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New Multiple Myeloma Drug JS-K Making its Way Through the Drug Development Process
New Multiple Myeloma Drug JS-K Making its Way Through the Drug Development Process image

Jan 22, 2016 / 11:00AM MST
HealthTree Podcast for Multiple Myeloma

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Episode Summary

Dr. Paul Shami, MD Huntsman Cancer Institute Interview Date: January 22, 2016 

 Dr. Paul Shami, MD of the Huntsman Cancer Institute shares his work on a new drug called JS-K, now in development for multiple myeloma and other cancers including acute myeloid leukemia (AML), liver cancer, brain cancer and other solid tumors. The drug works in four ways to kill myeloma cells: it kills the tumor cells directly, it prevents the vascular (blood vessel) system from feeding the cells to stop growth, it stimulates the cells to put a signal (CD155) on their top so that the immune system natural kill (NK) cells can do their job and it prevents the bone marrow microenvironment from facilitating future growth. The drug has been studied by multiple scientists in centers like that of Dr. Ken Anderson at Dana Farber and is making its way through the very thorough drug development process to come to the clinic. The drug is currently at the toxicology study stage so that it can obtain FDA approval to enter a phase 1 clinical trial. Dr. Shami shares his work to make this new drug a reality in the myeloma clinic and how its use may be effective in combination with bortezomib (Velcade) and elotuzumab (Empliciti). 

multiple myeloma 

Thanks to our Episode Sponsor, Takeda Oncology

Full Transcript

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We would like to thank today's episode's sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio and all that they do for multiple myeloma patients. Now, before we get started with the show I'd like to tell you a program you'll be seeing more on in the next few weeks. We call it Muscles for Myeloma. Now, at ASH I heard many doctors saying they were going to start putting patients into treatment categories like “fit”, “unfit” and “frail” when they were making treatment decisions rather than basing those decisions on age. One doctor used the example that an 85-year-old had a transplant because he was in such great physical condition, and he did just fine with it. Now, because these therapies can be hard on our bodies we need to be fit enough to handle them because getting them could give us long-term remissions and longer life. So everyone is different. I have friends who are coming out of transplant, going into transplants, some are on maintenance therapy, and everyone is at a different level of what they could possibly do. Muscles for Myeloma will be a fitness challenge based on your own personal goals. Who doesn't need that right after the holidays? So we'll be sharing more in the next few days on that but start thinking about how you can get moving and then think about others you'd like to invite to join you. Now, on to our show which is about a new and interesting drug. We welcome Dr. Paul Shami of the Huntsman Cancer Institute. So thank you so much for joining us today, Dr. Shami.

Dr. Paul Shami: Thank you. I appreciate the opportunity to be on the show.

Jenny: Well, let me introduce you before we get started, and then we'll start in with our questions for you. Dr. Paul Shami is leader of the Acute Leukemia Program at Huntsman Cancer Institute of the University of Utah, and Member and Clinical Investigator at Huntsman Cancer. Dr. Shami is on the Clinical Cancer Investigation Committee, the Academic Senate and Faculty Review Committee at the University of Utah in the Department of Internal Medicine. He's also Founder and Chief Medical Officer of JSK Therapeutics. He reviews publications including Leukemia, Blood, Clinical Cancer Research, Clinical and Laboratory Medicine, Leukemia and Lymphoma, Journal of Pharmacy and Pharmacology, the Journal of the NCI Editor, and Leukemia Research and Treatment just to name a few. Dr. Shami has received the Leukemia and Lymphoma Society Translational Research Award, the Rapid Access to Intervention Development NCI award, and the Chairman's citation for outstanding service in the fight against blood cancers from the LLS. Dr. Shami completed his education in Lebanon and his post-graduate work at Duke University. So again, Dr. Shami, we really welcome you to the show today. As I understand it, you are working on a brand new type of therapy in a totally different class from something that exists today. So maybe you want to give us just a little bit of background on the product and how you discovered this new treatment.

Dr. Paul Shami: Sure. Actually, this is turning out to be a really nice Utah story. There is this molecule called nitric oxide that we all make in our bodies. It has multiple different functions including function where certain types of immune cells use nitric oxide to attack microbes or tumor cells. That pathway of the immune effects of nitric oxide was initially described here at the University of Utah by Dr. John Hibbs. I was fortunate to train at Duke under Dr. Brice Weinberg who trained here with John Hibbs. The way I got into this was through initial work I did as a trainee in the Weinberg lab at Duke. What we looked at is the effect of nitric oxide on acute myeloid leukemia cells. We showed that AML cells are very sensitive to the effect of nitric oxide. The problem with developing these observations into a therapy is that nitric oxide has so many different effects in the body that it needs to be targeted to the tumor cells otherwise it would be too toxic to try to deliver it in an indiscriminate fashion. So after I moved to the University of Utah I was again fortunate to be able to establish a collaboration with a team of really wonderful chemists at the National Cancer Institute led by Dr. Larry Keefer In Dr. Keefer's group, Dr. Joe Saavedra was synthesizing a whole family of drugs that were designed to try to target the nitric oxide to the tumor cells. The chemists made a whole series of these compounds. In each one of those was actually engineered in a specific fashion to be able to enhance the delivery to tumor cells. They sent the compounds to us and we screened them in my lab. Out of the screen we identified this one compound that turned out to be the most active against acute myeloid leukemia. The compound is called JS-K. The letters stand for the initials of Joe Saavedra who synthesized the compound. It was compound number K of the series. Since then we have entered into collaborations with different groups. Through their work we have found that JS-K is active against multiple different cancers. Now, as far as multiple myeloma is concerned, a few years ago Dr. Ken Anderson from Dana-Farber, essentially one of the giants of the field, was visiting us as a visiting professor here. I talked with him about JS-K. He showed a lot of interest in it. So we sent him the drug and they did essentially most of the initial work on myeloma in his lab. At the time he had a fellow working in his lab, Dr. Tanyel Kiziltepe. She basically did most of the initial work that showed the activity of JS-K against myeloma. So that's how we discover the molecule. So it went from an initial biologic observation to actually very clever chemistry from the team of chemists of the NCI identifying the lead in my lab by screening it against leukemia and then for myeloma showing the activity in Dr. Anderson's lab. So it's clearly a multidisciplinary team approach with many different labs working together in synergy.

Jenny: It sounded like, from reading a paper that I read, that your work may have studied it for liver cancer also. Is that correct?

Dr. Paul Shami: Yes. So as I mentioned, we shared the compound with different investigators including Dr. Brian Carr who at the time was at the University of Pittsburgh. They studied it against liver cancer. Indeed it showed activity against liver cancer, in a rat model of liver cancer. Again, through our work and work of collaborators from different institutions in the United States and in Germany, JS-K has shown activity, as we mentioned, in myeloma, in AML, in liver cancer but also in lung cancer, kidney cancer, brain tumors, Ewing's sarcoma which is a devastating pediatric tumor, and then prostate cancer. So it has a broad spectrum of activity against multiple different cancers.

Jenny: It sounded like it has something to do with angiogenesis. Many patients may not know what that is. Do you want to describe how it works and how it kills the cancer cells and then as part of that describe how it relates to angiogenesis?

Dr. Paul Shami: Sure. So angiogenesis is a normal phenomenon that we all have in our bodies. That's the phenomenon by which we develop blood vessels to feed our cells, to feed our organs, to heal wounds, all those types of things. Any cancer cell needs essentially access to the blood supply in order to survive and feed itself. Cancer cells stimulate angiogenesis. It kind of taps into the body circulatory system to develop their own blood supply in a very pernicious way, frankly, just like cancer is and using a lot of the normal molecules that normally, for example, would help us heal a wound, but in the case of a cancer, it would essentially help feed the tumor. In fact if a cancer cell or small population of cancer cells does not have access to the vasculature, to the circulatory system, it would never grow to become a cancer. So a lot of research has gone on over the past several years to develop drugs that could inhibit angiogenesis. Some of the drugs that have been developed for myeloma work at least in part by inhibiting angiogenesis. These include, for instance, thalidomide and lenalidomide. As far as JS-K is concerned, again, just because it's a nitric oxide delivery drug, it has multiple different targets, multiple different effects including direct cytotoxic effects to the tumor. So by going into the cancer cell and releasing toxic amounts of nitric oxide it affects multiple different pathways inside the cells. Also as part of the work we've done with Dr. Anderson's group and with the team of investigators at the NCI we were able to show that JS-K inhibits angiogenesis, so inhibits the development of vessels both in vitro, so basically in "test tube” assays, but also in vivo. And the in vivo work, again, was done in the Anderson lab where they implanted mice with multiple myeloma cells. They showed that if you treat the mice with JS-K you could shrink the myeloma cells to allow the mice to live longer. When they got the tumors out and the tumors were stained for markers of angiogenesis, so checking for angiogenesis under the microscope, it was evident that JS-K had also inhibited the growth of vessels into the tumors. So it's very exciting because we have a drug that is directly toxic to the tumor cells by multiple different mechanisms but it also inhibits the tumors from developing their own blood supply. There's a very recent study form an Italian group that suggests that it could potentially work also through an immune-mediated mechanism. Maybe we can talk about this later in the show.

Jenny: Sure. Are you talking about that it might affect the bone marrow microenvironment in an additional way or that’s some other way? We better talk about it now because I might forget.

Dr. Paul Shami: Okay. We'll talk about it now. What that Italian group showed, and this was published just last year, what they showed is that if you treat myeloma cells with nitric oxide donors, so drugs that deliver nitric oxide, including JS-K -- so they tested two NO donors, one of them was JS-K, what they showed is that by treating the myeloma cells with JS-K you stimulate them to express a protein called CD155 on their surface. By doing so, they stimulate normal immune cells to kind of get angry and attack them. These cells are called NK cells, natural killer cells. That's, again, an additional mechanism by which JS-K could be working in vivo. The reason I was saying maybe later in the show is because we may be talking about potential synergies with other drugs.

Jenny: We will talk about that.

Dr. Paul Shami: Okay. So we'll talk about it once we get there. As far as the bone marrow microenvironment is concerned, one thing that the Anderson group at Dana-Farber showed is, again, multiple myeloma cells use the bone marrow environment to their advantage. The normal bone marrow stromal cells, kind of the support cells in the bone marrow, they use them to their advantage. What the Anderson group showed is that JS-K actually breaks that synergy that the myeloma cells have with a normal bone marrow environment. Again, it's yet another potential mechanism where JS-K could sensitize the multiple myeloma cells to other drugs in vivo by just inhibiting the advantage that myeloma cells have when they are close to normal bone marrow stromal cells.

Jenny: Well, to me it sounds like you're doing those four specific things. So it's killing the tumor cells directly, and then it's preventing kind of a blood vessel system from growing and feeding itself, and it's stimulating the cells to put a target on top so the natural immune system NK cells can kill them, and then it's preventing the bone marrow environment from being able to facilitate its growth. So that's a lot of different ways to target the myeloma in my opinion.

Dr. Paul Shami: Yes. That's what I find exciting about this agent is that there a lot of different molecular targets that could potentially work in synergy in vivo, so in the environment of the tumor, that, again, could make it a very potent drug especially if it can be combined also with other active agents.

Jenny: Now, you mentioned at the beginning of the show where you said nitric oxide by itself would be dangerous if you just gave it directly. So you went through a whole process to do the chemistry to find a delivery device basically to get to the cancer cells only. How does that work? Does it impact normal cells at all or there any side effects that you've seen?

Dr. Paul Shami: These are all great questions. There are drugs that are available like nitrates that you could use for blood pressure control, for example, because nitric oxide dilates blood vessels. So if you give a drug like this you will induce a drop in the blood pressure. There are other potential toxicities of nitric oxide but the blood pressure is the most obvious one just because of the normal physiologic effects of nitric oxide. The way that these drugs were designed by our chemistry colleagues is that they do not release a lot of nitric oxide spontaneously. So if you put them in a solution there's some very slow release but it's really not very efficient. However, they could react and break off when they react with, particularly a molecule called glutathione, and then break off and release nitric oxide. Now, there's a family of enzymes called the glutathione S-transferase which can actually catalyze or stimulate that reaction. A lot of different cancer cells actually have high levels of glutathione S-transferase in them because they use the GSTs to resist the effect of chemotherapy. So that was the idea, is to have a reaction that's catalyzed by an enzyme that is found at high levels in the tumor cells. We're not getting 100% selective delivery, I cannot say that, into the tumor cells but I think we are getting enough delivery into the tumor cells to have an effect in vitro and in vivo. Now, as far as toxicity is concerned using different in vitro assays, so far every time a group of investigators look at the normal counterpart of a tumor cell there was no obvious toxicity. To go back to the myeloma work, Dr. Anderson, they looked at normal peripheral blood cells, and it didn't seem that JS-K was toxic to normal peripheral blood cells, at least not the same doses that it was toxic against myeloma cells. We conducted experiments here with one of my bone marrow transplant colleagues, Dr. Thai Cao, where we did transplant experiments on mice and used stem cells that had been treated with JS-K. The mice that received the stem cells that were treated with JS-K fared just as well as the one that received unmanipulated stem cells. So far it doesn't seem, based on the data we have so far, that we have a lot of toxicity against normal cells. Now, I mentioned the blood pressure issue. That could be a problem with this agent because it's a nitric oxide releasing agent. However, we have developed a formulation, so essentially a means of dissolving the drug to be able to administer it clinically. With recent study we did to look at toxicity in dogs, the way we developed it to administer the drug, it seems that based on the measurements that the contractor did that we did not see a drop in blood pressure. So the way we're able to give the drug now, it's a two-hour infusion. The last set of measurements that we've had, it doesn't seem to be dropping the blood pressure in any significant fashion. I should say in that same study that was done, the drug was actually very well tolerated by the dogs who received it every day for seven days, kind of a schedule that potentially could be used to treat the patients basically. So it seems to be well tolerated but obviously we need to do the full set of preclinical toxicology studies as is required to do the initial phase 1 clinical trials to have a good idea of the toxicity profile of the agent.

Jenny: I have several questions about that whole process. First, one of the patients that was with me at ASH, Pat Killingsworth, he observed there are a lot of these new drugs out and available which is really exciting for myeloma patients but a big issue is drug resistance. So we have lots of choices now more than we ever did before but patients are still becoming drug-resistant. As I understand it, you've been trying to test this in drug-resistant myeloma cells. Do you want to talk a little bit about that?

Dr. Paul Shami: Yes. Again, I'll go back to the work that was done by Ken Anderson's group. As part of their work, they studied JS-K against a panel of sensitive and resistant myeloma cells. The drug actually showed activity against all of them including drug-resistant cell lines. They also tested it against myeloma cells that were isolated from patients, not cell lines that had been maintained in the lab. It showed activity in those cells that were directly taken from patients. We have tried in the lab several years ago to make a leukemia cell line resistant to JS-K. There are some means where you can try to culture cells with a drug at low concentrations and take those surviving cells and culture them again and so forth, until you isolate a population of cells that is resistant to the JS-K or any drugs that it could do that with. We have not been able to make a totally resistant cell line. Again, I cannot say that there will be absolutely no resistance once the drug is in the clinic but so far it looks that it's pretty potent. At least theoretically, you could argue that the drug had so many different targets that it would be difficult for tumor cell population to develop resistance to the drug. Again, this is all speculative. We will not know that until a lot more work is done especially until the drug gets into the clinic.

Jenny: With work you're doing in leukemia and also multiple myeloma, does it look like it works better for a specific kind of blood cancer or you're seeing results that are about the same for each one?

Dr. Paul Shami: I can't say that myeloma is more or less sensitive than AML cells. I think both cancers are sensitive to the drug. In fact the FDA has granted us orphan drug designation for both AML and multiple myeloma. I can't say that one tumor is more sensitive than the other. We would certainly want to develop it for both AML and myeloma. I think that would be ideal. As I mentioned, we have data from different labs showing activity in a multitude of different solid tumors. Beyond the hematologic malignancies I think there is great potential there as well.

Jenny: Now, earlier you kind of referred to this that we would talk about how this drug could potentially work with other multiple myeloma drugs. I think bortezomib is one of those drugs. Do you want to talk about why that might work well with Velcade and any other existing drug?

Dr. Paul Shami: Yes. Again, this is the work that was done by Ken Anderson. What they showed is that there is synergy with the bortezomib, with Velcade. Mechanistically, I don't think we know how this synergy occurs but this class of drugs are inhibitors of this proteasome pathway which also is very important or is directly related to the NF-kappa B pathway. So these are two molecular pathways. We know that nitric oxide actually can be inhibitory to the NF-kappa B pathway. So there's potential for synergy there, at least theoretically, where you're hitting the same pathway by two different angles. This is theoretical. We don't have any data to prove that. In the leukemia world we showed in my lab that there is synergy with cytarabine which is one of the main agents that are used for the treatment of acute myeloid leukemia. Another really exciting potential, and this is based on the most recent approvals and data, is one of the new agents that was approved last year, elotuzumab, Empliciti, is an antibody that targets this molecule called SLAMF7. One of the mechanisms by which this antibody works is by simulating natural killer cells to attack the myeloma cells. As I mentioned earlier, the group of Italian investigators showed that JS-K stimulates the myeloma cells to express a target for NK cells. So you could come up with an idea here of potentially doing some synergy studies between the two agents.

Jenny: Using elotuzumab with JS-K, you're saying.

Dr. Paul Shami: Yes.

Jenny: Well, that would be exciting, I think the more that we can use all these newly approved drugs the better.

Dr. Paul Shami: Yes.

Jenny: That would be fantastic. Does it an impact on any particular myeloma type that you've seen? I know that we've talked about myeloma being different kinds. So people have different genetic features in their myeloma. Have you noticed any difference between these different types of myeloma like high risk myeloma or standard or low risk myeloma?

Dr. Paul Shami: That, we don't know. We don't know whether different subtypes of myeloma would be differentially sensitive. More recently my colleague here at Huntsman, Tim Luetkens, from the myeloma group, screened JS-K against a panel of different myeloma cells that have different features. The drug was active against all of them. Like I said before, we really need to get more work done and certainly get into clinical trials to be able to definitively identify subgroups of myeloma that may be more or less sensitive to the drug.

Jenny: You talked about how it might flag the CD155 so the NK cells can kind of go and attack those. Is there any other effect that you've seen on the immune system? Because I know when they talk about myeloma drugs, some of the drugs depress the immune system like dexamethasone, and some enhance it like Revlimid. Maybe you just need to do more studies on it before you know this. But have you seen any other effect on the immune system besides that flagging which is wonderful?

Dr. Paul Shami: Right. We don't know. So we have not done any form of immunologic studies on using the drug. As I mentioned, we did this transplant experiment in mice using a transplant model. It did not seem to compromise bone marrow stem cells which obviously end up producing immune cells. Now, does it have any other effects on the immune system beyond just production of immune active cells? That, we don't know. We have not done any studies that would look at immune function with this agent.

Jenny: Okay. You kind of alluded to the different steps in the process. Maybe you want to walk us through how you start from a discovery of an idea in the lab and then the steps that you have to take. I think you're kind of in an unusual position to do this because many doctors are seeing patients, which you do, and are doing research, which you're doing as well, and then they kind of hand it off to a company to take it over and have it become a real product. But you're working on all aspects of that. So maybe you can give us an idea of how that works.

Dr. Paul Shami: Sure. I mean I can give you my view of it basically which may not be everybody's view. I think it's a pretty standard orthodox approach. So obviously you get an idea. There's a target that you want to target. The chemist then designs a drug. There are different ways of coming up with a design. What's being done a lot these days is let's says there's a protein that you want to target, people do so called virtual screens, so basically using computer software to identify candidate designs. Once you have this candidate design, whichever way you got into it whether it's just by brain power or computer power, you need to show its efficacy in vitro. So this is where tumor cells are cultured in dishes and so forth. You want to show that the agent or that family of agents is capable of killing tumor cells in vitro. Very importantly, you want to show that it can kill tumor cells at concentrations or at amounts that are not exceedingly high. I mean theoretically you can put anything in a culture. If you put enough of it, you can kill tumor cells but if the amount it takes to kill a tumor cell in vitro is exceedingly high then this is going to be too toxic to be developed into the clinic. So you try to identify the most efficient agent that is most lethal to the tumor cells at the lowest concentration. Sometimes there's some back and forth there between the chemistry and the biology where you go back to the chemist and they make some modifications to the molecule to make it more active and so forth. Once you've identified your so called lead drug you then do the studies in vivo. Depending on what tumor you're targeting, you then set up different in vivo models to show that the drug potentially works in vivo. Most of the models use mice actually. So if things look good at that point, then that's when you know that you have something that could potentially make it to the clinic. There, you have two very important things that need to be developed. It's not a one person show. This is where you need expertise for multiple different disciplines. One is your drug needs to be so called scalable. So you need to be able to produce it in large enough quantities to be able to do not just animal work but ultimately get it into large enough quantities to treat patients. A lot of times we have exciting molecules but they're so difficult to make, so difficult to synthesize, that it's never going to be practical to be able to produce enough quantities to get it into the clinic. So that becomes a lab reagent rather than a real drug. Fortunately with JS-K -- again, I'll go back to the genius of the chemists who made the drug, Keefer and Saavedra and their colleagues -- the drug is actually very scalable. So it can be produced in large quantities. Another hurdle is what's called formulation. If you have the powder in a tube in the freezer in the lab, that doesn't mean that you can administer it to a patient. So you need to find a way to basically package it so you could give it in some form to a patient whether oral or intravenous, et cetera. For the intravenous route, you need to be able to dissolve it in some solution that would be actually acceptable to be used in a patient. So for JS-K that was one of the big challenges that we've had with the drug is that it is very difficult to dissolve in water solutions like saline and so forth. Again, one of the major or the major efforts in my lab over the last few years has been to try to develop a formulation for the drug. I think we have something now that works using nanoparticles. So once you have formulation and you have scale up, then you can move forward and do what's called the pre-IND studies. IND means Investigational New Drug. So that's basically the permission you get from the Food and Drug Administration to take the drug into a clinical trial. So to get that permission you need to do the so called pre-IND studies which are mainly toxicology studies in animal. The most common species that are used, depending on the drug, but most commonly it's usually rats and dogs. That allows you to have an idea on the pharmacology of the drug, on the toxicology of the drug, how much can you push the dose, et cetera. So based on these studies there are means to then use a potentially safe dose to use for first in human studies. So you put that whole package together and then you present it to the FDA. If the FDA grants you permission to proceed with clinical trials then you go ahead and start with what's called phase 1 clinical trials which are the initial first in human studies. Again, the classic way of doing it is you start at the low dose and then you escalate the dose in groups of patients until you identify those that are tolerated. These initial phase 1 studies, again, give you also an idea on the pharmacology of the drug, how does it get handled by the body, and sometimes you get some early clues about activity. Once you have identified a dose then you can move forward to what's called phase 2 studies where you get a really good idea about the efficacy of the drug. The ultimate would be what's called a randomized phase 3 trial where you compare your drug or your drug in combination with something, with hat would be the standard of care at that point. So it's a lengthy process. The further down the road you get, the more expensive it gets. There's potential for failure every step of the way. With JS-K we are now at the pre-IND phase. So what we need to do is precisely to do these so called GLP studies in animals to characterize very well its toxicity profile and be able to devise or derive a dose that we could use to start initial phase 1 trials. We're at the stage where we need to do this whole package of toxicology studies before we would go to the FDA to get permission to do clinical trials. Now, where does a startup company come into play? As you mentioned, Jenny, one scenario would be to develop the drug and license it to a company and have it do everything until you get it into the clinic. This would be ideal, frankly. The problem is most companies, in general, want to see some initial clinical results before they take on a new agent. So in a way you're on your own to get it all the way to a phase 1. Most companies at least would want to see the toxicology package before moving forward. In our particular case we've received a lot of support from the government, NIH grants, et cetera, but it gets to a point where you cannot proceed further just with academic grants at the level of an academic lab like mine. So that's when you need a lot more resources to move forward. As I mentioned, established companies like to see results beyond where we are before they take on a new product. That's where founding a startup company comes into play because that allows you to get resources to be able to develop the agent and bring it to early clinical development. When you have a company, an entity, you can raise money potentially from the private sector with different sources there, and/or from the government through different grant mechanisms that are awarded to companies. That's what we've been doing basically. So we founded this company, JSK Therapeutics. We have been able to raise money both from private venture angel funds, and also we've received grants from the government. We are at the stage where we really need to get more resources to be able to complete that toxicology package and get it to the clinic.

Jenny: The whole process is not an easy process. I mean when you talk about even getting the NIH grants, that's very challenging. Nowadays one in 12 grant requests are getting funded. When I very first started this series with Craig Crews who is the inventor of carfilzomib, he said the same thing that you did. He just said it's a very long process. You have to kind of make this jump to show your results before it gets picked up. Then it can be very, very exciting after that. It's not easy. We live in the startup world in our family and see that all the time. It's a challenge to make that jump and to keep it going. It sounds so exciting what you're working on and very, very helpful for myeloma patients.

Dr. Paul Shami: We're definitely very excited about this molecule. What I like about it is that the work was conducted not just in my lab but by multiple different labs at different institutions working independently. So the results I think have been very solid by great investigators whether it's Ken Anderson, the NCI team, and the collaboration with a team of German scientists who did the brain tumor work. In a way it's been validated by different groups that have worked independently. We just need to cross this - people sometimes call it the valley of death for drug development –

Jenny: That's what Dr. Crews called it too. It’s true.

Dr. Paul Shami: It's like you want to cross that desert but you want to make sure that you have a vehicle that can get you through and enough water to survive.

Jenny: Absolutely. I want to be able to make sure that people have an opportunity to ask questions if they have specific questions. So let me do that first, and then I have another question for you before we finish. If you have a question for Dr. Shami you can call 347-637-2631, and press 1 on your keypad. Caller, go ahead with your question.

Caller: Hi, Dr. Shami. Thank you for your time and taking my call. I just would like to know what does it mean if you have an “orphan drug designation”.

Dr. Paul Shami: Yes. As you know, when a drug gets on the market it has to have some so called intellectual property protection so that the company that is commercializing the drug is able to do so with some protection for a certain period of time. Orphan drug designation is a status that is given to agents that are developed for diseases that do not meet certain criterion of incidents, so diseases that are considered to be somewhat rare diseases. So if you get orphan drug designation for a certain disease that falls into that criterion of an orphan disease then the drug has some additional protection. So you have several years of exclusivity that can come beyond what would initially be allowed from the initial patent for that drug. That's a way to provide an incentive to companies or investors to support the development of drugs for diseases that do not have a huge market share.

Caller: Okay. Thank you. Thanks for responding to that.

Dr. Paul Shami: Thank you.

Jenny: Okay. Thank you so much for your question. Does it speed it up as well or just give that protection?

Dr. Paul Shami: It's not the status that speeds up approval. It's mainly a status that provides protection. Now, there are other mechanisms that can potentially speed up approval but that's a totally different subject basically.

Jenny: My final question is how soon could this come to the clinic? I don't know how long it takes for the toxicology to --

Dr. Paul Shami: Yes. I would like this to come to the clinic yesterday, honestly. That is such an area of need. Any of those cancers we mentioned is an area of need. If we have all the resources we would need to do the toxicology package I think that could be accomplished in about a year's time. And then you put that filing together, all this information together into what's called an IND application, and then you go to the FDA. So if today, January 14th, if we started today and we have all the resources we need, we could potentially complete the tox package in about a year's time and barring any complications or any unforeseen problems with toxicology, then go to the FDA and get permission, maybe hopefully get into an initial clinical trial in 18 to 24 months from today. So that's if we have the resources we need. The problem is we need to raise those resources. That's been the challenge at this point.

Jenny: I totally understand. It's such a frustrating thing to try to have such a great idea and then feel like you're getting held up from getting it into the clinic where you want it to be treating patients. Our next caller, please go ahead with your question.

Caller: Thank you for taking my call. I am a Huntsman patient and actually was just released from the hospital a couple of weeks ago. I just endured my third stem cell transplant. I was diagnosed four years ago. It was brutal. My question is do you think that stem cell transplant may at some point become a thing of the past, that we might have better options that we just don't even have to think about this as part of our treatment plan?

Dr. Paul Shami: I mean that would certainly be the hope that at some point we would not be using brutal treatment. You're absolutely right. There's nothing gentle about a transplant. Just to give you kind of a parallel disease like chronic myeloid leukemia or CML. I mean if you went back maybe 15 years ago or a little bit longer than that, we used to try to transplant every CML patient if we could. I mean if the patient was young and healthy enough, that was the treatment to do. Nowadays we hardly ever do transplant on these patinets because over the past 15 years, such outstanding drugs have been developed for CML. I mean the dream obviously would be to have drugs like this for every single cancer that we could encounter. So we can only hope.

Caller: If you have to look into a crystal ball and give it some answer, would you have a date? For a year? How many years off do you think we are?

Dr. Paul Shami: Yeah. I wish I did. I have a very personal stake in myeloma. My own dad actually passed away because of myeloma. As I said, I wish we were there. Clearly the myeloma world has made huge strides over the past 15 years, thanks to a lot of these great investigators like Ken Anderson and all those investigators that have developed these drugs.

Caller: Okay. I just look forward to a future where I never have to think about transplant ever. So keep working hard for us.

Dr. Paul Shami: Thank you.

Caller: Thank you.

Jenny: Okay. Thank you so much. Dr. Shami, I think this is just a perfect example of when patients might want to step in and try to get involved as well because sometimes I think we hope somebody else is going to be funding different areas of research. We just hope that either the NIH is going to do it or private companies are going to do it. That's one of the reasons that we started the Myeloma Crowd and the Myeloma Crowd Research Initiative is because not all good ideas are getting funded. If we want a cure at a faster pace, patients themselves might decide that they can take it upon themselves and help do something about it. I know sometimes patients don't even know that they can do this but they can donate directly to different investigators or different labs within a hospital instead of just donating to the hospital generally. They can donate to a particular lab. So I guess I would just leave patients with that thought. Thank you so much for participating on the show today. I think what you're working on is very exciting and just a wonderful opportunity for patients to have a treatment that could work with existing drugs and could be quite effective with very low toxicity.

Dr. Paul Shami: Well, thank you for having me. I really appreciate the opportunity to be on the show. I think that you're doing great work with Myeloma Crowd. Advocacy is very, very important. As you mentioned, the limiting factor is not ideas it's resources. We're hopeful we'll get there.

Jenny: Yes. Absolutely. Well, we wish you the very best in continuing your great work, and hope that we can help you in some way.

Dr. Paul Shami: Thank you.

Jenny: Okay. Thank you so much and thank you for listening to Myeloma Crowd Radio. We know that patients can get involved to learn more about their own disease and even help accelerate a cure. We invite you to join us.

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