Summary

See also our Drug Development Database and Tutorial.

Howard Fillit, Jordan Tang, Frank Longo, Eli Michaelis, and Jens Eckstein led this live discussion on 16 September 2005. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:
With Howard Fillit, Jordan Tang, Frank Longo, Eli Michaelis, and Jens Eckstein on 16 September 2005.

Participants: Gabrielle Strobel (Alzheimer Research Forum), Patricia C. Heyn, (University of Colorado Health Sciences Center), Jan Teller (Dystonia Medical Research Foundation), Nico Stanculescu (Alzheimer Research Forum), Howard Fillit, MD, (Institute for the Study of Aging), Martin Cunningham (Neuroxyn Pharmaceuticals), Kelly R Koehn (Neuroxyn Pharmaceuticals), Jens Eckstein, Ph.D. (principal at TVM, a transatlantic VC firm), Cynthia Joyce (Spinal Muscular Atrophy (SMA) Foundation), Frank Longo (Department of Neurology, University of North Carolina-Chapel Hill), Eli Michaelis (University of Kansas), Jordan Tang (University of Oklahoma Health Science Center), Greg Brewer (Southern Illinois University School of Medicine), Edward Zamrini (University of Alabama Alzheimer's Disease Research Center), June Kinoshita (Executive Editor, Alzheimer Research Forum).

Gabrielle Strobel
I am Gabrielle Strobel, managing editor of the Alzheimer Research Forum. I will moderate today. Let me welcome all of you to our discussion. Let's perhaps start by giving our guests a chance to ask their questions first. Where can our panelists help?

Jan Teller
You may ask: What's a dystonia guy doing here? Well, for the last 10 years I've been studying AD, but recently joined the Dystonia Medical Research Foundation (DMRF). I hope my presence and questions will be tolerated…. So, how can a small foundation like DMRF get creatively and effectively involved in drug development? If you want to exclusively discuss AD, I'll just be quiet and listen!

Gabrielle Strobel
Jan, you are most welcome here. I suspect some of the issues are similar between AD and dystonias.

Jens Eckstein
Here is one question I have: Where is the bottleneck, actually? Is it novel targets, clinical models or financing? Any opinions?

Howard Fillit
I think there has been an explosion in novel targets during the past 5 years in Alzheimer disease. There has also been good progress in animal model development. Financing remains a key issue, in my opinion.

Frank Longo
I think that many potential targets get identified in various in vitro studies. One bottleneck is the ability to move into animal-based models. Components of the bottleneck include access to models, appropriately designed studies, selecting reliable outcomes, etc.

Jordan Tang
I agree that finance is one of the bottlenecks. Many of the targets are untried and represent a high risk.

Howard Fillit
I agree that access to models in AD is a problem, too. The models remain expensive, and some are limited by intellectual property and licensing issues. I wonder if that is as true in other disease states.

Eli Michaelis
Jens, I agree with Howard that the difficulty is not in identifying new targets but in moving to studies with good animal models and conducting the appropriate pharmacokinetic as well as pharmacodynamic studies. If the work is not done correctly it would be difficult to raise money to move further along the chain of funding.

Cynthia Joyce
We would like to learn about new ideas for managing intellectual property (IP) transfer from academia to industry. Our foundation is trying to recruit industry to the drug development effort for SMA and the tech transfer process is consuming an inordinate amount of time.

Jens Eckstein
From a venture capital point of view, the less bureaucratic tech transfer is, the better! Technology licensing offices (TLOs) have a pretty bad reputation in the industry and are perceived more as a nuisance. One reason for this is that a lot of them have the mandate from the universities to raise funds rather than get technology out the door.

Cynthia Joyce
That has been our experience. This is a significant bottleneck to doing the pharmacokinetic and pharmacodynamic studies you are discussing. Is there any movement on reducing the bottleneck on licensing models for drug testing?

Jens Eckstein
When talking about targets, one of the key questions remains validation—clinical validation, that is.

Eli Michaelis
Jens, clinical validation could benefit from a universal acceptance of surrogate markers for the disease. This is still lacking in this field.

Gabrielle Strobel
One often reads that the industry over the past five years or so has raised its bar on what kind of validation it expects before it considers taking on an academic project. Where is that bar now? What do you have to show?

Jens Eckstein
Validation in our shop means that one sees a clinical effect when hitting the target, that is, phase 2 data or in some instances, phase 1b data.

Howard Fillit
As Eli points out, while cognition is a "valid" clinical outcome, we don't have valid biological outcomes. That is a big problem for AD in moving from animals to humans. One unique problem in AD that we always talk about is that "mice don't write books." There was recently a conference on trying to identify cognitive tests that translate well from mice to humans.

June Kinoshita
Yes, and we have posted a summary.

Jordan Tang
Animal model work is definitely a slow step, although in working at drug targeting at the initial step of AD pathogenesis, the problem may not be as severe. There are very limited models available for academic labs for cognitive tests.

Greg Brewer
It seems that many problems with human trials are neurological issues. Does anyone have an idea how many and how to monitor these better in animal models, for example, pain, blurred vision, confusion?

Eli Michaelis
I agree with Howard that there are improvements being made in behavioral methodology. I would like to comment again on being able to perform good pharmacokinetic and pharmacodynamic studies on normal animals, and animal models of the disease are a prerequisite; otherwise, the results may be too "risky" for a company to invest substantial amounts of money.

Gabrielle Strobel
Eli, how do you recommend an academic investigator, say, a molecular biologist in neuroscience, should approach toxicological and pharmacological testing of a compound he or she considers promising? How to start this important piece of the package?

Eli Michaelis
Gabrielle, there are a few academic centers that are fully equipped to conduct pharmacokinetic studies and early toxicological studies. There are also several companies that perform these types of studies. What is needed is some early-stage financing that will allow for the conduct of such studies.

Gabrielle Strobel
Eli, is this a niche for foundations?

Eli Michaelis
Gabrielle, yes!

Jens Eckstein
In my opinion, it would be better to focus on safety parameters in the preclinical studies and then push into humans as quickly as possible. New biomarkers might make this move more feasible in the future since one could get surrogate readouts earlier in clinical development.

Gabrielle Strobel
Amyloid imaging biomarkers are being tested in humans, but they are based on PET and are expensive.

Howard Fillit
I personally "believe" PET amyloid imaging could change the paradigm, at least for targets on amyloid. In addition, similar imaging modalities for tangles or neuronal markers are on the horizon. Here's a factoid to consider that I think is still reasonably true. Of ~250 drugs approved by the FDA in the past 5 years, only ~10 were for CNS disease, all symptomatic therapies, and none were disease-modifying, so it's not just AD, but neurological disease in general.

Jan Teller
Howard, what, in your opinion, is the reason for so few CNS drugs approved by the FDA?

Howard Fillit
It's not the approval process; it's the ability of science/pharma/biotechs to deliver agents for approval to the FDA. These are difficult diseases and targets. I think outcome measures are secondary issues.

Jordan Tang
For an academic molecular biologist, it would probably take a very serious drug candidate before toxicology and pharmacokinetics can be considered. Besides, these tests are usually more expensive than the grant can support. So, some kind of commercial outfit needs to be organized. These all make it a difficult task.

Frank Longo
A potential important asset might be an NIH-funded mechanism/service in which a large number of investigators with multiple potential targets could assess compounds in animal models using a critical mass of expertise in trial design, pharmacokinetics, and toxicology. This would also allow some comparative function.

Howard Fillit
Of course, ISOA has given ~$24 million to over 130 "high risk" early stage drug discovery programs during the past 5 years. We have also supported some pharmacokinetics/pharmacodynamics toxicology, GMP synthesis, etc. There is a great demand for our funding, and we are trying to raise money to meet this need through a new public charity. The demand from academia and biotech, in my opinion, demonstrates that it's not a lack of ideas; it's a lack of funding.

Jens Eckstein
I agree that independent new drug (IND)-enabling toxicology is usually too expensive for research grants. This is a place where the NIH should really focus on since they have the resources as well as the expertise for these studies.

June Kinoshita
Frank seems to have suggested that the NIH can also play a role by funding core centers to provide these services to academics. Do you know of actual moves afoot within NIH to do this?

Howard Fillit
I think NIA does have a program for supporting toxicology studies now.

Jordan Tang
NIH Translational Research Award seems to be designed to do some of the preclinical studies.

Eli Michaelis
Jordan, if a scientist has access to other scientists with expertise in pharmacokinetics and toxicology studies, these early studies can be carried out in academic settings for considerably less money than in industrial settings.

June Kinoshita
To follow up on Eli's remark about academic pharmacokinetics and toxicology experts, I'd love to get them into the ISOA/Alzforum database!

Eli Michaelis
June, I can certainly try to put together such a listing, but not now.

June Kinoshita
Eli, we should keep in touch on this.

Frank Longo
Another key challenge for many is behavioral and cognitive assessment in animal models. There seem to be some commercial sources, but it's expensive and it's hard to execute animal work off-site.

Jens Eckstein
When working with academic labs on IND-enabling studies, it is very important to include someone who has done INDs and clinical development. There are a lot of tricks and pitfalls! Pharma people are a great resource in this respect!

Howard Fillit
Jens, I agree that most academic and some early stage biotech companies lack expertise in preclinical and clinical development. Partnering is definitely key, and planning needs to start early on.

Frank Longo
Even when one can access the technical capabilities, I have been amazed at how many opinions one can get on the best preclinical, IND-type strategies. It would be nice to have a consulting team to go to for advice.

Howard Fillit
In response to Frank's comments, the "drug discovery services" industry is now out there (see the ARF/ISOA Drug Development database and tutorials for more information on such services). What are people's experiences in consulting with them?

Eli Michaelis
Frank, I agree with you that this is a complex process and nothing is immediately obvious, including the opinions you receive. In our experience, we have found that if we have conducted some good studies of pharmacokinetics and have evidence of good pharmacodynamic properties without obvious short-term toxicology, then pharma companies become interested in co-funding or helping to launch a company for the further testing and development of a drug.

Jens Eckstein
I would also like to point out that VCs (venture capitalist firms) can be a great resource since they usually view the IND-enabling studies as one of the key components for an investment. They are very well connected and are in the people business; hence, call them up!

Jan Teller
Could someone comment on the applicability/validity of non-vertebrate testing in CNS diseases and its current perception by pharma and the FDA?

Frank Longo
The jump from mouse to human has been so difficult; I imagine an even larger jump is more difficult, but on the other hand, the elegance of some of the invertebrate models is impressive.

Eli Michaelis
Jan, non-vertebrate testing is, I believe, still a long way away from being accepted as a substitute to vertebrate testing.

Howard Fillit
Non-vertebrate testing has value for target validation in a biological sphere. But worms don't write books. That's the problem.

Frank Longo
I think Eli is right. One interesting area, though, is the potential ability to screen large numbers of compounds with invertebrate models; thus, what one loses in increased risk of applicability might be gained with the increment in numbers.

Greg Brewer
What are your opinions about getting a pre-IND plan from an FDA consultant vs. your own or a consulting firm?

Jens Eckstein
The most important issue when working with CROs is project management; one should not rely on their internal expertise since ultimately they need to earn money and have a kind of "conflict of interest" to only do what's necessary.

Frank Longo
I have had some good experiences in getting specific services; others are too expensive. Getting advice on the big picture requires some networking; I have no experience with the FDA.

Jens Eckstein
Pre-IND meetings are wonderful, although they do now (or early next year?) cost money. It's absolutely essential to establish a personal rapport with the FDA folks working on your IND and clinical trial, and a lot of mistakes and misunderstandings can be cleared away.

Jordan Tang
Our experience is to do all the toxicology and pharmacokinetics within the framework of a new startup. It enabled us to connect with expert service and advice. We would not be able to do it without a new venture.

Jens Eckstein
The problem is that it's very difficult to raise VC money with a new target idea and no clinical data.

June Kinoshita
To all, is drug delivery across the blood-brain barrier (BBB) a major obstacle to CNS drug development? One would think so, but many academic scientists I've spoken with seem to blithely assume that once they've come up with a compound, it's not a big deal for pharma to get them across the BBB. Does the neurodegeneration field (and its funding sources) need a wake-up call on this issue?

Jan Teller
June, excellent question!

Howard Fillit
BBB is a problem. No doubt. But I think we are learning more and more about the chemical properties of compounds that can cross, and how to design them.

Jens Eckstein
The earlier people with novel compounds hook up with formulation/delivery guys, the better!

Jordan Tang
For people in pharma who are working on drugs, BBB penetration is a big problem. It requires the design of very small molecules which are not compatible with many of the other good properties for a drug.

Eli Michaelis
June, you are right about the BBB being a true "barrier" to CNS drug development. But, it is not true that neuroscientists in the area of drug development have ignored that. I know that our scientists have developed in vitro models of the BBB that are used routinely, early in the drug design process, in order to select the best candidates for further development.

Frank Longo
The BBB problem is critical for VC. The medicinal chemistry costs and the uncertainty of whether a compound can be modified appropriately change the cost/risk equation.

Eli Michaelis
I would recommend to all to pay very close attention to the brain delivery issue. Big pharma has learned that lesson very well. Most failures in drug development have been associated with problems in delivery.

Jordan Tang
BBB is just one of the many problems. Selectivity is also a critical problem and, previously mentioned, toxicology and pharmacokinetics. Then there is oral availability. The problem is how to incorporate all these good properties in a small molecule.

Jan Teller
Is there anything happening on the nano-delivery front?

Gabrielle Strobel
Jan, I do not know where you are based but there is a conference on nanomedicine October 3 and 4 in Cambridge, Massachusetts.

Jan Teller
 Great!

Frank Longo
We recently had a series of compounds assessed commercially for BBB penetration in vivo in mice. The cost was about $10,000 for each compound.

Howard Fillit
We have certainly seen programs where animal model studies are proposed, without data on whether the compounds get into the brain. That's bad.

Frank Longo
It's expensive to obtain measurements of compounds in the CNS; thus, I imagine there are many unpublished studies of compounds not working in which the CNS bioavailability was not certain.

Eli Michaelis
June, the reason why I mentioned that pharmacokinetics studies should be done early on is so that direct measures of penetration can be made. Preferably, if scientists have access to BBB cell models, they will have determined if drugs do or do not penetrate the BBB so they do not reach the wrong conclusions.

June Kinoshita
Eli, are such BBB cell models readily available to academic scientists?

Eli Michaelis
June, the models have been around for nearly two decades and can be established in academic laboratories. Our scientists have been conducting workshops for academic and industrial scientists to teach them how to set up these models.

June Kinoshita
Eli, make sure I receive those announcements, and I can post the workshop dates on the Alzforum calendar.

Eli Michaelis
June, I will make sure that we put your name on the list.

June Kinoshita
Thanks, Eli!

Jens Eckstein
I think that the BBB problem is one piece of the puzzle. As for our shop, we are more concerned about mechanism of action/efficacy than the BBB. In our experience, the formulation/delivery folks can do wonders.

Eli Michaelis
Jens, the issue is not that you would equate rodent to human pharmacokinetics. It is that you would know how to interpret your pharmacodynamic results if you know how the pharmacokinetics profile is in the experimental animal you are using.

Jens Eckstein
Fair enough, Eli. But again, I would circumvent the pharmacodynamic/pharmacokinetics issue as long as possible and show efficacy by direct delivery.

Jordan Tang
We have used the cell model of BBB but still wanted to know how it comes out in an animal model. With the power of mass spectrometry, it is not too difficult to measure drugs in the brain.

Howard Fillit
I agree with Eli; the models have been around a long time, but I don't know about actual data on how predictive they are of clinical success.

Eli Michaelis
Howard, in our experience they are quite accurate, including the prediction of the pathway for the block in BBB transfer.

Howard Fillit
Another approach is using PET in early-stage clinical studies with labeled drug. I have seen that done.

Jens Eckstein
PET is unfortunately very expensive and clinicians have been very slow in adopting PET in clinical trials.

Howard Fillit
For AD, if the target is amyloid, I would prefer to see a change in amyloid deposition, for example. Rodent cognition testing is very poorly predictive of human success, as I understand the data.

Gabrielle Strobel
Howard, that is interesting. Can you elaborate? Do you mean PIB being used in AD trials?

Howard Fillit
PIB is good for amyloid imaging, but if one is trying to expedite pharmacokinetics/pharmacodynamics in humans, in CNS, PET may be useful with some drugs that, for example, affect metabolism neurochemistry.

Howard Fillit
That is, distinguish PIB as a biomarker study from the issues around; does a drug get into human brain and where in brain does it go…?

Frank Longo
I think that significant sensitivity and specificity issues remain with PET, even with the labeled compounds that bind amyloid.

Jens Eckstein
I should add that PET is especially expensive in the U.S. In Australia or New Zealand, PET costs a third or even a fourth of the U.S. price tag.

Gabrielle Strobel
One Australian center reported initial results of exploring the use of PIB in AD and related dementias at a conference earlier this year (see ARF related news story).

Greg Brewer
Given the BBB problem, is there any receptivity to craniotomy and direct injection or long-term pumping for chronic problems?

Howard Fillit
I don't think craniotomy is a promising way to go, or direct injection. But I think intranasal delivery looks very promising, especially new work in the last couple of years on this delivery method (see ARF related news story).

Eli Michaelis
Greg, if that is the only way to get it in there and it is a serious disease, maybe. However, I agree with Howard about the intranasal route.

Howard Fillit
There is hope for nanotechnology in delivery across the BBB.

Jens Eckstein
Intranasal delivery really has huge potential!

June Kinoshita
Do you think some promising compounds are being written off too soon because animal studies do not properly take into consideration the formulation and delivery issue? That is, do you worry that inattention or lack of experience to drug formulation and delivery could lead to false negative results in animal studies?

Jens Eckstein
June, that might be true; however, it is dangerous to optimize compounds towards rodent pharmacokinetics.

June Kinoshita
Jens, can you elaborate on your comment?

Jens Eckstein
Rodent pharmacokinetics can be very different from human pharmacokinetics, and you could have spent a lot of time and money to get it right with mice only to find out that the pharmacokinetics profile does not work for humans. If one wants to show the drug works, then go the intracranial route and don't worry too much about the pharmacokinetics in mice.

Gabrielle Strobel
Jens, there are a few vaccine approaches in AD that use the nasal route. Will drugs that come in through the nasal epithelium spread far enough in the brain, though?

Howard Fillit
Gabrielle, there are two well-established routes of delivery by intranasal, through olfactory and trigeminal nerve pathways. Both allow rapid delivery to the entire brain through specific routes. These have been worked out recently. Think about cocaine: It gets almost immediately to the hippocampus.

Gabrielle Strobel
Howard, does this apply equally to small molecules like cocaine and larger molecules like proteins, that is, an immunization antigen?

Howard Fillit
The advantage of intranasal delivery, by the way, is fewer systemic side effects. And yes, peptides are fairly rapidly transported to the brain. Vaccination is a different matter; that actually happens in the intranasal epithelium, not the brain.

Frank Longo
Assuming one gets the compound in the brain adequately, which is more important in terms of an early, efficient milestone? Cognitive effects, morphology, other endpoints? With limited funding, what area should be prioritized early?

Eli Michaelis
Frank, you are raising one of the most difficult issues in experimental design of treatment approaches. If you treat till you see a change in behavior or neurological signs, you may have allowed neurodegeneration to go on too long to see possible amelioration of the path at an earlier stage.

Frank Longo
Eli, I have the same sense you do. If one argues that synaptic function is one of the first functions to lose, though, perhaps cognitive testing would pick up an effect prior to looking at path changes, etc. I think it depends on which model and the mechanism of the compound being tested.

Eli Michaelis
Frank, I agree.

Howard Fillit
In humans, cognitive testing is ultimately key, but for proof of concept in animals, I think the biological target is more important.

Gabrielle Strobel
Eli, is there any practical way to measure synaptic function instead of behavior/neurologic function?

Eli Michaelis
Gabrielle, there are attempts being made to label neurons in vivo with fluorescent or chemiluminescent dyes and study dynamic changes with surface, highly sensitive cameras. This is an evolving technology and is not yet ready for direct assessment of synaptic function at this point in time.

Howard Fillit
I think the only way to look at synapse function now is at autopsy of the animals.

Greg Brewer
Synaptic function is most often assessed in vitro with isolated cultures or slices of rat hippocampal tissue.

Eli Michaelis
Howard and Greg, you are both right, but that terminates the ongoing study; that is, it becomes a single time point.

Edward Zamrini
We still do not know if we need to target amyloid deposition (bad or good because it gets rid of soluble amyloid) or soluble amyloid molecules.

Jordan Tang
Has there been a prediction model on the relationship of amyloid lowering and cognitive improvement?

Frank Longo
Jordan, I don't know of clear correlation between amyloid lowering and cognitive improvement clinically. It's also interesting to think about potential physiological functions of Aß and recent data suggesting that lowering it too much might be a limiting factor.

June Kinoshita
Frank, to which study are you referring?

Frank Longo
There was an in vitro study by Plant et al. showing that removing Aß was deleterious in the BACE knockout (KO) mice in which Y-maze performance was impaired (see ARF related news story).

June Kinoshita
Thanks, Frank.

Greg Brewer
Jordan, the behavior studies with mice together with the amyloid lowering data are what gave Elan enthusiasm to go to clinical trials with antiamyloid immunization.

Howard Fillit
Greg is right on that. It is a good example.

Greg Brewer
Frank, Jordan, the clinical data from the Elan phase II trial showed some cases of lower plaque load postmortem, but the cognitive scores were not remarkable, in my opinion.

Jan Teller
Jordan, both animal and human studies suggest that one has to lower soluble amyloid, but what is soluble Aß in the brain? What you define as soluble is after extraction from the brain.

Edward Zamrini
Historically, clinical trials have focused on cognitive testing. However, as we advance to neuroprotective therapies, we will need to rely on neuroimaging or biological markers, as neuropsychological markers will not be sensitive enough.

Howard Fillit
I am not sure I agree totally with you, Edward. I think the primary outcome will always be cognition because dementia is a disease of cognition, but to get an FDA approval for a disease-modifying agent will require biological marker studies as well.

Edward Zamrini
Howard, I agree with you when we speak of dementia/mild cognitive impairment (MCI). However, at some point, we will want to do prevention studies. Unless we have appropriate biomarkers that can detect subtle disease (or disease risk) changes, we won't be able to test enough compounds in enough people in a reasonable period of time.

Frank Longo
I think "biomarkers" is an attractive, powerful term; in the end, cognitive function might be the ultimate biomarker.

Jens Eckstein
Is anybody actually looking for a biomarker for "cognition"?

Howard Fillit
Greg points out an important problem in clinical trials to date: The effect size has been small for almost all therapies. I am not sure if this is because, once you've lost neurons, you remain demented and that's it, or if the drugs we have tested thus far just aren't good enough.

Gabrielle Strobel
The biomarker issue may simply take more time, as natural history studies track progression along with changes in blood and CSF samples. Such a study is underway.

Eli Michaelis
Jens, I thought that is what the synaptic integrity and synaptic function assessment was designed to be.

Howard Fillit
I also agree with Frank completely that cognition is a good clinical biomarker, but the FDA wants evidence of an alteration in the disease brain (read a change in a traditional biological biomarker).

Jens Eckstein
Howard, what's the FDA's argument here? That the cognition endpoints are too soft?

Howard Fillit
The recent paradigm of "prevention trials" has been delaying MCI to dementia. But preventing dementia has also been demonstrated in hypertension trials. Essentially, the answer to your question, Jens, is yes, but I don't think its just "bias" on cognitive measures, or softness; it's that cognition is a symptom. To get a labeling for a disease-modifying agent requires biological plausibility that the agent modifies something (read plausible mechanism of action).

Greg Brewer
Thanks, I gotta run. Bye!

Jan Teller
Instead of talking about cognition in general, shouldn't we talk about specific cognitive tasks that can be measured and, therefore, become biomarkers.

Frank Longo
Array/proteomic approaches are already influencing breast cancer trials; there is an example where marker data of a non-traditional type plays a potential clinical role.

Howard Fillit
Proteomic markers are certainly being studied in AD. But I still don't think even specific cognitive tasks will ultimately allow for a disease-modifying label from the FDA.

Eli Michaelis
Howard, are these proteomic targets outside the CNS or in the CNS?

Howard Fillit
Proteomics in CSF or blood.

Edward Zamrini
Helen Kim from the University of Alabama at Birmingham presented proteomic data (animal) at the June Alzheimer's meeting in DC.

June Kinoshita
David Bennett and colleagues at Perkin Elmer also recently published an interesting proteomic study of AD biomarkers in serum (Lopez et al., 2005).

Eli Michaelis
Thanks, June.

Jens Eckstein
The problem is that adoption of array/proteomic data in the clinic is terribly slow. It took oncologists more than 15 years to check on p53 status.

June Kinoshita
To all, we're nearing the end of the hour. Clearly, there are daunting challenges for anyone—academic, biotech, or pharma—trying to develop treatments for AD. But there are also untapped opportunities and insights that could help accelerate early-stage work, especially for academics. Could each of our invited speakers summarize the most useful take-home message for scientists who are "lost in translation"?

Jordan Tang
If the majority of AD cases are associated with the elevation of Aß (especially 42) in the brain, then it would be useful to have a way of measuring "soluble" amyloid in the brain. Obviously, this is difficult and has not been accomplished.

Howard Fillit
My advice to academics is to emulate Eli Michaelis at the University of Kansas and the multidisciplinary teams and centers built to do drug discovery. Traditional biology mechanism of action research programs can't do it alone.

Frank Longo
Take home message: Get lots of input from multiple academic and industry individuals who have experience with thinking in terms of milestones and valid targets. I agree the University of Kansas model is a nice academic/industry-type expertise blend.

Jens Eckstein
Frank, Howard, I agree completely!

Eli Michaelis
Since Howard and Frank mentioned it, I would like to invite those of you interested in the models we have for tech transfer to contact me and we can try to answer questions related to such efforts.

Howard Fillit
Or to emulate Jordan Tang, and once some IP is gotten, try to create an early-stage company (if you can get financing), and do the tech transfer, and then build the teams, outsource where possible, and as Frank said, get good advice.

June Kinoshita
It has become rather fashionable now for big university medical schools to set up drug discovery centers. Any opinions on which ones (besides Eli's) are successful models? What pitfalls should they watch for?

Howard Fillit
The Laboratory for Drug Discovery in Neurodegeneration (LDDN) at Harvard is another reasonable model. Jordan and Frank are other great models. Maybe icons!

Jens Eckstein
One major shortcoming of these centers is the lack of process development and formulation/delivery folks.

Howard Fillit
Jens, I agree, but that can be outsourced. Also, the emerging regional biotech centers are trying to build these capabilities.

Jordan Tang
The LDDN at Harvard is a great model for academia centers. A lot of good data can be produced to show feasibility that would make the project much more attractive to venture funds.

Frank Longo
I need to sign out. I learned a lot from everyone. Bye, all.

Eli Michaelis
June, you are right that it is difficult to bring together the expertise of a pharma company in a single center, but it has to be done if it is going to succeed. You need more than good biology and chemistry; you need a good understanding of pharmaceutics and a know-how of what industry faces in drug development.

Jens Eckstein
Outsourcing means good project management; that is, no matter what you do, you want to have people in the effort with expertise in process development/formulation/delivery.

Howard Fillit
Jens makes a great point.

June Kinoshita
Thank you, all. This has been a terrific discussion. We'll be preparing an edited transcript which we'll send around for corrections and amendments before we post it on Alzforum. I also hope you will all send me resources to include in the ISOA-Alzforum Drug Development database. We've been focusing on companies, but clearly we should be seeking academic centers with expertise to help other academics (and companies!).

Kelly Koehn
As CEO of a startup bio-pharm company with lead compounds aimed at amelioration of intracellular amyloid plaque, I need to harness all resources available to get to an IND. I appreciate the discussion today.

Jordan Tang
Thank you for the opportunity to chat.

Edward Zamrini
Thanks, everyone.

Howard Fillit
 Thanks.

Jan Teller
Thank you, all. Great discussion!

June Kinoshita
Thanks, everyone. Have a great weekend.

Eli Michaelis
Thanks to all.

Background

Introduction

Better treatments for Alzheimer disease—and other neurodegenerative diseases—are badly needed. But while many researchers have uncovered pathways, mechanisms, and molecules that could serve as valid drug targets, the idea of turning a basic research discovery into a drug development program may be daunting. Have you ever entertained the idea of venturing into drug discovery? Have you been bogged down by red tape, limited capital, lack of expertise, insufficient knowledge? Or has your pilot program never even gotten off the ground for all or any of the same reasons?

If you are in the midst of translating an important scientific discovery into a drug development program, or even better, if you are considering the possibility, then this live discussion is for you. This is a great opportunity to tap into the expertise of our five panelists who together can answer just about any question you might have on translational research. Are you aware, for example, of the following financial considerations:

  • NIH funding, even the translational research funding, is generally insufficient to carry the preclinical drug development to Investigative New Drug (IND) status. If one seriously entertains the idea of drug development, it is necessary to consider a new venture.
  • For a potential new venture, the lack of good business advice is often an obstacle to getting started. Unless you are located in a biotech hot bed, good business advice may not be easily available.
  • People in the business and venture world seem to operate on different value concepts and ethical guidelines from those that commonly operate in the scientific world. The cultural shock can be severe.
  • The difficulty in finding venture capital. Most venture capitalists want low risk and high return, which translates to a general lack of interest in early-stage drug development.
  • For scientists who are developing a career in basic research, it is a hard choice of whether or not to spend time away from the lab. Do you want to risk the next grant renewal for a start-up?

Or the following practical considerations:

  • For academic-based investigators, a common limiting factor is readily available expertise in small molecule target validation and strategies for characterizing pharmacokinetics and toxicology properties of novel compounds.
  • Availability, costs and housing requirements for transgenic mouse AD models present a challenge for preclinical studies. In addition, few of these models are commercially available.
  • Much of the current AD transgenic mouse model work has focused on decreasing amyloid deposition as an endpoint. Other endpoints such as neuritic dystrophy and loss of synaptic function are not as well studied; thus, designing preclinical trials with these endpoints is more difficult.
  • Animal behavioral studies are important but require a significant degree of expertise and are labor-intensive. Finding an appropriate collaborator can be a challenge.

These financial and practical hurdles can be overcome, and our panel is here to advise.

  • Howard Fillit is the executive director of the Institute for the Study of Aging (ISOA), a biomedical venture philanthropy that funds AD drug discovery. Since 1998, the ISOA has committed more than $23 million in support of 133 research projects and conferences.
  • Jordan Tang, head of the Protein Studies Research Program at the Oklahoma Medical Research Foundation, is no stranger to translational research. Jordan holds countless patents, including several for ß-secretase inhibitors.
  • Frank Longo is chairman of the neurology department at the University of North Carolina School of Medicine. Frank brings to the discussion his expertise as a physician and clinical trial leader. He also serves on the scientific advisory board of the ISOA.
  • Eli Michaelis is University Distinguished Professor and Chairman of the Department of Pharmacology and Toxicology at the University of Kansas. He is also the Director Higuchi Biosciences Center and Center for Neurobiology and Immunology Research.
  • Jens Eckstein is a principal at the Boston office of the venture capital firm Techno Venture Management. He brings a unique blend of expertise to the discussion. Having spent several years as chief research scientist in the biotech industry, he can speak to both sides of the venture capital coin.

For further background information, see our Drug Development Database and Tutorial

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References

Webinar Citations

  1. Lost in Translation? Charting the Course in Preclinical Therapeutic Development: A Panel Discussion

News Citations

  1. Sorrento: They’ve Just Got to Have It—Where’s That Biomarker? Part 2
  2. Sniff This: Therapeutic Peptides Through the Nose?
  3. Target BACE: Better Than Ever?

Paper Citations

  1. . The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J Neurosci. 2003 Jul 2;23(13):5531-5. PubMed.
  2. . High-resolution serum proteomic profiling of Alzheimer disease samples reveals disease-specific, carrier-protein-bound mass signatures. Clin Chem. 2005 Oct;51(10):1946-54. PubMed.

Other Citations

  1. Howard Fillit

External Citations

  1. ISOA

Further Reading

No Available Further Reading