mean that
(26:17):
protease inhibitors in general would never work, or that a
different drug based on the same idea wouldn't produce different results.
In fact, in the early nineties, several pharmaceutical companies other
than Merk were attempting to develop their own protease inhibitors.
In May of nineteen ninety four, a company called Hoffman
Laroche became the first of Mrk's rivals to put a
(26:40):
protease inhibitor in front of the FDA.
Speaker 11 (26:42):
But new drug called the most important advance since AZT.
Speaker 1 (26:47):
The drug was called sequineverr.
Speaker 11 (26:49):
Sha quivnaire, the first of a new generation of AIDS
fighting drugs.
Speaker 1 (26:53):
Hoffman Laroche was asking the FDA for accelerated approval, which
was exciting news for AIDS activists patients across the country.
Merk's protease inhibitor hadn't panned out, but maybe Hoffman the
Rosch's version would turn out to be the real deal.
Speaker 3 (27:08):
Researchers caution against too much optimism, but it is the
most powerful weapon yet developed against the AIDS virus.
Speaker 1 (27:15):
There was, however, a surprising hitch in the company's plan
to get sequinevere to market quickly. A small but influential
group of former act UP members was standing in the way.
They called themselves the Treatment Action Group or TAG for short.
(27:36):
TAG included many of the science oriented activists from act UP,
including Mark Harrington. As you heard in our previous episode,
Harrington and some of his colleagues had split off from
act UP, in part because they wanted to work with
government officials, not just antagonize them. By nineteen ninety four,
TAG was in regular contact with the FDA, and one
(27:57):
of its members served on the Agencies of FI Advisory Board.
As the FDA considered the possibility of early approval for sequinivere,
the activists in TAG made it known that they were
against it. I asked Harrington to explain their thinking. So
TAG opposed fast tracking the drug, and I think as
we tell our listeners about that, that their first instinct
(28:20):
will be to say, wait a second. I thought these
guys wanted to fast trike the drugs.
Speaker 4 (28:24):
What happened Berlin happened.
Speaker 1 (28:26):
After the conference in Berlin, where it was revealed just
how much of a failure AZT was. Harrington had come
to view the drug as a cautionary tale. Years earlier,
AZT had been fast tracked and given the benefit of
the doubt. Now the pitfalls of moving too fast were
all too clear.
Speaker 4 (28:45):
We recognized that some of the things that we'd done
to change clinical trials had led to false answers that
weren't accurate. We found out that the fast tracking for
drugs resulted in some drugs that didn't work being released
onto the market.
Speaker 1 (29:00):
Harrington felt that he and his fellow activists had been
naive for years. They had agitated for drugs to be
released as quickly as possible to people with AIDS on
the theory that anything was better than nothing, and.
Speaker 4 (29:13):
We had gotten a scientist in the regulators to also
be naive. But everyone was tired of all the deaths
and all the sick people and the lack of hope.
Everyone wanted these drugs to work, but just wishing.
Speaker 1 (29:24):
Doesn't make it so sequinevere. The protease inhibitor developed by
Merk's rival Hoff and Laroche struck the members of TAG
as yet another source of false hope. Among other things,
Harrington was alarmed by the way Hoff and Laroche had
conducted its trials.
Speaker 4 (29:42):
They did a little study in fewer than three hundred people,
and in summer of ninety four they wanted to FDA
to give it accelerated approval, and we said, no, this
is three hundred people. You want to do the first
of a new generation of AIDS drugs with a shitty
inadequate sample size. That's far too load to tell us
even if there's a side effects, let alone whether the
(30:02):
drug works, and you need to redraw your whole clinical
development plan from scratch.
Speaker 1 (30:09):
From tag's perspective, if sequinavere were approved hastily, it had
a good chance of dominating the market for protease inhibitors.
That was what had happened with AZT after the FDA
fast tracked approval of that drug back in nineteen eighty seven.
David Franz explains.
Speaker 6 (30:26):
They did not want an AZT like scenario to take place.
If sequinavere was probably the least promising of the protease inhibitors,
and yet if it had gotten to market before anybody else,
they worried that it would you take all the oxygen
out of the air for the other developed compounds.
Speaker 1 (30:47):
TAG demanded that Hoffman Laroche go back to the drawing
board and dramatically expand the trial size for sequinavier. They
proposed eighteen thousand participants, a sixtyfold increase from the original study.
Hoffman Laroche executives weren't exactly pleased to hear this, and
to gin up support for their fast track application, they
(31:08):
faxed tag's proposal to a bunch of other AIDS activist
groups across the country. When those activists learned about tag's opposition,
many of them were outraged.
Speaker 6 (31:19):
When TAG went their own way, they stepped on a
lot of feet. In fact, they stepped on just about
every foot in the movement. AIDS activists had never before
this point tried to slow down a drug to market,
and it created an amazing shit storm in the activist community.
Speaker 1 (31:37):
Dozens of AIDS groups signed a statement registering their disagreement
with TAG over sequinivir, but TAG by this point had
built up a lot of sway with the FDA, and
Hoffman Laroche's application was rejected.
Speaker 4 (31:50):
The controversy was fast and furious between libertarian activists who
really thought people should just take anything they want, and
then kind of more rigorous activists who thought we needed
better data before approving drugs that were going to be
taken by hundreds of thousands of Americans and millions of
people around the world. People from the community were yelling
at each other and calling each other killers and murderers
(32:12):
and so on.
Speaker 1 (32:13):
TAG made it clear that they were not just singling
out Hoffman Laroche. They wanted every drug company working on
protease inhibitors to take their time to run large, rigorous
trials that would yield rich, clean data. Other activists stuck
with what they had been saying for years, and people
with AIDS didn't have time to wait. Back at Murk,
(32:43):
Emilio Emini and his colleagues were continuing to track the
participants of their protease inhibitor trial. Remember, they had seen
their virus levels plummet in the first week of using
crick savan, and then like clockwork, the numbers had shot
back up in all of them, all of them except
one patient, number one hundred and forty two. For some reason,
(33:09):
that patient's viral load remained nearly undetectable, not just at
first but for months afterwards.
Speaker 2 (33:16):
And that one patient, for reasons that to this day
are never never been really understood, that one patient, the
virus level came down but never came back up again.
Speaker 3 (33:30):
And this was.
Speaker 2 (33:31):
The first time any patient, as far as we knew,
that had been treated with an HIV inhibitor, had actually
demonstrated the ability for prolonged virus suppression. And we kept
following that patient and never came back up, and just
stayed down.
Speaker 1 (33:48):
Amini and his colleagues didn't just write this off as
an anomaly. The data was real, and patient one hundred
and forty two wasn't some kind of superhuman And.
Speaker 2 (33:58):
What we said to ourselves was, well, the fact that
it happened in one patient doesn't tell us that, you know,
we have a high probability that we're going to be
able to do this, you know and everybody. But you
know what it does tell us. It tells us for
the first time that it's actually possible to do it.
Speaker 1 (34:16):
Patient one hundred and forty two became Mrk's north star.
Speaker 2 (34:20):
In fact, various members of the team had mouse pads
actually made up that actually showed the virus load in
this one individual. It was a way of saying to ourselves, look,
we actually did it. Now what we now need to
figure out is how do we do it in everybody.
Speaker 1 (34:38):
Emini and his colleagues followed their small phase one study
with a much bigger Phase two trial that would track
thousands of subjects over many months. Even just producing enough
drugs for a study that big was a challenge.
Speaker 2 (34:50):
The process of making the drug was not trivial. It
would require the establishment of literally a brand new chemical
manufacturing facility. One of the steps was an extreme exotherm,
which is a way of saying that it was an
explosive step that if you didn't do it carefully, it
would blow up your factory literally.
Speaker 1 (35:08):
While the trial got underway, Amini and his colleagues began
testing out different doses of cricksivan on patients. They also
tested the drug in combination with other kinds of drugs,
including AZT. That was a relatively new idea meant to
address HIV's ability to rapidly mutate around pretty much every
(35:28):
drug researchers had thrown at it.
Speaker 6 (35:31):
A thought occurred to scientists, and it was simultaneously in
multiple labs that it's simply a matter of math that
two drugs is better at preventing the virus from mutating
in ways that will escape the drug treatment.
Speaker 1 (35:47):
Emilio Emini was one of the scientists who'd helped make
this discovery. It's so called combination therapy was more effective
than using a single drug. Before protease inhibitors were developed,
there had only been in two classes of drugs to
try in combination with each other, AZT and one other.
Now there were three each one would attack HIV in
(36:10):
its own way and essentially back the virus into a
corner until it could no longer mutate its way out.
Speaker 6 (36:18):
People wanted to try a third drug and to see
if attacking the HIV virus in three different ways would
indeed flummix the HIV to the point of being able
to actually produce lasting results.
Speaker 1 (36:33):
A group of patients were given cricksavan along with AZT
and the other drug. The early results were remarkable, and
by the end of nineteen ninety five, Amini and his
colleagues at MURK were ready to tell the world about
what they were seeing.
Speaker 8 (36:52):
There's a major new reason for hope in the fight
against age. Tonight, researchers at an age conference in Washington
say a new class of drugs were working.
Speaker 1 (37:01):
On January thirtieth, nineteen ninety six, Amini was in Washington,
d c. To address the annual Conference on Retroviruses and
Opportunistic Infections. There, he delivered some major news.
Speaker 9 (37:14):
Studies presented at the conference show that over a six
month period, the drug sharply reduced the level of virus
in the body. Also, over a six month period, people
taking the drugs died at half the rate of people
not taking the drugs.
Speaker 1 (37:27):
Crick Savan, combined with the two other drugs, had made
HIV undetectable in most patients, and the effect didn't appear
to be temporary. At the time of the conference, it
had persisted for six whole months. Audience members gasped at
the data. For the first time since the AIDS epidemic began,
a treatment was having a lasting impact. The three drug
(37:50):
combination was working. After all those years of disappointment. AZT
did end up being part of an effective therapy, but
the development of proteus inhibitors had made the crucial difference.
By March, crick Savan and two other protease inhibitors have
been approved by the FDA. They were the fastest approved
drugs in the agency's history.
Speaker 2 (38:11):
I'd be lying if I didn't say it wasn't emotionally
and personally very satisfying. And what was most gratifying was
not just looking at the virus load. But it was
clear that as soon as the drugs became available and
started to be used appropriately as a combination from the
very beginning, that the impact it was having on progression
to as was us extraordinary.
Speaker 1 (38:35):
The three drug combination became known as the Triple Cocktail.
It came with difficult side effects at a huge price
tag upwards of fifteen thousand dollars a year. Still, many
people were able to obtain it through their health insurance
or through the federally funded AIDS Drug Assistance program. That summer,
Mark Harrington began taking the Triple Cocktail and experienced an
(38:58):
almost immediate change.
Speaker 4 (39:00):
My fire load went from over two hundred thousand to
nothing over the next three months, and it's been either
very low or undetectable in the twenty five years since.
And none of us could really believe it at first.
It was too good to be true, But the truth
was that these drugs really did stop the progression of HIV.
Speaker 9 (39:21):
Nobody is proclaiming a cure for AIDS yet, but based
on the results with a new drug combination, many people
are starting to believe it may soon be a possibility.
Speaker 1 (39:31):
Harrington's friend and fellow activist Garantz. Frankie Ruda had joined
the movement at the tail end of the Reagan administration.
By nineteen ninety six, she had scaled back her involvement
and had enrolled in college hoping to become a doctor.
She still remembers where she was when she heard the
triple cocktail was working.
Speaker 10 (39:49):
I was in New York that summer, and I remember
talking to folks and sort of getting the news and
just like being in this elevator to this crappy little
apartment I was sharing with some friends in college.
Speaker 2 (40:00):
Like.
Speaker 10 (40:02):
Feeling like, even though I knew it was the work
of men and science, it felt like some grand act
of mercy made manifest. And I think the Lazarus effect
that people described for these medications on people sort of
coming off their deathbeds and coming back to life gives
(40:25):
you a sense also that even the scientists and the
doctors had to take a recourse in biblical and religious
language to describe what happened, because it felt like a miracle.
Speaker 9 (40:38):
Where once there was only desperation, there is now genuine hope.
Speaker 13 (40:42):
Started getting weight, and little lakers and pains and problems
that I had in my body started resolving, and sort
of like everything went back to normal.
Speaker 15 (40:51):
And now I feel that I have a great potential
to live a much longer lifespan than was originally fought
when I was diagnosed in nineteen eighty seven, and I
look forward.
Speaker 3 (41:02):
To being here for my daughter's graduation next year from college.
Speaker 1 (41:06):
I have a fourteen month old grand.
Speaker 2 (41:08):
Baby that I you know, so I'm looking forward to
a future.
Speaker 1 (41:13):
The opportunistic infections disappeared, a ma seated people began gaining
weight again. The so called AIDS wards in America's hospitals
emptied out and closed down.
Speaker 9 (41:23):
In New York City, which has the most AIDS cases
in the country, the death rate from AIDS dropped almost
half from nineteen to day last January to eleven a
day in July. Across the country, hospitals are seeing fewer
AIDS patients and fewer deaths.
Speaker 4 (41:38):
When I found out that they were working for me,
and they were also working for other people that had
started them, I could exhale, you know, I could say, okay, okay,
we can move on now. We have got to this point.
Speaker 9 (41:57):
Nineteen ninety six was a watershed year in AIDS.
Speaker 13 (42:01):
It was the first year, the first time that treatment
actually outpaced the virus.
Speaker 4 (42:07):
And the first time in fifteen years of the pandemic,
we had something that we could offer to anybody with
HIV or AIDS that could keep them healthy if they
had HIV OR, that could reverse their AIDS and save
their life if they had AIDS, and that was truly unbelievable,
and yet it was true.
Speaker 1 (42:26):
With that, a new era in the history of AIDS began.
But the nightmare wasn't over yet, not even close. On
(42:55):
next week's season finale, why the HIV AIDS epidemic persists
after the development of the Triple Cocktail, and why it
continues to this day.
Speaker 13 (43:06):
Anytime you're talking about sex and drugs, it's a moral
issue rather than a public health issue.
Speaker 1 (43:14):
Fiasco is presented by Audible Originals and Prologue Projects. The
show is produced by Andrew Parsons, Sam Graham Felsen, Madelin
kaplan Ula Cualpa, and me Leon Nafock. Our researcher is
Francis Carr. Editorial support from Jessica Miller and Norah waswas
archival research by Michelle Sullivan. This season's music is composed
(43:37):
by Edith Mudge. Additional music by Nick Silvester of God Mode,
Joel Saint, Julian and Dan English, Noah Hect and Joe Valley.
Our theme song is by Spatial Relations. Our credits song
this week is Philosophers by Peter Sandberg. Music licensing courtesy
of Anthony Roman audio mixed by Erica Wong with additional
(43:57):
support from Selina Rabbe. Our artwork is designed by Teddy
Blanks at Chips and Y. David Blum is the editor
in chief of Audible Originals. Mike Charzak is the vice
president of Audible Studios. Zach Ross is head of acquisition
and development for Audible. Thanks to Peter Yasse, Nancy Cole,
Elliott Siegel, and Catherine Siegel. Thanks to you for listening.
(44:22):
Come back next week for the final episode of our season.
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