2 Episode results for "Predisposition Syndrome"

Episode 148: Akshay Sharma on gene therapy's setback, biotech's brashest VCs, & the FDA's future

The Readout Loud

35:42 min | 4 months ago

Episode 148: Akshay Sharma on gene therapy's setback, biotech's brashest VCs, & the FDA's future

"Welcome to this week's of the read out loud a weekly biotech podcast from stat. I'm meg terrell. I'm adam feuerstein and damian garden. it's thursday february eighteenth. And here's what we're gonna talk about this week. I will break down a significant setback for bluebird violence gene therapy program with some help from dr akshay sharma of saint jude children's research hospital then stat colleague. Kate sheridan joins us to discuss her. Deep dive into flagship pioneering the superlatively successful venture firm behind madonna. Just don't call it a venture firm finally once in store for the fda after a year that many say dented the goldstar regulators credibility. We discussed the prospects for the next commissioner. But first a word from our sponsor hi i'm angus mccauley from stat. I'm here with chris. Banco the ceo of connector a software company that power patient centric research. The newest version of the apple watch includes real advances in terms of collecting health. Data using fit for purpose sensors. Chris do you think it will help. Advance the overall use of wearables in clinical research. The apple watch will definitely impact clinical research. Perhaps most of all by helping participants feel comfortable taking the trial home with them. The days of awkward clunky looking sensors are over for research to truly benefit. It's critical for patients to feel comfortable incorporating these technologies into their everyday life. Today's tools blend right into their routines and they're not just willing but often excited to wear them for more information on connects visit connects a health dot com. That's k. o. N. e. s. a. health dot com earlier this week bluebird bio was forced to suspend clinical trials involving it's gene therapy for sickle cell disease after receiving reports that to patients treated with the one time medicine were diagnosed with cancer. These new cases follow an earlier cancer diagnosis in december. Two thousand eighteen and a refocusing attention on whether there's a causal link with bluebirds gene therapy while bluebird investigates there's rising concern that these cancer cases could have a broader impact across the gene therapy field. We're going to discuss some of the implications of that and one under appreciated aspect of gene therapy with an expert later on in the show but before we do adam. Can you tell us what we know. So far about any link between bluebirds gene therapy and these cases of cancer. Yeah you know. We don't have much definitive information right now. Because bluebird has only learned about the two new cancer cases and is still investigating them. But here's what we do know. So one person who received bluebirds gene therapy five years ago and again. This person received that gene therapy because he had sickle cell disease up but that patient was recently diagnosed with a form of leukemia. Now the second case involved a person who received bluebird therapy more recently but then rather quickly was diagnosed with mild as plastic syndrome or md s. And that's a cancer like disease. That could also progress to leukemia now. According to bloomberg there is no definitive evidence collected yet which points to its gene therapy as the cause of these cancers but at the same time the company can't disprove that link So now it's clinical. Trials have been suspended so maybe just step back for a moment and explain at least theoretically how gene therapy might cause cancer so let's step back even further and kind of go over what gene therapy is right. Gene therapy is a procedure in which a damaged disease causing gene is replaced with a healthy gene. That functioned normally now to do that. They use viruses. These viruses are engineered to be harmless. And they're used to deliver the healthy genetic material inpatients because viruses are very adept at infiltrating cells. Now however if that virus shuttles that genetic material into the wrong place. On a patient's chromosomes it could for instance switch on cancer causing gene or it could disable a gene that prevents cells from turning into cancer so the cancer risk associated with gene. Therapy is really small but still it's enough that companies put in place safety checks to make sure that these viruses don't miss the liver that genetic payload and still the these safeguards how are like. They're just not foolproof. So figuring out the root cause of these cancer cases we talked about is obviously deeply important. For bluebird in the short term but as mentioned earlier there are potential repercussions for the entire gene. Therapy field right. Yeah that's damian. So this bluebird gene therapy uses a particular type of viruses called a lengthy virus to deliver those healthy genes into patients. Now lentiviruses are particularly adept at integrating into the genome of target cells. Which makes them effective delivery vehicles for gene therapies that target cells that divide or turnover rapidly. So that's true with sickle cell disease for instance which involves red blood cells Now if these lundy viruses are found to carry an unacceptably high cancer risk you know. That's obviously a big problem. For bluebird but also for a host of the other companies that are developing gene. Therapies that utilize lenny viruses as delivery vehicles. So we should note that. It's entirely possible that these cases of cancer have nothing to do with the lenghty virus component of bluebirds gene therapy. And a rather stu random chance however it's also possible that the culprit is a decades old. Chemotherapy called butyl fan. That is used to prepare patients. For gene therapy. This is one of the more underappreciated in less discuss aspects of gene therapy so to help us understand what's going on with the situation. We're joined by dr shave. Sharma a bone marrow transplant expert at saint jude children's research hospital. Welcome to the podcast. Thank you so much damian and thank you for the opportunity to speak to all of you today. we'll maybe let's start with your thoughts on kind of the situation overall. When you saw the news what do you think might be going on. Here honestly was a shock to many in the community both providers what taking care of patients as well as the patients Off spectacle cell disease. Something that we all need to be aware of and should be obviously looking out for is that there may be multiple mechanisms which are involved are multiple risk factors which may be involved. I am aware that many in the field and lay public are definitely concerned that this could be related to lend viral vectors as we just talked about that is obviously a factor that is under investigation and a point of concern but lengthy viral vectors. Not unique to sickle cell gene therapy lengthy viral vectors off. Some kind have been used in over ma many hundred patients so far for multiple diseases. So that's one aspect that needs to be investigated but many people don't know that sickle cell disease by itself is a myeloid leukemia. predisposition syndrome. There was a study published a couple of years ago from california where they found that the risk of myeloid malignancies in patients with sickle cell disease was very high in fact it was almost four times higher than the general population and patients of had severe sickle cell disease. And then of course. There is the question of exposure to milo toxic agents such as butyl fan which was discovered to be the case in the previous patient that was described almost two years ago so i wanted to zoom in on the fan aspect in particular. I think people might be surprised to learn that. Chemotherapy is a necessary step in the gene therapy treatment process. These patients are seeking treatment for an inherited disease like sickle cell disease. They don't have cancer. So why are they. Getting chemotherapy damian. That's a very good question in fact that's something that i'm asked all the time. When i i meet with patients who are want to undergo either transplant gene therapy. You know people normally assume that. Chemotherapy is only used to treat cancer. But that's not absolutely true. We do use milo toxic. Our agents are drugs which are which stem cells in order to create space in the bone marrow so that then we can put new stem cells. Either from somebody else as happens in the case of aboard marrow transplant or genetically modified stem cells from the patients themselves. Back into their bone marrow. So right now. Chemotherapy is an essential part of just gene therapy. But all types of transplants that we are doing for inherited disorders of the hemorrhoids system. Not just tickled disease. But palestinia certain bone marrow failure syndromes immunodeficiencies et cetera. Is there an established link between the use of fan and an increase risk with so-called secondary cancers even even years later so we know from you know giving chemotherapy to patients Over the last several years that data is a data connection of some milo toxic agents and development of second cancers down the line what i mean by second cancer as most of the times. Obviously these chemotherapy agents have been used in patients who have had some type of cancer previously so these minor toxic agents not just beautiful fan but other milo toxic agents such as taiyo tampa mel philan- etc class of that we call alka liters. They are known to be associated with occurrence of cancer in these patients. Many years down the line and as far as the hamada boyd cancers are concerned myeloid neoplasms such as am l. and md are the most common occurrence. So when you sit down with your patients with sickle cell disease to discuss potentially curative. Jennifer therapy was the reaction to the need for yourself and bone marrow conditioning. To be honest with you. It is a challenge for many patients to grasp that because first of all. They're not prepared to are. They don't even know that they are going to receive chemotherapy in order to undergo gene therapy or transplant. There is very little information out there and quite frankly a lot of misinformation out there about transplant. Angie therapy man. How these treatments work and so i always tried to make sure that all my patients understand completely. What the risks are i. Try not to give them percentages. Because you know to say something like there's a twenty percent risk of x. y. and z. is is not appropriate in my opinion because when it happens to that patient for that patient twenty percent risk doesn't mean anything for them. It's one hundred percent or zero percent right. And so i tried to tell them what's common what's going to happen. What might happen. And what's unlikely to happen. And at the same time. I try to help them understand these rats and balanced them with the risks associated with their underlined sickle cell disease. Many patients who are choosing to undergo either transplant gene therapy. Currently they obviously have severe sickle cell disease to begin with so sickle cell. Disease is a pretty bad disease which reduces the life expectancy by almost half. But when i'm talking to a patient who is in their teenagers are early twenty s. It's very difficult for them to grasp that. And that's what i envision. And i tried to do in in multiple meetings when i'm discussing either. Gene therapy transplant for them. So that the on me look at the acute toxicity and the effects of chemotherapy. But also the long term picture of what might happen. If the choose not undergo transplantation especially if they already have a very severe sickle cell disease. So you've been following the efforts to develop safer drugs than than beautiful fan for bone marrow conditioning. How far along are these research programmes. And is there anything to your mind. The teams particularly promising. There are at least three agents which i believe are quite far advanced and their clinical or preclinical development. So one agent. That i have seen which seems to be quite promising. Are cd forty five. Antibodies which are labeled with the radioactive antigen There is a trial which has ongoing currently called the sierra trial which enrolls patients were aml an md s. It's restricted to adult patients right now. Who are unable to tolerate. Chemotherapy prior to transplant and in that trial the cd forty five labeled to radio. Iodine has bruin to be a much safer alternative and much effective alternative honestly compared to chemotherapy drugs which certain older patients are. Frankly unable to tolerate another agent which we have recently learned about as a secret antibody which has been used in patients with severe combined immunodeficiency. It's a naked antibody. Secret as an antigen which is present on hemorrhoids stem cells. It's been used in patients with in a clinical trial with patients with severe combined immunodeficiency out of stanford and the results honestly in those patients have been quite promising and those are pediatric patients. I must point. Magenta therapeutics has another drug that they are currently developing a which has the same secret antibody combined to a cytotoxic. There was data presented by dr john dimsdale at believe last year's ash conference where he showed in to monkeys. They use this antibody and it was able to completely deplete their Stem cells and then they were able to rescue that by giving them autologous. John modified stem cells. So you mentioned earlier that you know when you when you talk about these bone marrow conditioning processes you know both shelves and the side effects there you have to balance that with the fact that these patients have severe sickle cell disease and there's obviously risks associated with that. But i wonder if you look ahead to a point where maybe gene therapy for sickle. Cell disease is approved And does require bom conditioning with fan at least initially like how widespread of acceptance do you think you'll see this gene therapy in the sickle cell patient community. Yeah adam that's a very difficult question to answer. But i think we have to assume that exposure to fan. You know whether it is related as it pertains to developing second cancers or as it pertains to all these other side effects including infertility which is a major concern for patients undergoing curative therapies for sickle cell. Disease i think it does make a huge impact and it does in some way reduced acceptance of these knowledge curative therapies to only a few patients who are obviously seeing an impending mortality risk to them. Obviously every therapy has its on side effects but if it can sure that the side effects associated gene therapy and the conditioning that requires are obviously less than the side effects associated with the disease itself in the long term in the next twenty to forty years. I think that's what's it finally going to lead to a widespread acceptance of these gene therapies at least in the developed countries sharma. Thanks for joining us. Thank you so much and thank you for having me turn. Venture capitalists are some of our societies beth self mythology if you spend time run vs biotech or otherwise. You're likely to hear about how they live at the absolute bleeding edge of new ideas and about how they're exceptionally good at turning those ideas into large sums of money. There's perhaps no better example of this than flagship pioneering the cambridge massachusetts-based venture fund. That has made a comment. On its seat investment madonna. The firm is produced dazzling returns in recent years and by its own account. That's the result of simply thinking better and harder than other. Vc's one press release described. The company as unique disruptive unforeseen an unprecedented all in the same paragraph. But a clear explanation of flagship. Success can be found in the firm's culture which former employees say is hardly for the faint of heart stats kate. Sheridan reported out an excellent story. About how flagship actually works and she joins us today to talk about it kate. Welcome back to the podcast. Yeah thanks guys. So flagships claim basically is that it's unique among venture firms that invest in biotech. What did you learn in your reporting. Do they actually go about this business differently. The answer to that question is a little complicated. Yes and no. I think flagship is possibly unique. Among venture firms for filing patents. That is pretty unusual for a venture capital firm even biotech and their mindset. I think truly is actually a little bit different than than other. Venture capitalists a lot of folks. I spoke to at flagship. Certainly believe that as you say but also the the things. They learned the things that they find most valuable and important. It's not necessarily a therapeutic from the get go it's it's the idea itself Which i think is really interesting however some of the things. They do are very much similar to two other venture capital firms the way they spin out companies the way they fund their companies Is like what any venture capital firm would do their series as bc rounds. They also like many other kind of venture creation style firm support their companies by offering administrative functions. That are kind of housed within the firm itself so while flying should definitely has its unique points. It's not necessarily wholly unique. I suppose so much of the firm's culture and trademark bravado seems to start with new bar fan flagships. Ceo what's he like. And what role does he play in the organization like every firm of course flagship has a set of partners. And i don't want to minimize their contributions certainly not not in the slightest But based on my reporting New orleans the firms north star. You know he sets the tone. He guides and shapes the philosophy. Many people contribute to the culture. But it really does seem that. He plays a really fundamental role in in defining. What flagship is and does one of the things that that struck me reading. This is so much of the the flagship magic is not. Just you know the ideas as you mentioned and also the financial success. But it's very much one of branding and marketing. And you touch this in your story but this seems to come from a fan and be shared along the way or down the line i should say. Flagship is very invested in like the semantics and the descriptions of its work like. What did you learn in importing out when a source of mine told me that The quote that's that's included in the article about semantics and word choices being very very important to flagship and specifically are that just clicked immediately for me right. I think we've all seen the press releases for companies that described the work. They're doing in terms and this. This approach is very intentional. As flagship is told me repeatedly they take crazy ideas. that's what they do. That's their whole shtick. But i think it was really interesting to kind of see from people who who had a lot of experience with the firm that that's work from that it has come from From the top. So kate tell us a little bit about the process. That flagship uses to kind of find these modern as in the making a and and why there are so many whiteboards for sure so about the whiteboards. That's kind of what someone told me. They spend a lot of their time Doing and what they do with. Whiteboards is basically just kind of thank Think out loud on the whiteboards. There don't think necessarily about what kind of drug They might like to make but rather what kinds of concepts might fit together to make something that could be interesting and potentially useful lacob scientific experts and what flagship likes to hear from us. Experts is not. This idea is a great one but rather this idea is is crazy. It'll never work. It's a little bit out there. That's that's what they go for. And if all that sounds sounds good and if they can file broad patents They will consider building a company around it. They express these ideas in the form of what if statements eventually not. What if we could make a better jack inhibitor. But what if cells could talk to each other and then eventually if the if the partners like the idea They'll they'll put the money into it and they'll find some lab space for it and they'll start testing some of the basic ideas and run some of the basic experiments to support the idea. In that way at this point we start getting a little bit closer to adventure creation. Model that that folks industry will will know But that's that's the early stages anyway. The process sounds wacky and like it couldn't possibly work I guess in one sense you have to say. isn't it. good that people are thinking like this and people who have the resources to try. These things are thinking so differently rather than like what. If we could make a better jack inhibitor. I mean we do need better jack. Inhibitors presumably also. Those could serve a role. But it's kind of a different a different approach and we mentioned before that flagships been incredibly successful making money for its investors. So how much better is the firm doing than its peers. It's doing very very very well for itself. I wanna caveat everything. I'm about to say by saying that. My numbers are a little out of date. I'm planning on updating than later this year And also that these numbers will include The value liquid holdings in stocks for example and in companies. That aren't even public yet. So all that said Flagships performance has been really exceptional. The the data that i've been able to collect indicate that for one fund They've been able to create a nine x return. So one dollar into flagship in our two thousand and ten fund would create nine dollars as of the end of two thousand nineteen which is massive. It's really massive. Their forms overall. I found in in one of my reports is less consistent perhaps than some other firms who have been just machines and turning out Pretty good returns but not nynex returns But ever since flagship decided to go all in on venture creation their performance has been really really good that nine x is before the pandemic. that's before the pandemic i mean. Wow so sitting here in two thousand and twenty one flagship has made all of this money. And it's become something of a household name at least in our corner of the world but you know that's all taken place during a prolonged boom biotech in general. So how does flagship keep up this pace and you know. Do they have a plan to adapt if the broader market sours biotech. Yeah i mean. The rubber really meets the road for biotech venture capital firms. When peos happen and so far. It's been a very good time to be a biotech company. By showing people have been able to to put companies out in the market that don't have clinical data or even really the promise of clinical data. We saw that a little bit with somma. They haven't started clinical trials yet and both for for quite some time ultimately that that kind of data is going to be what makes flagship and its investors money so if people are demanding more evidence from companies that are that are going. Public than flagship is going to be stuck funding companies much later into the development process while still trying to maintain the kind of massive ownership stake that they typically have. But let's add. Flagship is a firm. That i think really prides itself on being able to evolve They are doing some new new things. some of which. I don't think i fully understand yet. But i'm looking forward to seeing how they play out. I'm thinking right now about Pioneering medicines which again is a new initiative. That i'm still trying to fully understand But potentially is is one way for them to to move away from being completely dependent on the performance of untested companies in the public markets. Okay thanks for joining us. Thank you this. Podcast focus on biotech and no federal agency is more important to this industry than the food and drug administration. Actually one could argue and we did on wednesday night in an impromptu conversation on the audio social networking app clubhouse and the national institutes of health is also up there. Given how much basic research it funds but francis collins is sticking around as an i h director so today we're going to focus on who president joe biden will pick to lead the fda so the race according to multiple meteo ports including from our own stack colleague. Nick clark comes down to fda veteran. Dr jenny woodcock versus johns hopkins. University's dr joshua scharfstein who is seen as less drug industry friendly and the lobbying is strong for both candidates Earlier this month eighty five. National groups ran a full page ad in the los angeles times. Supporting woodcock calling her a passionate advocate for patients and consumers an ally to patient advocacy groups and a fearless leader at the fda where she has served since nineteen eighty-four. She's currently the acting fda commissioner meanwhile a group of doctors and public health experts published an open letter in support of scharfstein saying he would strengthen the fda's gold standard as a regulator have gone on the attack in favor of scharfstein and against woodcock most notably perhaps his yale epidemiologists aids activists. Gregg gonsalves says who accused woodcock on twitter of being a little too close to the drug industry that regulates. But does it really down to just these two. And how important is biden's pick for who leads. Fda in the midst of this pandemic and after the agency's reputation took a beating capitulating to president. Donald trump on hydroxychloroquine and convalescent plasma. So guys. I wonder your thoughts adam. Is this pick more important than usual for the fda. Will i think for the reasons that you stated mega. It is really important. I think that we all have seen the credibility of the agency from a science perspective. Take a hit of the last four years where politics intruded into decision making processes the policy initiatives that the fda you know we we've had podcast episodes and segments about this so from that perspective bringing in somebody who can help restore the the image of the fda the credibility of the fda within the scientific community within the general public. I think is is really important. I wonder also damian. I mean what do you think the job of this new commissioner is going to be and how is it similar or different to what we heard from helen branch while last week for rachelle valenki the new. Cdc director and needing to potentially boost morale at the agency or is the sort of external public. Trust even more important for fda. I think that's interesting. I think both of those things are probably top of mind for the people looking to pick someone which is to say that you know. Is that a mention. The fda has been bruised This past year in the public eye but that is also undoubtedly had an effect on the internal politics of the agency. And then you know maybe most importantly their ability to retain talent which we know is just a longtime struggle at fda which employs people who quite often can make more money at the company's regulated by the fda but then you have also the public perception aspect which which has not gone. Well i think by all accounts in twenty twenty related to near the relations with trump. but also you know a few other things. I mean even even dating back to the opioid crisis and some of the Issues around vaping that predate fda commissioner. So i guess you know the next person. Whoever it ends up being will have to kind of fight that battle on both fronts to reassure the people within the agencies such that they stay around and stay committed to the mission but also to reassure the united states at large that as you mentioned this sort of gold star regulator is how it's longman perceived is still an education and important institution so meghan. We're one month. Roughly one month into the biden administration in. We're having this discussion about who the next. Fda commissioner will be. Do we feel like you know. Do we wonder why the decision or why naming that person is taking this long or you know. Is this kind of standard practice. Actually looking back at the history. I have to credit damien with actually doing this research. And telling us about it you previous. Fda commissioners often were not named until april or may or nominated. It is a position that needs to go through. Senate confirmation. So it's more complicated than naming the cdc director. But as we've been talking about we're in a pandemic where the fda so important we're about to see the next Review of covid covid nineteen vaccine next week. Jj vaccine has its advisory committee meeting on friday. The twenty sixth so the fda is playing this integral role in it just for vaccines It's for tests. it's for You know drugs. I mean it's a lot of things for the pandemic and then of course everything else that it does And so yeah would think you would have heard a little bit more of a concrete discussion around who it might be. And and of course we've been hearing about these two different candidates but there's a lot of suggestions that might actually not be down to these Only two candidates yeah. i think. What's maybe more unusual is that we just haven't heard other names floated out there. We've heard these two names right woodcock scharfstein and it's pretty consistent and you would think that maybe that other names could floated out there. You get into the press. And i'm not like totally plugged into the whole. Dc thing but even like the really most plugged in dc reporters haven't been writing. Stories speculating on other potential. Fda commissioner nominees. And i think that's sort of unusual. I mentioned two names. That i have heard. Not as from a from a well-placed source in terms of saying they are actually under consideration. But from somebody who has advocated on behalf of cancer patients Sending why not. Rick pastor who of course has been leading the cancer unit add fda forever and why not amy abernethy who is a more newcomer to leadership at the fda. You know who we know for her work at flat iron and who has done a lot with real world evidence and a big data And who could bring a different kind of perspective as commissioner in that way. I think it's interesting. Thinking about rick. Pastor amy abernathy and some by extension janet woodcock versus joshua scharfstein in that the differences between them are not partisan than like i. I'm not sure that there's a discrete democrat or republican way to run the fda but they're definitely ideological and so when you hear things about like good advocate for patients Or flexible regulator or open minded or at cetera. That's often put in contrast to someone like scharfstein which is maybe a little bit unfair to him. I don't think he's close-minded minded per se but like the traditional idea of the regulator who who keeps industry in line in in the idea of protecting the safety of the american public and i wonder sometimes that push and pull gets a little bit can be a little bit reductive. We frame the fda so often in the context of new medicines. I think there's probably a large contingent of people within the fda within the health community in general who look at scharf. See not as a hardliner on the drug industry but as a person with an admirable record in public health and that includes tobacco and regulating food and all the other things that the fda does. So it'll be interesting to see how those constituencies kind of line up as this conversation goes on because it's it's an agency that does much more than just review drugs. And i guess maybe. I'll put potentially last question to you since you've been covering this industry the longest Janet woodcock has been an fda since nineteen eighty-four and in your real leadership roles at least since one thousand nine hundred four You kind of can't be at an agency like that for that long. Without some bad things happening And a lot of those are kind of late at her feet You know they're the letter supporting scharfstein mentions For the fda bad decisions it's around opioids hydroxychloroquine obviously during this pandemic viaducts and attempt larssen. Of course the drug for duchenne muscular dystrophy. We've talked a lot about on this podcast. Which just seems like a clear shot to against woodcock given. She was so into role in that decision. I wonder your thoughts on having covered this industry so long. How much of that can sort of be said is is tied to janet woodcock decisions. And how much is you know the agency as a whole and she was there that it strikes me about gentlemen because i think that she is very much a person who has Tried to advance the fda. And i think she's she thinks about the fda the legacy of the fda what the fda can do when she's making some of these controversial decisions. And i think like the templars indecision for instance was probably one in which you know. She was thinking they're about you. Know what impact. That decision would have on the fda. Let's say for instance if they had rejected templeton And it was later found out to be ineffective drug because essentially what you have done is denying a medicine for for dying children and that that can cause a lot of blowback on the fda so for her. It was a better decision to approve the drug. Even if the evidence supporting that drug was i you know the let's call it iffy or controversial You know on the same side you know. She's also somebody who has probably more than anyone else tried to bring the patient perspective into the fda and make sure that sort of realized that they're not reviewing drugs making the decisions in a vacuum. That patients are very much at the center of everything that the fda does on the drug side so with all of that said we should note that for all we know. It may not even come down to these two potential candidates and furthermore there may not be that much of a sense of immediacy within the white house. Because you mentioned earlier. Janet woodcock is currently acting commissioner and is obviously qualified for that role. She's qualified to be the actual commissioner. So we may have just spent a lot of time dancing around at issue that pederson super pertinent so before we go the first two episodes of stats new podcast. First opinion launched this week. Host pat skirt sits down with emergency room. Physician j barrack and health equity specialist. Lauren powell listen to first opinion on apple podcasts. Deter where ever. You get your podcast. Thank you to theresa. Gaffney for producing. This week's episode of our senior producers highland benito analysts ambrose and our executive producer is rick burke and is always. We'd love to hear from you. Tell us what you like about this week's episode. What you didn't like and who you think should lead the fda you can do all of that by sending us an email at read out loud at stat news dot com and if you like what we do leave a review or a rating on apple podcasts. Or whichever platform. He used to get your podcasts. See next week

sickle cell disease cancer fda bluebird damian meg terrell adam feuerstein damian garden dr akshay sharma saint jude children's research Kate sheridan angus mccauley bluebird bio plastic syndrome leukemia dr shave saint jude children's research predisposition syndrome scharfstein myeloid malignancies
NEJM This Week  May 9, 2019

NEJM This Week - Audio Summaries

30:38 min | 2 years ago

NEJM This Week May 9, 2019

"Welcome. This is the New England Journal of medicine. I'm Dr Michael bearer this week may ninth two thousand nineteen we feature articles on from the license for stroke up to nine hours after onset. Transmission of the Nipah virus in Bangladesh. Progesterone in women with bleeding in early pregnancy, a tight or reversal agent Mozelle, KOMO hammer Toma of the liver and Deisler one syndrome and inflammatory remarks about cardiovascular disease, a review article on chronic kidney disease in agricultural communities. A case report of a man with neck pain, and swelling and perspective articles on the current opioid crisis. And the Sackler legacy on stopping the gaps in epidemic preparedness on physician participation in lethal injection and on the meaning of the baseline mindset. A new video in clinical medicine demonstrates, elliptical excision of the skin this procedure can be used in the diagnosis and management of skin and subcutaneous lesions may be performed with minimal risk in most patients, and may avert the need for other more invasive procedures visit any jam dot org to view this video. Thrombosis guided by perfusion imaging up to nine hours after onset of stroke by Henry Ma from the university of Melbourne Park Ville, Victoria, Australia. The time to initiate intravenous thrombosis for acute ischemic stroke is generally limited to within four and a half hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have a schemic, but not yet infarct brain tissue on imaging in the extend trial patients with schemic stroke and salvageable brain tissue were randomly assigned to receive intravenous of place or placebo between four and a half and nine hours after the onset of stroke or an awakening with stroke if within nine hours from the mid point of sleep after two hundred twenty five of the planned. Three hundred ten patients had been enrolled, the trial was terminated because of a loss of equa poise after the publication of positive results from previous trial, the primary outcome of a score of zero or one on the modified Rankin scale at ninety days indicating no or minimal deficits respectively occurred in thirty five point four percent of patients in the outta place group and in twenty nine point five percent of patients in the placebo group symptomatic interests rebe real hemorrhage occurred in six point two percent of patients in the Aalto place group and in zero point nine percent in the placebo group. Among these patients who had schemic stroke and salvageable brain tissue, the use of Aalto place between four and a half and nine hours after stroke onset, or at the time, the patient awoke with stroke symptoms resulted in a higher percentage of patients with no. No or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the outta place group Randolph Marshall from Columbia University. New York writes in an editorial that the era of time based treatment with intravenous outta place in patients with acute stroke may finally be drawing to a close the battle. Cry of time is brain has reigned unopposed until now, although the study was terminated after only two thirds of the intended population were enrolled, the likelihood of a good outcome. A score of zero or one on the modified Rankin scale at ninety days was forty four percent higher in the outta place group than in the placebo group. This trial represents a major successful step in using an image guided approach to extend the seemingly immutable time. Limit for pharmacologic. Rumble ISIS in patients with acute stroke. The trial will need to be validated. It was stopped early. Going to the publication of results of another clinical trial, which was not truly a quivalent to the extent trial because it targeted patients who were likely to be eligible for thrombosis at the standard times and did not use pin number based image guidance further randomized clinical trials that compare intravenous thrombosis with Rahm beca me in the late time window among patients selected on the basis of pin. Number based imaging are warranted alternative from Belichick agents, such as connective place are also being tested despite the work to be done. The extent trial shattered an important barrier to the treatment of acute stroke. Transmission of Nipah virus fourteen years of investigations in Bangladesh by beer, get Nicolay from the attitude. Pesto Paris Nipah virus is a highly virulent ZOA nodding pathogen that can be transmitted between humans using data from all Nipah virus cases identified during outbreak investigations in Bangladesh from April two thousand one to two thousand fourteen this study investigated case patient characteristics associated with onward transmission and factors associated with the risk of infection. Among patient contacts of two hundred forty eight Nipah virus cases identified eighty two were caused by person to person transmission corresponding to a reproduction number that is the average number of secondary cases per case patient of zero point three three the predicted reproduction number increased with the case patients. Age and was highest among patients forty five years of age or older who had difficulty breathing case patients who did not have difficulty breathing infected zero point zero five times as many contacts as other case patients did Sierra logic testing of one thousand eight hundred sixty three as symptomatic contacts revealed no infections spouses of case patients were more often infected fourteen percent of fifty-six than other close family members. One point three percent of five hundred forty seven or other contacts zero point nine percent of one thousand nine hundred ninety six the risk of infection increased with increased duration of exposure of the contacts and with exposure to body fluids, increasing age and respiratory symptoms. Were indicators of infectivity of Nipah virus interventions to control person to person. Transmission should aim to reduce exposure to body fluids? Stopping the gaps in epidemic. Preparedness a perspective article by Jeremy Farrar from the Wellcome Trust London. I isolated in Malaysia in nineteen ninety nine Nipah virus rapidly went from unknown to endemic in Bangladesh, which has seen an outbreak almost every year since two thousand one large gaps remain in our understanding, however such as how the virus crossed India to spark in EPA democ in Kerala on the country's southwestern coast in two thousand eighteen several life threatening viruses have been identified for the first time in the twenty first century, the World Health Organization in conjunction with global experts has drawn up a list of nine known infectious diseases and one unknown disease x in a blueprint for research and development. These infections have the potential to cause public health emergencies, and we lack the. Tools to diagnose treat or prevent them. The world is therefore particularly vulnerable to these infections. And yet they've been neglected in research and development. The list is not exhaustive and many infections. Pose a major threat new patterns of viral emergence and spread are being driven by ecological and Sociologic changes such as climate change migration of vector species to new areas changing interactions between people and animals, increasing connectivity between communities more and faster. Travel urban is Asian and political, instability and conflict our preparations for EPA makes must keep pace with such changes. A randomized trial of progesterone in women with bleeding in early pregnancy by Ari kumarisami from the university of Birmingham in the United Kingdom bleeding in early pregnancy. Is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy in this trial, four thousand one hundred fifty three women at forty eight hospitals in the United Kingdom were randomly assigned to receive vaginal suppositories containing either. Four hundred milligrams of progesterone or matching placebo twice daily from the time at which they presented with bleeding through sixteen weeks of just station, the incidence of live birth after at least thirty four weeks of Jeff station was seventy five percent in the progesterone group and seventy two percent in the placebo group the sensitivity analysis in which missing primary outcome. Data were imputed resulted in a similar finding the incidence of adverse events did not differ significantly between the groups among women with bleeding in early pregnancy. Progesterone therapy administered during the first trimester did not result in a significantly higher. Incidence of live births than placebo in an editorial Michael Green from Massachusetts General Hospital. Boston writes that threatened abortion is defined as bleeding through the vagina with a closed cervix that occurs before the age at which a fetus would be viable ex utero. The estimate of the percentage of threatened abortions that progress to pregnancy loss has varied from ten percent to twenty percent or more. Thus most women who have bleeding in early pregnancy. Do not lose their pregnancies. But of course, there is justifiable interest in identifying a treatment that can improve the chance of the birth of a live born healthy baby among pregnancies at substantial risk of loss. Much of our modern understanding of the endocrine illogic features of pregnancy can be. Traced to the nineteen thirties when it was recognized that an anterior pituitary like hormone human, Corey onic Genotropin rose rapidly after implantation of the consensus, and then fell while estrin and pregnant dial levels rose rapidly for the remainder of pregnancy by nineteen forty. It was also recognized that an initial rise in these hormones followed by a premature fall was associated with spontaneous abortion, regardless of whether the pregnancy was recognized in retrospect, it is likely that the initial rationale for hormonal therapy. That is the observed fall in pregnancy hormone levels before pregnancy loss was in fact, a consequence rather than a cause of pregnancy failure the subsequent enthusiasm for hormonal therapy was driven by overestimation of the incidence of pregnancy loss in the absence of therapy. And by reports of seeming success in uncontrolled case series, the current trial of treatment for threatened abortion provides much needed information regarding both the true risk of pregnancy loss in the absence of treatment and the small statistically insignificant difference in the incidence of live births between treatment and expectant management in a contemporary context. Antibody based Tyke Cabral or reversal agent in healthy volunteers by Deepak Bhatt from Brigham and women's hospital heart and vascular center, Boston Taikang, galore is an oral p two y twelve inhibitor that is used with aspirin to reduce the risk of schemic events among patients with acute coronary syndromes or previous myocardial infarction spontaneous major bleeding and bleeding associated with urgent invasive procedures are concerns with Tigres Laura as with other anti platelet drugs. The anti platelet effects of taika gore. Cannot be reversed with platelet transfusion, a rapid acting reversal agent would be useful this phase one trial evaluated intravenous PB to four five to a monoclonal antibody fragment that binds taika gore with high affinity as a Cabral or reversal agent in sixty four healthy volunteers after. Forty eight hours of Tikal or pre-treatment platelet aggregation was suppressed by approximately eighty percent PB two four five two administered. As an initial intravenous bolles followed by a prolonged infusion. Eight twelve or sixteen hours was associated with a significantly greater increase in platelet function than placebo as measured by multiple as-as taika gore reversal occurred within five minutes after the initiation of PB to four five two and was sustained for more than twenty hours. There was no evidence of a rebound in platelet activity after drug sensation adverse events related to the trial. Drug were limited mainly to issues involving the infusion site in healthy volunteers, the administration of PB to four five to a specific reversal agent for Takagi lower provided immediate and sustained reversal of the anti platelet effects of tycoon. Floor as measured by multiple essays. Ms ankle moham- are Toma of the liver and Deisler one syndrome by Maria up Alana's res from the Jewish General Hospital. Montreal MS Anka moham- are Toma of the liver NHL with a reported incidence of zero point seven cases per million population per year accounts for approximately ten percent of liver tumors in persons younger than twenty one years of age, and is the second most common benign liver tumor in children after he mentio- mo- children with M H L may present with an enlarging painless abdominal mass the tumor is characterized by primitive mic sword. Stromer with cystic -ly dilated bile. Ducts alterations involving chromosome nineteen q. One three are a recurrent underlying cause of 'em H. L? These alterations activate the chromosome nineteen micro Aren a cluster. Other cases remain unexplained. These authors described to children with M H ELS that harbored germline Deisler one pathogenic variance analysis of tumor tissue from one of the children revealed to Deisler one hits mutations in Deisler. One dysregulates micro are as mimicking the effect of the activation of the chromosome nineteen micro are in a cluster. These data suggest that M H L is a new pheno type of Deisler one syndrome. Deisler one syndrome is a tumor predisposition syndrome that features several disadvantage Unedic cystic conditions in young children, most notably plural. Pulmonary blast Oma and cystic Neff froma. Chronic kidney disease of unknown cause in agricultural communities. A review article by Richard Johnson from the university of Colorado Anschutz medical campus Aurora in recent years numerous cases of chronic kidney disease have emerged among agricultural workers as well as among others performing manual labor in various regions of the world, for example, during the nineteen nineties clinicians in Central America noted that a large number of young sugar. Cane workers were presenting with end stage kidney disease and early report on an upsurge in chronic kidney disease in Central America came from El Salvador in two thousand two one striking finding was that the patients once evaluated did not have any of the conditions known to cause end stage kidney disease, spates of disease have also been identified in Sri Lanka, India and other hot reach. Regions of the world. This review describes the clinical presentation and epidemiology of chronic kidney disease, that is endemic in this workforce in these areas as well as possible causes the disease does not appear to be due to the classic causes of kidney disease such as diabetes, hypertension and glimmer healer disease. Those affected are usually men who have worked for two or more seasons are between twenty and fifty years old are ACM dramatic and have normal or only slightly elevated blood pressure and normal blood glucose levels, the disease is strongly associated with working and living in a hot environment. But whether the cause is a toxin and infectious agent a heat associated injury or a combination of factors is not yet known a forty four year old man with neck pain and swelling a case record of the Massachusetts General Hospital by Phillips sale. Taylor and colleagues a forty four year old man who's admitted to the hospital because of pain and swelling on the left side of the neck twelve weeks. Earlier the patient had undergone uncomplicated placement of an implantable cardio vertu defibrillator through the left symbolic vein. Five weeks after implantation the patient awoke with a headache and neck pain on the left side when numbness and tingling developed in the left fingertips along with shooting pains in the left arm and Toews he presented to the hospital C T and geography of the chest and abdomen revealed a partially visible mass in the left superclub akilah region. Ultrasonography of the neck revealed a complex mass measuring four point three centimetres in diameter. These findings were thought to be most consistent with a hematoma. Needle aspiration of the mass revealed five milliliters of thin Brown fluid that was suggestive of old blood three weeks after discharge the patient. Return to the emergency department for recurrent, swelling and pain in the neck ultrasonography, again revealed a heterogeneous Hypo a Kohic lesion needle aspiration was again performed and revealed one point five milliliters of thick red fluid that appear to be consistent with blood when the patient presented for the third time with the same concern. It was clear that the differential diagnosis needed to be broadened to counter possible. Heuristic errors a biopsy of the mass was performed biopsy results were most compatible with metastatic post puberty, immature territory with maturation of Mizan. Komo components. The link between Hamadeh polices and atherosclerosis a clinical implications of basic research article by Menno de vinter from the Amsterdam university medical centers, the Netherlands, the decrease in the incidence of cardiovascular disease, and the improved prognosis in persons with a diagnosis of cardiovascular disease are due in part to the development of new treatments based on a cruel of knowledge about disease mechanisms more specifically the introduction of lipid lowering therapy such as statins and PCS k nine inhibitors as well. As changes in lifestyle have reduced the risk of cardiovascular disease by an impressive twenty five to thirty percent since the nineteen sixties and nineteen seventies. However, cardiovascular disease remains a major cause of disability and death in the western world and new strategies to lower the large residual risk of cardiovascular disease are needed. There is mounting evidence. That atherosclerosis is driven. Not just by dislike -demia, but also by inflammation clinical evidence. Supporting this link includes the results of the Cana Kenya. Mab anti-inflammatory thrombosis outcomes study Cantos, which showed that targeting inflammation, improved cardiovascular outcomes. A recent study provides a molecular explanation on the basis of their studies of zebra, fish and mouse models the authors described a mechanism link between cholesterol, metabolism and inflammation, the findings revealed that pathways of tomato. Polices and cholesterol, metabolism are closely linked and control each other. Preying on prescribers and their patients pharmaceutical marketing, I- Atra, genyk, epidemics, and the Sackler legacy a perspective article by Scott Podolsky from Harvard Medical School Boston in two thousand eighteen Massachusetts joined more than two dozen other states in suing Perdue pharma, the makers of Oxycontin for the harm. They inflicted in our state by helping to drive the current opioid crisis drawing particular attention to the actions of the family that controls the company, the Sackler lers the case against Purdue has been framed in terms of unconscionable corporate and individual profit at the expense of the public's health, chiefly through the manipulation of prescribing practices and of the approach to pain recommended in clinical journals, medical curricula and professional guidelines as a Boston Globe writer, mused physicians are persuaded by Mark. Getting just like everybody else. Now, there's a discomfiting thought discomfiting as the thought may be it is not new marketings role in physician education has long been evident to pharmaceutical companies journal editors and therapeutic reformers alike, and though the Sackler family did not invent the practice of selling drugs to physicians. They were pioneers who story illustrates the ways marketers developed naturalized and monetize the interface between the pharmaceutical industry and prescribing physicians under Sackler guidance Pfizer increased, its drug Salesforce from eight detail men in nineteen fifty two two thousand by nineteen fifty seven including at one point seventy medical students. Internal memos revealed that the marketing campaigns for Tara Meyson and soon tetris in tetracycline were conducted like. Military campaigns and described in the language of combat the prey described in an internal Pfizer sales document from nineteen fifty four entitled easy prey for Tara Meyson referred not to the microbes Tara Meyson killed, but the prescribing physicians whose behavior could easily be swayed by marketing tactics. Physician participation in lethal injection a perspective article by Deborah Denno from Fordham University School of law New York on April first, the US supreme court rejected a Missouri death row inmates. Claim that executing him using the state's lethal injection protocol would violate the eighth amendment's ban on cruel and unusual punishment because blood-filled Schumer's in his head neck and throat could rupture and cause him to choke and suffer. Excruciating and prolonged pain many commentators found the five to four decision in Buccleugh V precise shocking. A stunning rebuke of eighth amendment precedent that shows divisions in the court over the use of the death penalty. Although it's difficult to predict the extent of Buckley's constitutional footprint, the opinions unusual facts and circumstances throw into sharp relief, the pervasive. Nece of physician participation in lethal injection, despite the medical communities professed condemnation of such involvement the role of doctors in all forms of execution during the past century has been thoroughly documented and in Buccleugh the court confronted a case regarding execution methods that was built almost entirely on medical input. Michael Buckley, who has congenital cavernous human Joma, the need for physician involvement in this case was clear from the start given that Buckley's challenge to the lethal injection protocol was based on a medical diagnosis yet. Buck Lou also reveals to an unprecedented degree the extent and complexity of the medical community's role in guiding and carrying out executions at baseline up perspective article by Paul burgle from the Medical College of Wisconsin, Milwaukee. This is Mr. L the resident begins yesterday, he underwent tracheostomy revision. But he developed post operative respiratory failure. He needed the ventilator overnight, but we liberated him this morning long story short he can transfer to the floor. He's back to baseline this final word reverberates in Dr Burgos mind, transmogrify ING from two innocuous syllables into an unshakable conceptual beast baseline noun won a pre existing condition requiring no further explanation a prima facial diagnosis irrelevant to immediate therapeutic goals a curiosity killer. Wait, why is it his baseline Dr Bourboule asks the resident misinterprets or cleverly sidesteps the question. He's usually on four leaders of oxygen at home. I meant why should he need a tracheostomy at all? I don't know obesity hyperventilation syndrome. He. He's had it for years, the resident eagerly divests himself of this alleged learning opportunity as the other overwork trainees grow restless, the question for many impatient. Internal medicine teams is not weather, but to what extent we should juggle treatment of patients acute health problems with care for their coexisting, chronic conditions, increasingly impatient, internal medicine teams, focus exclusively on a patient's immediate crisis leaving the rest for ambulatory care. But by adopting a baseline mindset, we are creating physicians who prioritize throughput over critical appraisal, skills and inquisitiveness. Our images in clinical medicine features. A fifty nine year old woman who presented to the emergency department with a four day history of inflammation and pain in the right eye. She had been blind in the eye for several years before presentation, the physical examination showed prop toasts of the right eye with Perry, orbital inflammation, afoul, mo- plea and to write relative Afrin pupil defect. M R I revealed. A right orbital mass measuring two point eight by two point five by two point three centimeters with intraocular and extra ocular components. Abdominal anthrax imaging showed numerous hypnotic masses. Abdominal anthrax lymphatic apathy and vertebral sclerotic Ossius disease findings that were consistent with widely metastatic disease. The right. I was in nucleated for palliative relief and to obtain tissue for diagnosis. Immuno history. Chemical evaluation supported the diagnosis of UV melanoma, the patient was treated with Bolivia MAB and Nevada MAB, but she died from progressive disease. Two months after presentation a sixty six year old man presented to the emergency department with a two month history of abdominal bloating and worsening constipation. His medical history was notable for untreated, hypertension, and hyperloop -demia. He'd been an active smoker for more than twenty years and his father had died. Suddenly at sixty two years of age from an unknown cause. The patient's blood pressure was one hundred sixty two over eighty three millimeters of mercury and the physical examination revealed. A painless pulsa total abdominal mass see the video at any J M dot org. The federal pulses were palpable on both sides CT and geography revealed a large fused form in for renewal. A Arctic aneurysm measuring eleven by ten. One point five by fourteen centimeters the patient underwent surgery during which the aneurysm was exposed and replaced with an a auto by ilyaronoff graft. He also began medical treatment for hypertension, and hyper LIPA -demia at a six month. Follow up. Visit the patient had no pulse. Atoll abdominal mass had good perfusion to his legs and felt well this concludes our summary. Let us know what you think about our audio summaries, and he comments or suggestions may be sent to audio and any J M dot org. Thank you for listening.

Progesterone early pregnancy kidney disease Bangladesh Sackler abdominal mass neck pain hypertension ischemic stroke inflammation New York Massachusetts General Hospital New England Journal of medicin threatened abortion Dr Michael bearer India Aalto taika gore Tara Meyson