I have
found very interesting review of the situation with oncology products
development. The information is very compact and concrete. I sincere recommend reading
it for those who works with drug development process.
Here is my
comments:
Numbers are
impressive:
Currently, there are over 725 anticancer drugs in
clinical development and at least another 300-500 in preclinical and research
stages. Over 3,500 novel approaches have been evaluated clinically or
preclinically in the last decade. Currently, more than 10,000 clinical trials
with novel and approved agents, alone or in combination, are ongoing with over
12% having entered phase III status. Globally, over 1,000 distinct commercial
entities are developing oncology drugs or have technologies applied to this sector
Not bad.
Nobody knows how many of these drugs will pass the Death Valley but the amount
of the candidates is huge!
Several hundred cancer-related targets have been
identified and over 160 distinct have been evaluated in clinical trials but few
of these efforts led to commercialized products, with none providing a bona
fide 'cure'. Currently, over 210 novel targeted agents are being evaluated in
phase I clinical trials, and many have entered phase III trials.
Well, it
looks like we have an understanding of the value of targeted approach. Do we
have anything else? Actually yes:
Patient selection based on verified tumors'
molecular profile, personalized medicine, and advances based on in vitro
testing (IVT)… The IVT sector has grown exponentially in the
last decade. Over 250 companies are developing some type of IVT in cancer. IVT
include screening tests, diagnostics, pharmacogenomics, prognostics, disease
monitoring tests, theragnostics, toxicogenomics, etc. For instance, over 30
companies have development programs in IVT in ovarian cancer, 42 in lung
cancer, 19 in bladder cancer, etc.
Not
everyone works with targeting and with HTS! This is a positive moment. Anything
else? Yes:
Trials combining novel targeted agents
Targeted agents currently constitute the majority of novel drugs entering clinical trials. Over 200 novel targeted drugs are in phase I clinical trials, mostly small molecule protein kinase inhibitors or monoclonal antibody (MAb)-based blockers of cell surface receptors. These newer agents are addressing over 160 distinct molecular moieties shown to play a role in malignancy. Novel targeted agents are usually evaluated as monotherapies or in combination with approved/marketed agents. It is anticipated that in this decade, such agents will also be clinically evaluated in combinations with each other. Such an endeavor will take clinical development to a new level of complexity but may also have surprisingly beneficial results.
Targeted agents currently constitute the majority of novel drugs entering clinical trials. Over 200 novel targeted drugs are in phase I clinical trials, mostly small molecule protein kinase inhibitors or monoclonal antibody (MAb)-based blockers of cell surface receptors. These newer agents are addressing over 160 distinct molecular moieties shown to play a role in malignancy. Novel targeted agents are usually evaluated as monotherapies or in combination with approved/marketed agents. It is anticipated that in this decade, such agents will also be clinically evaluated in combinations with each other. Such an endeavor will take clinical development to a new level of complexity but may also have surprisingly beneficial results.
MAbs – also
targeted therapies. Fine. But note that MAbs usually used in a combination with
proved chemotherapy. Why? It is another subject for discussion.
Currently, over 130 MAb-based agents are in clinical
development with 20 having entered phase III clinical trials.
We say
nothing here about the cost of these drugs. Do we have something else? Yes,
very mechanistic and creative with magic-bullet ambition – antibody-drug
conjugates:
Antibody
engineering technologies and novel immunoconjugates, radioimmunoconjugates,
fusion proteins, and antibody-drug conjugates (ADC)
Monoclonal antibodies (MAb) are the backbone of the oncology drug sector. No fewer than 125 companies are focusing in oncology applications of MAb in this ever advancing field. The attractiveness of MAb is their ability to target surface receptors with exquisite specificity and also, in many cases, stimulate the immune system to destroy cells expressing such receptors. In the past decade over 650 distinct MAb have been evaluated in oncology. Although effective as signal transaction inhibitors on their own, the targeted specificity of MAb makes them excellent ferries of drugs/toxins, and radioisotopes to cancer cells. Such an application of MAb is currently exploited in antibody drug conjugates (ADC), a burgeoning area of drug development with 11 drugs in clinical trials with one in phase III.
Monoclonal antibodies (MAb) are the backbone of the oncology drug sector. No fewer than 125 companies are focusing in oncology applications of MAb in this ever advancing field. The attractiveness of MAb is their ability to target surface receptors with exquisite specificity and also, in many cases, stimulate the immune system to destroy cells expressing such receptors. In the past decade over 650 distinct MAb have been evaluated in oncology. Although effective as signal transaction inhibitors on their own, the targeted specificity of MAb makes them excellent ferries of drugs/toxins, and radioisotopes to cancer cells. Such an application of MAb is currently exploited in antibody drug conjugates (ADC), a burgeoning area of drug development with 11 drugs in clinical trials with one in phase III.
The idea is
very “sexy” – let’s just wait for the first results in coming years!
Next we
have something less targeted:
Immunotherapies/vaccines
Although the human immune system is capable of raising
an immune response against many cancer types, it fails to eradicate cancer in
most patients, possibly because of negative regulation of the immune system by
the tumor. Immune surveillance is the major mechanism by which malignant cells
are recognized and eliminated by the immune system before they can develop into
clinically detectable tumors. Although, immune system failure may contribute to
the survival and proliferation of cancer cells, it is now theorized that tumors
adopt ways for evading eradication by the immune system. After several failures
of cancer immunotherapies in late phase trials, interest has been rekindled in
this area by several positive developments, primarily by favorable results with
Dendreon's prostate vaccine Provenge. Over 125 immunotherapeutics/vaccines are
in clinical development, with many demonstrating favorable activity with low
toxicity.
We have to
wish good luck! Vaccination has eradicated a lot of dangerous diseases – hopefully
vaccines will help us to treat cancer!
A real
non-targeted and fresh approach:
Oncolytics/virotherapy approaches
After many years in development virotherapy is beginning to show effectiveness in the clinic. As many 32 distinct oncolytics have been investigated over the last 10 years with 11 agents currently in clinical development in various cancer indications.
After many years in development virotherapy is beginning to show effectiveness in the clinic. As many 32 distinct oncolytics have been investigated over the last 10 years with 11 agents currently in clinical development in various cancer indications.
Very
interesting! Hopefully we can get a real “wild card” here… I have to check it
closely!
Then we
still have a “classical approach” – proven strategy which helped to develop a
majority of blockbusters:
Novel cytotoxics
Cytotoxics remain the backbone of cancer treatment for both advanced disease and in adjuvant and neoadjuvant settings. Nearly every approved and most novel agents are being combined with a cytotoxic regimen. Therefore, considerable effort is dedicated to improving every aspect of cytotoxic chemotherapy. In the past decade over 663 distinct cytotoxics were evaluated preclinically and clinically with 228 currently under development; 98 incorporate some type of a delivery system and 32 are prodrugs. Among 195 currently in clinical development, 32 novel agents have entered phase III clinical trials. Many clinical programs involve approaches to improve the performance and reduce the non-specific toxicity of leading marketed chemotherapeutics as well as of several experimental drugs that were withdrawn from development because of unacceptable toxicity and formulation difficulties.
Cytotoxics remain the backbone of cancer treatment for both advanced disease and in adjuvant and neoadjuvant settings. Nearly every approved and most novel agents are being combined with a cytotoxic regimen. Therefore, considerable effort is dedicated to improving every aspect of cytotoxic chemotherapy. In the past decade over 663 distinct cytotoxics were evaluated preclinically and clinically with 228 currently under development; 98 incorporate some type of a delivery system and 32 are prodrugs. Among 195 currently in clinical development, 32 novel agents have entered phase III clinical trials. Many clinical programs involve approaches to improve the performance and reduce the non-specific toxicity of leading marketed chemotherapeutics as well as of several experimental drugs that were withdrawn from development because of unacceptable toxicity and formulation difficulties.
What else? Drug delivery!
Advances in drug delivery, including
nanotechnology
Drug delivery is the second most important challenge of targeted therapeutics after proof of efficacy in vitro and in vivo, and perhaps one of the key reasons drugs that perform well in small animals models fail in humans. New therapeutic approaches such as microRNA inhibitors reignited the quest for effective drug delivery systems. Nanotechnology is currently the holy grail of drug delivery in oncology being pursued by 40 distinct entities, each developing its own version of this promising approach, which may revitalize the cytotoxic drug sector that is still the standard treatment for almost all types of advanced disease and enable the clinical application of such novel technologies as RNA interference (RNAi).
Drug delivery is the second most important challenge of targeted therapeutics after proof of efficacy in vitro and in vivo, and perhaps one of the key reasons drugs that perform well in small animals models fail in humans. New therapeutic approaches such as microRNA inhibitors reignited the quest for effective drug delivery systems. Nanotechnology is currently the holy grail of drug delivery in oncology being pursued by 40 distinct entities, each developing its own version of this promising approach, which may revitalize the cytotoxic drug sector that is still the standard treatment for almost all types of advanced disease and enable the clinical application of such novel technologies as RNA interference (RNAi).
Sure!
Inclusive nanotechnology! How else?
We can see
that all approaches could be roughly divided in two categories:
·
Molecular
targeting approaches (small molecules and MAbs) – automated based on HTS,
genomics, proteomics etc
·
Non-molecular
targeting approaches – creative, original and non-trivial
In general
I could judge the situation as optimistic – not every product is based on
concept of molecular targeting paradigm.
Basically I
think that in a coming decade (2012-2022) molecular targeting approaches will
be less popular and we will see a lot of disappointed failures in their
clinical trials programs. Simultaneously we hopefully will experience emerging
of a promising drug delivery solutions, virotherapeutic or totally novel approaches
which will be able to revolutionize cancer treatment. However I doubt that modern paradigm will be replaced – it is so inert that it can take a couple of
generation’s work to completely discard the targeting “key-lock” paradigm.
No comments:
Post a Comment