DRUG DEVELOPMENT DECONSTRUCTOR MANIFESTO: : “Tell me how you read and I'll tell you who you are.” ― Martin Heidegger
Friday, August 31, 2012
Big Deal!
Genmab has agreed a deal that could be worth over $1.1
billion with a unit of Johnson & Johnson for the rights to a cancer agent,
giving the U.S. company a 10.7 percent equity stake in the Danish biotech
group.
Genmab said on Thursday that J&J unit Janssen
Biotech Inc would obtain global license rights to cancer agent daratumumab.
Janssen Biotech will make an upfront payment of $55
million for the license and Johnson & Johnson Development Corp would invest
475 million Danish crowns ($80 million) in new Genmab shares, the company said.
I would
just wish J&J good luck with this deal: I hope that they know what they are
doing! Monoclonal
antibodies are still very sexy for Big Pharma, let them burn some more
money!
Thursday, August 30, 2012
Targeted failure of the week. No 15 and 16.
Today we have 2 compounds:
Tivatinib (see the structure) against lung cancer:
Tivantinib, an oral medicine, aims to block an enzyme known as c-Met, which plays a role in the growth and spread of cancer.
Shares of cancer drug developer ArQule (ARQL) are dropping after the company disclosed problems with a clinical trial being conducted in Asia. ArQule’s development partner Kyowa Hakko Kirin of Japan suspended patient enrollment in a late-stage human study of the lung cancer drug tivantinib due to safety concerns.
Pomaglumetad methionil, or mGlu2/3 - the second failed drug, is for treatment of schizophrenia:
Eli Lilly and Co said it would stop developing an experimental schizophrenia drug after a recent analysis showed that a late-stage trial on the drug was likely to fail.
An independent futility analysis concluded that the second late-stage study on the drug was unlikely to meet the main goal of the trial, the company said .
Well, and what compound will fail next?
Wednesday, August 29, 2012
Classical Medicine vs Alternative Medicine. A draw.
”Classical”
science and medicine is in a dead end with the targeted
paradigm and personalized
medicine and is not useful anymore in the development of new medicinal
products. In order to switch the attention from this failure, adepts of the “classical”
approach blame other competitive approaches that they are not scientific,
pseudoscientific etc etc etc. Well, I do agree that the vast majority of these
approaches (90 or 95 or even 99%!) is bogus, no doubts about it! But WHY people
constantly seek alternative approaches for treatment? The answer is soberly
simple: because the “classical” medicine DOES NOT PROVIDE cures which is supposed
to do. A classical doctor cannot just say: “Our modern monoclonal antibody
cannot cure your breast cancer therefore you have to die – AND DO NOT GO TO
OTHER DOCTORS, game is over”. If the doctor cannot help with classical approach
– (s)he cannot exclude the possibility that other “non-classical” modes of
treatment will be helpful! But the desire to exclude competitors is extremely
huge! One of the nice examples is here:
the author tries very desperately to deconstruct alternative medicine. I would just
recommend to the author: forget homeopathy, diet science, urinotherapy etc and
just find something which will cure cancer, - and believe me: everybody will
forget this bogus alternative medicine and will build a monument to you!
Tuesday, August 28, 2012
Multiple Sclerosis: is simplicity best or who win the race?
Very
interesting article is here.
Just to
summarize the situation with MS treatment: we have very nice treatment Copaxone
which will
become generic in a couple of years. Then we have an experimental oral drug BG-12:
The company's experimental drug BG-12 (dimethyl
fumarate) is in late stage clinical trials. BG-12 is designed to treat
relapsing-remitting MS. When given twice daily, BG-12 cut the relapse rate by
44 percent at two years compared with a placebo. When given three times a day,
it cut the relapse rate by 51 percent. If approved BG-12 could become the
world's leading treatment for MS.
44 and 51%
are much-much better than Copaxone
(which) reduced the rate by 29 percent versus a placebo.
And now we
have yet another experimental drug: Laquinimod.
At this moment I will not say much about the clinical trials, I will just see on
the structures of the drugs! Something unusual? Yes, both compounds look
extremely simple (heterocycle molecule on the picture is Laquinimod), especially BG-12! And I would like to ask anybody who works
in this field: how in the world these simple compounds can treat MS??? One of
the answers is here:
The mechanism of action is not fully understood, but
preclinical studies have suggested that BG-12 may have complex neuroprotective
and anti-inflammatory effects, acting via the Nrf-2 pathway. Activation of the
Nrf-2 pathway defends against oxidative-stress induced neuronal death, protects
the blood-brain barrier and supports maintenance of myelin integrity in the
central nervous system.
But this
answer is basically making the picture even more complicated…
I cannot
connect the dots… And in my experience it usually does mean just one thing:
BLUFF! And the first I could imagine that clinical trials with BG-12 were
accomplished in a “creative” way. Let’s wait what FDA and EMA will say – we
have 4 years to wait:
An extension study for participants on the DEFINE and
CONFIRM studies to assess the long-term effectiveness and safety of BG-12 for a
further two years. Estimated completion date June 2016.
I would
like to wish a success for all the companies who are developing novel drugs
against MS. I hope that BG-12, Laquinimod and other novel drugs will be helpful
against MS – no doubts about it! What drug will be more useful? Only time will
show…
Monday, August 27, 2012
Pemetrexed – just wait 5 years...
Eli Lilly & Co. (LLY) won a U.S. appeals court ruling that upholds the validity of a patent for the lung- cancer drug Alimta and blocks generic competition through 2017.
The U.S. Court of Appeals for the Federal Circuit today rejected arguments by Teva Pharmaceutical Industries Ltd. (TEVA) that the patent was invalid. It affirmed a lower court ruling. The decision was posted on the court’s website.
Alimta, whose chemical name is pemetrexed, generated $2.5 billion in sales last year for Indianapolis-based Lilly, making it the company’s third biggest-selling drug. Alimta is designed to hamper cancer cells’ ability to use folic acid to grow after an initial treatment with other drugs.
Teva, based in Petah Tikva, Israel, had argued that Lilly had patented a compound that wasn’t much different from what was covered by two earlier patents. The three-judge panel said the lower court was correct to rule that the 2017 patent is distinct from the earlier inventions.
Well, just 5 years... And then – generic!
Sunday, August 26, 2012
Saturday, August 25, 2012
Targeted failure of the week. No 13-14.
This time we have solanezumab (monoclonal failure against AD):
After years of anticipation and growing skepticism, Eli Lilly this morning disclosed that an Alzheimer’s medication failed to meet the primary endpoints, both cognitive and functional, in a pair of Phase III double-blind, placebo-controlled trials in patients with mild-to-moderate Alzheimer’s disease. Although disappointing, the outcome was actually mixed, but may still renew questions about the future for Lilly as it grapples with its commitment to Alzheimer’s research.
And BMS-986094 (which targets polymerase, an enzyme essential for the replication of the hepatitis C virus):
(Reuters) - Bristol-Myers Squibb Co (BMY) said it would record a $1.8 billion charge related to the discontinuation of its much-anticipated hepatitis C drug that was dropped after a patient died of heart failure.
The company will recognize the charge in the third quarter of 2012, it said in a regulatory filing on Friday. It does not expect the charge to result in future cash expenses.
The pharmaceutical company said on Thursday it would drop development of the drug, called BMS-986094, after a patient who was treated with the drug in a mid-stage trial died of heart failure and several others had to be hospitalized.
Bristol had voluntarily stopped the mid-stage trial earlier this month.
The drug, which was acquired by Bristol through its $2.5 billion purchase of Inhibitex Inc, belongs to a promising new class of hepatitis C drugs known as nucleotide polymerase inhibitors.
What targeted drug will fail next?
Friday, August 24, 2012
Magentic nanoparticles in drug delivery as a "rocket science"
The article-review is here. It is very interesting - no doubt about it. The approach probably will be used somewhere in the future (2100? - not earlier, it is for sure). The picture for illustration of the scale differences is one of the best I've seen:
Global Markets for Asthma: Fresh Numbers
The report is here (just for $4850!!!):
The global market for asthma and chronic obstructive pulmonary disease (COPD) prescription drugs was valued at $34.9 billion in 2011. This figure is projected to reach $38 billion in 2012 and $47.1 billion in 2017, increasing at a five-year compound annual growth rate (CAGR) of 4.4%.Combination asthma/COPD drugs are expected to be worth $17.4 billion in 2012 and should reach $21.3 billion in 2017, a CAGR of 4.1%.
The segment made up of asthma drugs is projected to increase from $15.3 billion in 2012 to $20.2 billion in 2017, a CAGR of 5.7%.
COPD drugs are expected to increase from $5.3 billion in 2012 to $5.6 billion in 2017, a CAGR of 1.2%.
The global market for asthma and chronic obstructive pulmonary disease (COPD) prescription drugs was valued at $34.9 billion in 2011. This figure is projected to reach $38 billion in 2012 and $47.1 billion in 2017, increasing at a five-year compound annual growth rate (CAGR) of 4.4%.Thursday, August 23, 2012
Alzheimer’s R&D: targeted failure
A
very interesting article regarding failures with novel drugs against AD.
We know
that monoclonal antibodies are sh…t and will not be useful:
The biggest hope for the treatment of Alzheimer’s
disease in a long time just went up in smoke. The next high-profile drug
candidate will probably be toast in a few weeks, analysts say.
The easiest
thing now would be to write off the whole field of Alzheimer’s R&D, and declare
that scientists have to go back to the drawing board.
This is the major category of drug getting most of the
negative attention because of the failure of the Pfizer/J&J/Elan drug and
expected failure of Lilly’s drug, also an antibody. These drugs are designed to
specifically bind to and clear plaques that are piling up in Alzheimer’s
patients, causing neurotoxicity that leads to all the tragic symptoms of the
disease.
Scientists have long been attracted to anti-amyloid
beta antibodies for Alzheimer’s, because they can be designed to specifically
bind with the amyloid beta peptides while mostly sparing healthy tissues. While
the failure of bapineuzumab (or “bapi” for short) is a downer for the field,
some people, Ives included, say Pfizer/J&J/Elan may have a better chance
using the drug in an Alzheimer’s population that hasn’t yet displayed many
symptoms.
Essentially, the argument is that the companies were
trying to help patients after it was already too late. “Think about a car
wreck,” Ives says. “Bapi is like a tow truck clearing away the wreckage, but
there’s already been a wreck. You really want to prevent the accident.”
And to go
back to the drawing board will be the best idea. But what will be proposed
instead of mAbs? Almost the same “targeted” approaches!
Gamma Secretase inhibitors and modulators:
One other major class in development are drugs that
regulate the gamma secretase, Ives says. These drugs are synthetic chemical
compounds that can be made into oral pills, which can conveniently be taken by
patients on a daily basis at home. They are designed to bind with an enzyme,
gamma secretase, which chops up larger amyloid into smaller amyloid beta
peptide pieces. In patients with Alzheimer’s, gamma secretase enzymes
overproduce longer amyloid beta peptides that pile up to form plaques that are
toxic to nerves.
Drugs from the past that sought to inhibit gamma
secretase, like Lilly’s semagacestat, looked to have potential for a while, but
failed in the third and most expensive phase of clinical trials.
Early-generation gamma secretase inhibitors also shut down all kinds of other
essential protein processing in cells, which led to toxicity that prompted drug
developers to limit their dosing and stop trials, Ives says.
And another
one:
BACE Inhibitors:
Another class
of drugs in development can be filed under the header of beta secretase, or
BACE, inhibitors. These drugs are also small molecule compounds made to bind
with a different kind of enzyme in cells, one that performs its amyloid
processing work at an earlier step in the amyloid pathway than gamma secretase,
Ives says. Drugmakers have labored for years against these targets, because
inhibiting beta secretase can clearly reduce production of amyloid beta
peptides in their various lengths, which should reduce the troublesome plaque
deposits.
Companies like
Lilly, Merck, and Roche all have drug candidates moving through
early-to-mid-stage clinical trials, and they generated a fair bit of buzz at
the Alzheimer’s Association meeting in Vancouver, BC in July, Ives says. As
Alzheimer Research Forum science writer Esther Landhuis described it recently,
drugs in this class have long struggled to get into the brain, to stay there,
or to fend off other molecules that would render them inactive. “At long last,
drug developers have overcome these and other hurdles, and well over a decade
of effort developing beta-secretase (BACE1) inhibitors is starting to pay off,”
Landhuis wrote.
One big
question with BACE inhibitors, Ives says, is what happens over time to people
who have so much of their amyloid processing shut down. If people take these
drugs for three decades to prevent Alzheimer’s, what kind of unforeseen side
effects might pop up? “That chapter remains to be written,” Ives says.
I would
conclude: It is better not to get AD due to it seems like new efficient treatment
will not be developed in the nearest decades…
Targeted failure of the week. No 12.
It is not
for sure (!), BUT it is very close to be true that in the nearest future we will
get another candidate: Bavituximab (sure - the monoclonal antibody!)
Peregrine (the company owned the medicine – my comment) has been working on Bavi (the short name of the
drug – my comment) for nine
years and still has not even reached Phase III. It has been working on Cotara (another
drug of the company – my comment) for an even longer period of time, and Cotara has now been put on the
back burner after Peregrine stoked shareholders' hopes for years with press
releases about Cotara's Phase II trials. Normally drugs that are actually
game-changing treatments reveal their amazing capabilities in a shorter period
of time, particularly for diseases that have median survival periods of only a
few months. If either Cotara or Bavi were revolutionary treatments, it seems
unlikely that they would have needed nearly a decade to prove themselves. And
if Bavi were really an amazing treatment for a variety of cancers, we would
think that another pharma company would have recognized that by now and already
partnered with Peregrine.
What “targeted”
candidate will be next?
Do not use Avastin!
From here
New guidance for doctors issued by the National Institute for Health and
Clinical Excellence (Nice) does not recommend Avastin (bevacizumab) to treat
women with the disease, it said.
Wednesday, August 22, 2012
Cell therapy – let’s blow a new bubble!
As we have already proven
the main target of Big Pharma is to profit from different bubbles but not to develop
a useful medicinal products. The creature and design of such bubbles is very
important issue and it usually takes a decade to complete it. We can name a
couple of last successful examples here: personalized medicine and “targeted”
medicines. The targeted approach is almost expired (we are somewhere close to "return to "normal"" point, see the picture) and is not “sexy” anymore
however personalized medicine is still alive (but
not very long, we are exactly on the top - "new paradigm!" point) and successfully consumes tremendous amounts of resources. What
will come next? As far as I understand it will be cell therapy (I have written
already a little bit about this issue here).
The approach of using cell therapy complies with all criteria to be attractive
for Big Pharma:
1. Cell therapy is absolutely
ineffective – no new dangerous disease will be cured. The market will be not
affected
2. The manufacturing and development
are very expensive – it will be very simple to motivate high prices for R&D
and final products
I think we are very close to "take-off" point (see the picture). And in press and mass media we have
a lot of bogus-articles which just blowing the bubble. One very nice example is
here:
The regenerative medicine space is a somewhat young
industry that presents the possibility of finding a cure for diseases that were
previously untreated, or simply managed. The healthcare system consists of an
aging population, and with a growing healthcare burden, it seems reasonable
that the approval of cell therapies could be a part of our immediate future.
Already we are seeing a change in government outlook, as many governments and
economies invest millions into the research of cell therapy and regenerative
medicine.
For the first time, regenerative medicine is more than
skin cream; instead, it has become medical therapies that treat or cure
cardiovascular and degenerative diseases (which one and where the results? – Pharmalitet comment). With the number of companies
beginning clinical studies for cell therapies, investors should feel optimistic…
- Nice language to use “should” instead of “are”!
The cell therapy industry is a more risky investment,
yet presents the potential for a large return. At this point, the data proves
efficiency for many of the top candidates, therefore, leaving the question
regarding approvals and regulator acceptance as the only relevant discussion. – Exactly! And so far – so bad?
The Tissue Engineering and Regenerative Medicine
International Society (TERMIS) is the world's largest professional organization
for tissue engineers; and it just recently announced the results from a survey
of 37 organizations for public and private sectors. The results showed that
government remains highly invested in regenerative medicine, with more than 55%
investing over $5 million in the space. In addition to strong government
support, both the public and private sectors showed an increase in interest and
investments in the space. – Absolutely, this is very direct sign that the bubble is being blown!
And the
conclusion is amazing:
As we progress into the next few years, several
companies will inch closer to regulatory decisions, and the space itself will
be determined by the outcome of candidates such as Baxter's CD34+ cell therapy
and the regulatory acceptance of Osiris' Prochymal. It will be an interesting
space to watch, but with key developments and progress that continue to shine,
it does appear the future is bright for innovating cell therapies.
And
everybody seems to be happy! But Big Pharma will be happy in the first place! J
Masterpiece of the day. Matematics as cryptomatics
Do you think it is hard to understand physics? Do you need to hide the knowledge? Just use mathematics!
Tuesday, August 21, 2012
FDA approval: how to use it?
Do you
think you can make money on stock market? Why not? Everybody can do it, there
are a lot of strategies including the simplest one: when stock price goes up -
you go long, when it goes down - you go short. You have nice triggers: 31
Drugs Facing FDA Approval in 2012-2013. Good luck!
Monday, August 20, 2012
Sunday, August 19, 2012
Big Pharma and patent cliff: how to make a “win-win” situation
The patent cliff (for some fresh numbers see also here) is one of the dangers that threaten Big Pharma, however Big Pharma is very creatively prepared to handle this problem.
When a patent expires, the original holder and the first generic manufacturer to file with the US government both get an exclusive six-month right to sell an unbranded alternative. So branded drug makers figured they could settle patent suits simply by giving up that right - with no actual payment changing hands. A generic challenger would receive a lucrative six-month monopoly when the patent expired, while the original holder would avoid what it considered an early end to patent protection.
Pfizer essentially took that approach in settling with Teva Pharmaceutical Industries over the rights to the antidepressant Effexor XR. According to a lawsuit brought by drug retailers, Teva delayed its generic version for two years in exchange for Pfizer's promise not to compete once Teva did start production. The drug's annual US sales topped $2.5 billion over those years, the suit claims.
The companies deny wrongdoing and say the deal was just a licensing agreement. But the Federal Trade Commission argued this week that Pfizer made an unlawful payment.
Patent protection allows big drug companies to recoup the enormous costs of bringing compounds to market. But they shouldn't be allowed to chisel the public for more years than they deserve of outsized profits. The judge hearing the case can protect consumers' wallets by saying so.
Well, very smart, no comments. Big Pharma is out there to make profits, preferably in a monopoly way, not to provide inexpensive and efficient medicinal treatment.
Saturday, August 18, 2012
Friday, August 17, 2012
Music of the week. M. Farmer
Who would doubt that she becomes undressed in the end of the movie? Typical french :)
HTS as a religion.
We know
that the
modern paradigm of drug development i.e. targeted approach based on key-lock
analogy (see also here)
is
not ontologically consistent. One
of the latest articles in BMJ is also worried about the situation – a lot
of resources are spent with an extremely little outcome. I think that even the majority of
practitioners of the modern paradigm understand that the current approach is
very narrow-minded, simplified and the real picture is
far more complicated.
Basically I
think that the situation is typical for the time close to paradigm shift. And
it is not surprisingly that still there are practitioners fanatically devoted
to the old (inefficient and mechanistic) paradigm. There are no any arguments
which could “open their eyes” – it should be understood. They will defend the
old dogma till the dearth – no matter what…
One of such
I think par excellence practitioner
of the modern paradigm has
described the modern approach in a very informal way. It is impossible to
take a quote from the article – the whole article is worth a thorough reading,
not less the comments of other practitioners to this post. And I follow the
blogs of a couple of such scientists with a great pleasure.
Thursday, August 16, 2012
Oxaliplatin - now generic!
Non-targeted but very efficient (as other platinum-drugs carboplatin and cisplatin) is available as generic medicin.
The drug is a generic version of Sanofi's Eloxatin, which had sales of $1.7 billion during the 12-month period ended in June
The structure is simple, the mechanism of action is known - we just wish the successful application!
The drug is a generic version of Sanofi's Eloxatin, which had sales of $1.7 billion during the 12-month period ended in JuneThe structure is simple, the mechanism of action is known - we just wish the successful application!
Wednesday, August 15, 2012
Tuesday, August 14, 2012
Communist propaganda about Big Pharma and innovation crisis?
The article in BMJ is highly
recommended to read. A lot of facts in a form of cold numbers and a very sober
conclusion:
Data indicate that the widely touted
“innovation crisis” in pharmaceuticals is a myth. The real innovation crisis stems
from current incentives that reward companies for developing large numbers of
new drugs with few clinical advantages over existing ones.
Some
quotes:
The preponderance of drugs without
significant therapeutic gains dates all the way back to the “golden age” of innovation.
Out of 218 drugs approved by the FDA from 1978 to 1989, only 34 (15.6%) were
judged as important therapeutic gains. Covering a roughly similar time period
(1974-94), the industry’s Barral report on all internationally marketed new
drugs concluded that only 11% were therapeutically and pharmacologically
innovative.13 Since the mid-1990s, independent reviews have also concluded that
about 85-90% of all new drugs provide few or no clinical advantages for patients.
How have we reached a situation where so
much appears to be spent on research and development, yet only about 1 in 10
newly approved medicines substantially benefits patients? The low bars of being
better than placebo, using surrogate endpoints instead of hard clinical
outcomes, or being non-inferior to a comparator, allow approval of medicines
that may even be less effective or less safe than existing ones.
[M]arketing has become “the enemy of [real]
innovation.” This perspective explains why companies think it is worthwhile
paying not only for testing new drugs but also for thousands of trials of
existing drugs in order to gain approval for new indications and expand the
market. This corporate strategy works because marketing departments and large
networks of sponsored clinical leaders succeed in persuading doctors to
prescribe the new products. An analysis of Canada’s pharmaceutical expenditures
found that 80% of the increase in its drug budget is spent on new medicines
that offer few new benefits.
And the
following quote is my favorite one!
This hidden business model for pharmaceutical research, sales, and
profits has long depended less on the breakthrough research that executives
emphasise than on rational actors exploiting ever broader and longer patents
and other government protections against normal free market competition.
Companies are delighted when research breakthroughs occur, but they do not
depend on them, declarations to the contrary notwithstanding. The 1.3% of
revenues devoted to discovering new molecules compares with the 25% that an
independent analysis estimates is spent on promotion, and gives a ratio of basic
research to marketing of 1:19.
There are a
lot of other very interesting and reasonable ideas and facts in this article. I
have written about the very bad situation with the innovations and how Big
Pharma is not interested to promote them, Ok, but here we have a second opinion
in face of two (I am sure) very clever and honest professors. I suspect that
they have to be communists…
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