The following interview took place on April 9, 1997. The subjects include: research management; vaccine development, manufacturing, and testing; the FDA regulatory process and good laboratory practice; delivery of vaccines, anticancer drugs, and gene therapy; and drug synthesis and screening.
Nanoparticles, which are the size of microorganisms, have interesting surface properties applicable to molecular transport and drug delivery. This technology led to the founding of Structured Biologicals, which grew into Ben-Abraham Technologies Inc. in 1996. By the end of 1997, the company expects to have 15 employees at their lab in Atlanta.
Dr. Alex D. Kanarek, director of R&D, adds, "The company's intention is to be a development corporation which will take vaccines and drugs to the clinical testing stage. At that stage, we may either continue to develop the drug ourselves (which would require either acquiring manufacturing facilities or contract out -- or make a strategic alliance), or we will just sublicense the product to an existing manufacturer, who will then make it, distribute it, and pay royalties."
What strengths give your company a competitive edge? Applied to what?
The competitive edge is entirely in the quality of the research -- and the fact that the U.S. Patent Office has approved a range of patents covering many different applications, which we will use both for mesne production and for products. We have a critical handle on being able to make specific types of drug formulations and specific types of vaccines, and these cannot be copied by other people without infringing on the patents. The patents cover many different formulations, and so an entire area of application has been tied up. This is our competitive edge.
We will maintain this edge by driving a very firm, fast, very well directed development program to bring product to the market soon: all patents expire and as they get older the opportunities for competition increase. The longer we are in our development phase without a product on the market, the easier it becomes for another company to find a way around the patent and build on our expertise to come up with something they could market without infringing the patent.
It's essential now, and with all biopharmaceutical companies, to improve the speed to market. The time to market is the most critical factor now. Our competitive edge will be maintained by rapid time to market, which requires a very, very firmly guided development program. We don't have time to do an experiment twice; it has to be done right the first time. That's our philosophy.
What are your goals and objectives?
The objectives are to bring to the IND stage (that's the submission of an Investigation of a New Drug application to the FDA) a minimum of two vaccines and one drug formulation within the next 4 years; hopefully, within the next 3 years. I have laid down the objective to have the first IND submitted before 1998. That is very ambitious, and we will be extremely lucky to achieve that. But I believe in stretching people as much as possible without cutting corners.
How do you plan to achieve such an ambitious goal?
We will achieve that by hiring high-grade people and by a strict project management system: every stage of the development process is clearly defined. We break down the work and assign priorities to those experiments which are defined in the life of what has to go into the investigation of a new drug application. We will not be doing esoteric research. If we need to test a particular compound for its pharmacokinetics or toxicology, those tests will be done on the basis that the test satisfies FDA requirements for good laboratory practice, the results are reliable and validate-able, and every experiment will be designed to meet that type of objective: will the results be applicable to drug application, and will the drug support our claims for the product?
This is how the program will be driven. It is essential, very early on in the game, to go to the FDA and say, This is what we intend to do, we're going to make this formulation, we're going to make that vaccine, these are the technologies we're using. (There is an educational phase in this, in that we will explain to them what our technology is all about -- because they won't have read the patents.) This is before we ever write any application or before we even do any of the critical studies. You go to them and say, "In support of an application for the clinical testing of this particular compound or this particular product, we intend to do A, B, and C. Please may we have your comments."
Someone stood up at a meeting last week and said, "You never ask the FDA what to do. They are not in the business of running your business. They're in the business of controlling what goes into the population. So you tell them what you propose to do, and they tell you whether it's acceptable." This is a critical, early phase: decide what you're going to do, go talk to the FDA about it, modify your plans accordingly, and then just get on with it.
And keep them informed of how your development is going, so they have an idea of when your IND is going to be arriving. They usually ask for a pre-IND meeting immediately before you plan to submit that big dossier; they would like you to tell them, "This is what we've achieved, this is the data that you're going to be seeing." You may have to go back and do a bit more, but it's better to do that before you've submitted all the paperwork -- otherwise it takes a lot longer to correct it.
What's most important?
The most important thing is planning. The scientists I employ must understand clearly the implications of the work that they're doing. I think it's not a question of going into the lab and saying, "What would happen if we did such-and-such?" We will have to go into the lab and say, "We're going to do such-and-such because this is the result we're looking for." If the result is positive, we can move ahead; if it's negative, we'll have to think again. It's not a "What if...". Rather, "Does it or does it not satisfy these criteria (whatever they are)? If not, why not?" Not, "Wouldn't it be nice to put this together and see if it produces an immune response?"
According to the patents, these things are vaccines. Prove it.
You plan every experiment with a clearly defined outcome. If the experiment cannot achieve that outcome, then the experiment is wrong in design. You may not have all the knowledge that you need to predict the outcome; but if so, maybe you take a step back and do another experiment. Once you get to critical experiments, you should know that the outcome will be either A or B. And you will then have a decision point -- not left with, "That was a bit iffy. Let's do it again." No, you do it again only if it's necessary to confirm a good result, such as in another set of animals or in people. But you have to be able to sit down with your scientists and say, "Do you really understand what will happen when you do this experiment? Because we are going to be looking for such-and-such a result."
Does that make any sense?
Yes, and that brings us to the section on projects:
At the beginning, do you ask: "What results do we expect from this project? When do we expect them? ...." (Do you have a timetable?)
We have a timetable, we have a clearly defined set of objectives (and time frames for those objectives), we have made the best estimate on how much it will cost to do that work, and we have ensured that the capital is there to fund this work.
The most critical factor is the people, and this is why it has taken us quite awhile to hire the people we're looking for: we want people with a good scientific background and understanding of the sort of work we're trying to do, and I've also tried to find people who have an understanding of the regulatory aspect of the whole business. A lot of university researchers have no idea about the sort of things the regulatory authorities would demand of research to back up an IND. They do not understand GLP, good laboratory practice, which the regulations require.
The reason why contract research laboratories are doing such a good business is because these people have become specialists in satisfying GLP. Sometimes, it is cheaper to go to a specialist, give them the compound, and have them do the test because their facilities and methods of working have already been improved by the FDA. Start-ups provide a lot of business to contract researchers, then to contract manufacturers who can show they comply with good manufacturing practice, and then to contract researchers in the clinical phase. There are companies making a fortune out of clinical research for small companies because they can show they comply with good clinical research practice.
A company whose compound or drug (or even a food) has not complied will get nowhere, and the compliance gets more difficult every year. So, it's not enough to have good scientists, you need to have a good scientist who's had some exposure to the exigencies of the regulatory process and the necessity to comply.
Otherwise, you have to do everything twice, the second time under GLP -- and that's the time you don't have to spare, for speed-to-market.
Exactly. We want to do it right the first time, so we do it under GLP.
I already have the laboratory audit manual for good laboratory practice, so that I can put our own lab through that analysis, internally, wearing the hat of the quality assurance manager. Then, I can say eventually to somebody, "Yes, this was all GLP work," -- even down to the fact that the records were kept in hard notebooks with waterproof pages, each page is numbered, each page is countersigned every night. And then the records are copied onto this computer, which has a backup, removable Zip drive; and the big floppies go into the back room, so we have all our records kept.
When do you appraise the progress of a project, so that you have control?
We have "set milestones", and these milestones have been agreed upon with [Morehouse] University. A typical milestone would be, we will repeat the demonstration of the proof of principle. "Proof of principle" would be: When you make this product on an experimental basis, this vaccine, you put it into rabbits and mice and guinea pigs, and you get this type of immune response; and therefore the principle is demonstrated, that this is an immunogenic product, a vaccine type product. The claims of the patents are that you can do this, but the only research work was done in a university laboratory.
So our first major milestone is to take some critical experiments from the patent on which the claims were based (and which demonstrated originally that this was an interesting and good concept) and repeat that proof of concept. Within 6 months, we will have repeated critical experiments that demonstrate the proof of the concept.
Once that is done, the next analysis phase will be on the success of scale-up procedures. If you can do it in a teacup, you have to be able to do it in a 500-liter tank. So that a lot of work will have to be dedicated to analyzing the various stages of the process and finding anything that might create a problem in the scale-up. There are some processes which you can do very simply on the lab bench which you can't do in a pilot quant. You have to have pipe work, you have to be able to move stuff from one tank to another, you can't do it (as the patent talks about doing it) in a 50-liter working batch, you have to start to think about large-scale manufacturing of the raw materials -- in our case, say, a virus preparation which has to be grown in a mass-cell culture.
Parallel to the research that people are doing on the definition of the product and its ability to immunize, there will be work being done on the scale up of the process: are we going to go to roller bottles; are we going to go to stationary cultures or stirred cultures; use two 80-liter bottles or a 500-liter tank; are we going to have to use microcarrier cultures -- all these things are standard procedures now for viral vaccine manufacture, but we have to find out which is the best one.
So, immediately after proof of principle, the next milestone is the creation of a pilot-scale manufacturing process. And then the stage after that will be the manufacture of products for testing using that process. And that's when validation starts to come in because, as you go through the steps of the procedure, there will be tests. You draw yourself two trees: one tree says from the starting material to the finishing material these are the stages you go through, and the other tree says as you get to this stage you're going to test it for such and such.
I'll give you a specific example. You start off with a master cell culture (that's going to be the culture from which all your vaccine lots will be derived), and you break it up into small amounts and put it away in liquid nitrogen; so you can go back and use the same cell culture at the same level of growth (some generation number). You want to know that that cell culture is free of extraneous agents. There will be quite a lot of testing for other viruses and bacteria and so on to be done on that. So you have your master cell culture, and you have the QC, the quality control, of that. At the next stage, you have your first virus grown up in that, a 50-liter lot, and that will have to be grown to show it's the right virus and nothing else is there, it's sterile, and how much of it you have. Are you going to have to treat that virus with a solvent to inactivate it and extract the bits you want to have? Then you have to see if it's fully inactivated, have you got the bits you want, have you classified them by monoclonal antibody or something like this where you're going to do SDS-PAGE analysis. As you go down the process, the analysis and the quality control gets sharper and sharper, until you have the one molecule that you're interested in. The process and the means whereby that process is controlled and analyzed are developed in parallel.
Stage 1, proof of concept; stage 2, an acceptable small-scale manufacturing process; stage 3, the quality assurance that you lay on that, and if the lots pass that, then we have material suitable for the IND-testing stage: toxicity studies, formulations, stability of a formulation (to show that it can stand being put in the fridge for a year).... You can see how the milestones build up.
With several projects going on, is there a systematic review of the projects all together?
Yes. They're interrelated to a certain extent, but if one is falling behind, for whatever reason, we may need to adjust the milestone agreement with the University. Normally, they give us a grace period of a couple of months, but if we find that one of the projects may not be yielding the expected results, we have the right to abandon that and replace it with another project.
All projects will be reviewed at least on a quarterly basis for their ability to keep up with the projected development schedule and yield the anticipated results. If the people on that project are having trouble, we want to know about it pretty fast because we do not want to send good money after bad, so to speak. If one of the concepts is less viable, there are plenty of others we could do. Take an example: if one particular method of making a targeted anticancer drug turns out not to give us the concentration of drug that we were anticipating in the organ or the tumor, we would seek a means to abandon that approach and replace it with a backup. There's always more than one way.
We have to be far enough down the line to know that the results we're seeing are reliable -- and that we are placing the correct interpretation on those results. Still, we have to be prepared to abandon a project that is not yielding results. I will certainly be having a quarterly review, and there's not that many of us (there will be a team of 10), so we expect to interrelate on a daily basis. I would like to encourage people to come and talk once a week about what they've achieved, but that may be too soon because some experiments run for 3 weeks. I expect they will update me with reports on a monthly basis, and quarterly there will be a full review of a project: what have we done, how much we have spent, how far are we behind or ahead, what are we doing in next quarter -- and if we're not sure of that, should we be abandoning this or putting it on the back burner and concentrating on something else.
We have adequate resources, but not unlimited resources. We would certainly like to know that our resources are being applied to the very best of our various opportunities, to reach the market as quickly as possible. And I know that the board of the company will meet quarterly, and they will be expecting a progress report from me anyway. [laughs]
Where do you see opportunities for your company?
We are going to make opportunities for the company by acquiring other technology, which may or may not be synergistic with what we have already. The first set of opportunities have already been defined, in that we know that the products that will come from our projects have application to significant markets. We know also that the technology has other applications which we haven't had an opportunity to investigate so far, and the University has agreed to allow us to make a supplementary proposal to them if we come up with a further application.
And one very strong application is in gene therapy because we believe that the same transport systems could be used to carry genetic material, DNA. This has two strong applications: one is the use of DNA from microorganisms as a vaccination technology, and this is coming along quite interestingly at the moment; and there are the applications, more long term, of being able to replace or modify genetic defects by providing a repair mechanism or a new piece of DNA which can be incorporated into the patient's cell and correct the condition. Cystic fibrosis is the example that's currently furthest ahead in this; multiple sclerosis is another one that's under consideration. Dr. Ben-Abraham is very interested in the potential for using gene therapy in the treatment of cancers because certain cancers are genetically involved. Usually, that predisposition to a tumor results from the suppression of a gene which normally suppresses the tumor (a double negative, so to speak). If you can identify that, maybe you can find the means to turn that suppressor back on again. So here's a whole area, and this is a strong area of possibility for us.
Apart from that, we've looked at some other vaccine applications. We're in the late stages of negotiation with a researcher who has developed a full treatment of melanoma. It appears to be helping patients with advanced melanoma, improving their survival time, reducing the growth rate of the tumor. We are very interested in this; we believe that we could bring it to the market ourselves.
Where do you see challenges?
There are two. First, there's the question of being able to maintain our base in terms of funding. That's always a challenge. There are fashions in investment. Biotechnology has had a good year -- and a bad year. Sometimes IPO's are very successful, second and third fundings even more so; other times they are not. We are about to complete our NASDAQ listing, then we will be seeking additional funding. The challenge there is to persuade the investor that it's better to buy our shares than those of other biotech companies -- and there are plenty of them out there, competing for the same investment dollar.
The scientific challenge is to be able to demonstrate very effectively and very rapidly that this apparently brilliant technology, which resulted in a very broad range of patents, can really be turned into products that will be of benefit to people and the company. The benefit to people is that we hope to prevent diseases for which there's currently no preventative mechanism, no vaccine; and we may be able to very much improve the means by which certain anticancer drugs work by this targeting process. The benefit to us will be to make good deals, either for direct marketing of these products or with suitable corporate strategic partners.
That's another challenge, of course, finding a suitable corporate partner. The most difficult thing is to determine the optimum time to make the approach, to find the psychological point at which you go to a large company and say, "Look what we have for you. You've been waiting for this; it's the best thing since sliced bread." They have to agree with you on that; it has to be better than what other small companies are offering them. This is a major challenge because a company like ours could not consider taking a major new product to the market alone. We do not have the manufacturing facility, the quality control facility, the marketing operation, or the sales and distribution network. It takes a long time to develop those; in fact, you can see that the industry is contracting in that sense: people are merging to achieve a more efficient development, manufacturing, quality control, and marketing operation.
My immediate challenge is to get my team in and up and operating -- and get this very ambitious program working as fast as possible.
What do you find dissatisfying about your current situation?
The main dissatisfaction has been that it's taken longer than I anticipated to do the corporate paperwork: transferring the company from Canada, getting our NASDAQ listing, those sorts of things. And finding good staff.
What journals/newsletters do you read?
I read BioPharm, Nature Bioscience, Nature Biotechnology. Apart from that I do a lot of literature searches on the Internet. I subscribe to an operation called Paper Chase, which is a literature database out of Harvard that's accessible on the Internet. You can do literature searches on any particular item, and they're usually not more than a month out of date, so you can get the latest papers published. I do a literature search once a month on the topics of interest to me, and it saves me from reading an awful lot of journals. I can print out the summaries and then read the original paper at the Morehouse library.
The papers we're interested in can appear in all sorts of journals. There's Vaccine, Virology, Journal of Immunology, as well as their equivalents in other countries. But the only way to keep up to date on the technology is to have a database do it for you.
There's so much published, and a lot of it's rubbish. That's because people don't get grants unless they have bibliographies. In industry, you don't need to publish to survive. You need to do a good job and get results, and then you get a raise and stay in your job. I consider myself a successful scientist, but I don't have more than 6 papers to my name. I have a lot of patents and achievements, in the sense of real products.
What are the trends in the regulatory environment and how do they affect your planning?
One very strong trend at the moment is a serious attempt by the FDA to reduce the time taken to review documentation and reduce the amount of duplicate documentation. The other major trend, of course, is harmonization of regulations between the major geographical areas of the world. A product approved in the United States would not have to go through a complete re-approval process, a re-submission process, in Europe for example.
In a nutshell, the regulations for drugs are becoming more stringent, but they're trying to reduce the superfluous paperwork. And time to market improves as a result.
What changes in industry, science, and technology have already occurred, but have yet to have full impact? (That is, what has already happened that will create the future?)
The whole business of genetic manipulation is playing a larger and larger role. It's not the only approach to new drug therapy or prophylaxis. There's also the ability to create a tailored compound, to design them on the computer if you like, to synthesize them in the laboratory. The screening methods for new compounds are much, much more sophisticated than they used to be. A lot of screening can be done in a completely theoretical sense. You can create on the computer the shape of the molecule, and you can test it for its ability to interact with defined receptors or metabolic pathways -- all before you even make the drug. I think this is an amazing advance over the system where you'd make 64 different forms of the same compound, put them into mice, and see which one was the least toxic and apparently the most effective.
Whole classes of drugs now are being designed specifically by being able to define the pathways that they are to interact with, and then to define the form of a molecule which will interact with that pathway. The reductase inhibitors are one particular class of compounds that has been developed that way. And this is in the pharmaceutical side. You mustn't forget that beyond DNA and genetic engineering therapy there's a lot going on in the synthetic drug area as well. People are interested in peptide therapy, so you have the means to design and synthesize clever peptides. The whole question of protein sequencing, of peptide sequencing is much more sophisticated than it used to be. You can take a machine, press a couple of buttons, and get exactly the peptide you want: the length, the formulation, the folding -- it's all there.
Another trend is to go into the most distant parts of the world and have another look at what's in the soil and plants, searching for new antibiotics, new drugs. People are looking again at a lot of folk remedies and finding there actually were things in those preparations that actually had pharmaceutical activity. You find that nature's variety is greater than anyone can possibly envisage.
So, you have the two parallel trends. On the one hand, the ability to do so much more electronically and synthetically. On the other hand, the necessity to look again at what we have in a cornucopia called nature.
I had heard of "dry" chemistry, where the search is through databases of synthetic compounds -- re-examining what we already have -- for specific molecular behavior and structures and then assembling new ones via computer modeling.
Yes, now that people know more about the means of interaction between molecules and pathways. There is a natural process, and it can be interfered with. That's what pharmaceutics is all about. Maybe you stop an enzyme from acting, maybe you interfere with the movement of a neurotransmitter. The more you know about the pathway, the more you know how to interfere. The more you know about the different stages of an organic process within the body, the more times you can interfere with that process. If you know more about a bacterial metabolism, then you know how to interfere with a synthetic antimicrobial. The more you know, the more you can apply.
What other Southeastern companies are doing interesting research?
I've heard a little about AtheroGenics, a spinoff from Emory which seems to be doing some extremely interesting work in new means of combating atherosclerosis and clot formation. And another company, Vaxcel, which is working on vaccine agulant systems.
If you could speak with anyone, who would that be?
Louis Pasteur.
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