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Infectious Diseases

Tone It Down!

I’ve had a number of people ask me about the news stories the last few days which keep saying that there’s a a “cure for HIV” coming. This all goes back to a Maryland company, American Gene Technologies, and a gene therapy they’re working on called AGT-103T. This is an attempt to use a lentiviral-based gene therapy to produce patient-derived CD4 helper T cells that will allow the immune system to recognize and eliminate HIV, while themselves remaining (in theory) immune to infection (through modification of CCR5 and CXCR4). That retroviral attack on this T-cell population is, of course, a hallmark of HIV itself and a fundamental reason the disease is so serious.

None of this is unreasonable; this seems to be a perfectly valid approach to HIV treatment, and I wish AGT good luck in the clinic. But throwing around the word “cure”, before you have treated a single human patient, is flat-out irresponsible. That’s right; this is all publicity for the filing of an IND (the approval needed to begin human trials). And AGT seems to enjoy this approach – here’s the boilerplate language at the bottom of their press release:

American Gene Technologies (AGT) is a gene and cell therapy company with a proprietary gene-delivery platform for rapid development of cell and gene therapies to cure infectious diseases, cancers, and inherited disorders. The Company’s mission is to transform people’s lives through genetic medicines that rid the body of disease. The Company expects to take its patented lead candidate for an HIV cure into the clinic in 2019.

There are a lot of things that can go wrong with gene therapy, and there are a lot of things that we don’t yet understand about its applications. AGT knows this; anyone who works in the field knows this. And that’s why I say that using “cure” for what are actually just interesting ideas in preclinical development is just not right. There are a lot of very sick people out there; AGT and the rest of the biopharma industry are trying to find new medicines to help them. But no one is well served by setting off “Single-dose cure!” headlines before a treatment has gone into a single human being. To AGT’s management and press office, this message: raising hopes like that is not some sort of PR coup – it’s cruelty. You have no idea if you have a cure yet, and you know it. That gets proved in the clinic, and you haven’t even received approval to dose anyone in Phase I, much less anyone who actually has HIV.

It’s a bad look for you, and it’s a bad look for the industry. Sure, we should tell people what we’re trying to accomplish. But that needs to be tempered with the reality of our clinical failure rates. We get humbled all the time in this business; the record is there for anyone to see. So perhaps a little preliminary humility is in order? You can always set off the fireworks after you get some actual results.

37 comments on “Tone It Down!”

  1. Concerned Chemist says:

    Should there be some sort of accountability for this? Important people across industries eat this stuff up and spread it like wildfire, how does it stop?

  2. Ed says:

    Funnily enough, I was just at a research conference for the sort of rare, devastating, genetic disorder where gene therapy is probably best shot at an effective treatment. Nobody used the “C” word – not even the biotech companies running gene therapy trials. The preclinical researchers and physicians were even more explicit that today’s best gene therapies were not going to be a true cure, even if they are dramatically effective.

    To take zolgensma as a specific example (AAV9 SMN1 vector for spinal muscular atrophy), most (but not all!) patients were stabilized over the 24 month trial. This is for a disease where affected infants are expected to be essentially immobile and respirator dependent by the end of the trial, so this is certainly an amazing improvement.

    However, what’s going to happen to them in 10, 20, or 50 years? Nobody knows. Given that some patients didn’t completely respond in the trial, there will probably be a few more that will have some disease progression over the next several years. And there will probably be some subtle pathologies that are revealed only in old age – what’s the SMN1 loss of function phenotype for a 60-year old cardiomyocyte or peripheral neuron that wasn’t successfully transduced by the AAV9 vector? Again, nobody knows. Gene therapy, today, isn’t likely to be a 100% cure. Maybe it will be in the future but we won’t know for sure until the treated patients die of old age after a long, healthy life.

  3. petros says:

    Gene therapy has been an area of intense hype for many years. I attended a Cystic Fibrosis Foundation conference some 25 years ago where it was stated that gene therapy for CF would be available in less than 5 years. 25 years on while some progress has been achieved it has still not been possible to identify a suitable delivery system to provide a commercial gene therapy

    1. John Wayne says:

      Spot on. Delivering a polyanionic polymer to cells safely is a challenging task with a limited toolbox. This has put a ceiling on potential impact of gene therapy and siRNA therapy in the clinic. Don’t tell the hype train, but it will do the same to CRISPR as well.

      It is kind of an exciting problem. If you can move the needle on delivery it could enable multiple technologies to make a difference in human health.

  4. Troy Boy says:

    I’m less concerned about this type of hype. I think the public largely knows that this type of language is largely aspirational. No one starts out their phase I clinical trial saying, “We hope that we see a 3 month survival benefit for 25% of patients with advanced cancer X–that is, if it ever makes it to the market.”

    Everyone wants to feel like they have a chance at defeating their disease. To not give patients hope is also a form of cruelty. You’re in effect saying, “Go home, wallow in your disease and die because the odds are stacked against you!” I know that only 10% of therapies that make it to Phase I clinical studies are eventually approved and make it to market. But this might be the one out of 10! One way to guarantee failure is to never try.

    But I think you also need to consider the past successes of drug discovery that we’ve had–and that’s particularly apropos to HIV. Do you think that before the first Phase I clinical trials with HIV protease inhibitors that the researchers didn’t have the goal of an HIV cure in mind? What about combination therapies? Research and technology have relegated an HIV diagnosis from a death sentence to a manageable chronic disease. Stop to think about that!

    So now the company is trying to rid the body of the HIV virus–which would be in effect a cure. I wish them luck! And I, for one, don’t want to quibble with the aspirational language they use to move forward.

    1. Hap says:

      I’m not so sure that people take the language as aspirational – VCs and investors don’t seem to make the assumption that the language is aspirational, and given their investment and professional status in the field it seems hard to then assume that nonprofessionals with an interest would make that assumption. Promising what you can’t deliver (or don’t know you can’t deliver) seems a whole lot less honest and harder on patients with a disease than not offering hope (and not offering hope when you don’t have it yet is not the same as precluding hope from others).

      Given that the cure language is primarily used by snake oil salespeople with no actual hope to offer (and too many customers for what they do offer), it also seems to put them in the wrong company if they are actually trying to provide a cure.

    2. Karl says:

      “I think the public largely knows that this type of language is largely aspirational.”

      I think not.

      I’m part of “the public”, albeit rather better informed than most, and I think it fair to say that most people will read the PR as meaning that they can expect to see scripts written for the cure in a few months, maybe a year at most; the delay being caused by Pharma and the guv’mint doing the regulatory two-step. I can pretty much guarantee that anyone not reasonably well-connected to the process is going to miss the implication of “expects to take … into the clinic”.

      This isn’t aspirational language. It’s lying, IMO.

    3. Magrinho says:

      It’s a false premise to state that, in effect, not lying will crush the hopes of patients.

      Read the press release again – it’s a lie. Full stop.

      Lying is bad – can we agree on that?

      1. Manuel Torres says:

        Last year I told my boy that if he trained hard for his junior triathlon he would most certainly win it. I knew he would never win it as he had never done one started training only 3 months before and he was up against boys and girls who were in clubs and had been training with their triathlon mad daddies for at least 6 months. He was beaming when he managed to beat most of those club kids and out of 300 kids came 38th. Now I most certainly lied there but was it bad? I most definitely think not. Hope is the basis of progress. And I for one do not mind people laying it on a bit for hope.

        1. Chris Phoenix says:

          I won’t say if it’s bad or not, but I would never have done it that way. I’d rather my kids learn to think rationally and accurately about the world and about how to set and achieve goals.

    4. Churlish says:

      I am also very skeptical that the public will approach claims like this with appropriate skepticism. Exhibit A has to be the near-universal uptake of dietary supplements with no evidence to support their “aspirational” claims, further worsened by their wildly unreliable drug composition (i.e. dose and presence of labeled compound, absence of adulterants). I’d also argue that the release of overenthusiastic press releases that sometimes accompany academic research has meaningfully contributed to the now-widespread perception that most drugs are primarily created with public research funding, which is both inaccurate and may pose an existential threat to the biopharma industry and drug development as it currently exists.

    5. loupgarous says:

      When I was in clinical trials for Lu-177 PRRT, no one used the word “cure”. The most “aspirational” the language got was “stabilizing the patient’s condition”, which it had done in the majority of cases (or FDA wouldn’t have granted NDA on it).

      I was good with the idea that I wasn’t being offered a definitive cure, but a chance at possible improvement in my condition, and regardless of the outcome, a chance to help hit back against neuroendocrine cancer by increasing the fund of knowledge about its treatment.

      Communicating with desperately ill people and their families about possible treatments ought to be part of every physician’s skill set. Holding out the magic word “cure” before IND approval ought to make reasonable people in the industry uneasy, just as Sarepta’s full-court press on eteplirsen after an ADCOM had ruled against approval, trotting out the genuinely desperate Duchenne’s sufferers and their families for more FDA hearings provoked its share of criticism.

      Physicians and drug developers are ethically obliged to be totally accurate in describing treatments to prospective patients and their families – and this is especially true in the case of new therapy for dread diseases like HIV infection.

    6. Manuel Torres says:

      I just watched a children’s movie of which the core message was: hope makes the impossible possible. It think that’s a beautiful message and one we should all listen to. As a HIV positive person I jubilate their hope and their positive languague and wish them good luck in their trials.

      1. loupgarous says:

        Hope sustains people in trouble. It did for me, when I was first diagnosed with a rare neuroendocrine cancer with limited options for treatment and unreliable diagnostic tools. It made me seek out clinical trials for my condition. No one offered me a cure. They offered me a chance at clinical improvement, and thankfully, I got it.

        Effort, knowledge and luck made what was impossible possible in my case. We all hope AGT-103T works in clinical trials and improves the lives of those infected with HIV. But we also hope American Gene Technologies describes what they do in realistic terms, and stops sending out press releases that inspire unrealistic hopes.

    7. JMocha says:

      I couldn’t have said it better!

  5. Wheels17 says:

    First off, I’m not in the business, only an interested observer. I have no connection to this company.

    Their statement may raise false hopes, but it really seems to me to be an honest statement. My understanding is that the protease inhibitors and combination therapies mentioned in the comments do not eliminate HIV from the body. They reduce the disease to a chronic, survivable state. But if the treatments are stopped, the disease progresses.

    This company is stating that they are working for a cure (elimination of the disease without ongoing treatment) rather than a new ongoing treatment program. They couch it in terms of “expect” and “candidate”. The probability that they will succeed is low, but it reads to me as an honest statement of intent, not a declaration of success.

    1. Thomas says:

      The chance of success for any drug specific development seems pretty low. “Expect” implies a high chance of success. One only “expects” to win the office lottery if one has tilted the odds – in general, the words “hope” or “could” are used.

    2. loupgarous says:

      Gene therapy in general has many hurdles to overcome before it can confidently be held out to patients as a cure for any disease:
      – it’s hard to modify patients’ genomes to incorporate therapeutic genes, and you have to repeat the treatment in most cases to treat the disease in question;
      – the immune system often treats the viruses used to deliver gene therapy as invaders, and the body reacts accordingly, with an immune response agains the viral vector;
      – viral vectors (viruses used to deliver gene therapy) don’t always deliver good genes to treat patients, and sometimes can make patients more ill than they were before treatment;
      – not all diseases which have a genetic cause will respond to gene therapy because they are also caused by things other than genetic defects, or by multiple such defects;
      – it’s possible, using a virus to carry a missing gene into a patient’s genome, to alter the patient’s germline – changing the patient’s testes to express the missing gene, which is forbidden in many countries;
      – genes intended to work in one (gene locus) part of the DNA may effect other gene loci. If this affects a tumor suppressor gene, the patient may get cancer (3 of 20 test subjects who got an experimental gene therapy for X-linked severe combined immunodeficiency came down with T-cell leukemia);
      – finally, some gene therapies which have been approved for use in humans are hideously expensive – such as Glybera, which costs $1,600,000/patient.

      Using the term “cure” for any gene therapy product without mentioning these drawbacks is irresponsible, at the very least.

    3. Skeptical says:

      Yes, if everything goes perfectly, this *might result in a cure for some patients.

      That fact doesn’t make their press release true.

  6. electroneutron says:

    Even if this jumps through all the various clinical rings of fire – do you think there is any chance the cost of manufacturing these therapies and resulting likely pricing will not be an impediment to adoption when he have pretty effective preventative therapies now?

    1. electroneutron says:

      Meant to also say therapeutic antiretrovirals too for unprevented cases.

    2. loupgarous says:

      Whether this treatment (assuming it passes clinical trials) will be worth the expense depends on whether a course of the treatment is more or less expensive than lifetime antiretroviral therapy.

      The same calculation will eventually apply to hepatitis C treatments. It’s probably less expensive to use the new drugs for hepatitis C than liver transplantation (which requires lifetime immunosuppressive drugs), but they’re rationed under some states’ Medicaid programs. A cost/benefit calculation in those states requires patients’ liver function to be sufficiently impaired before the new drugs can be purchased for those patients.

  7. ChairmanMao says:

    One of the guys on the Board is Tommy Thompson, former US Secretary of Health and Human services under G. Bush, so that gives the company free reign for scientific hyperbole that mortals and science peons that frequent here just wouldn’t understand and shouldn’t understand.

    We call it the George Shultz effect, made famous by Elizabeth Holmes.

  8. Joe Psycho says:

    I’m joe psycho,Remember me from “stopping early” UPDATE:

    On 5mg prednisone (just enough to keep the skin on my face) and 480μg ciclesonide (inhaled steroid) twice daily and 5μg tiotropium (maximum dose of each) and my neighbors burn wet leaves and brush, creating massive clouds of smoke that can be smelled in the house even with 2 military grade air purifiers with their fans set to maximum, so I still have up to 6 asthma attacks per day. The albuterol side effects are so bad me and my parents call it “satan in a can”. Side effects include violent and/or aggressive thoughts, anger, hyperactivity, panic attacks, urinary retention, psychosis and rarely auditory hallucinations on top of the usual side effects. So you can see why I would rather control my asthma with 20-40mg prednisone and have the munchies and hot flashes and gain some weight than be batshit crazy 24/7. I have developed a benzodiazepine addiction due to the psychosis and need to control it plus the fact I am an insomniac. And today I woke up at 1:15AM to an asthma attack. Please help me get some prednisone so I don’t have to be a psycho everyday. My life sucks ass more than a vacuum cleaner in a donkey’s rectum!

    1. loupgarous says:

      Two words: “second opinion”. Or even a third, fourth or fifth opinion. And good luck.

  9. David T says:

    The boilerplate quoted refers to a ” lead candidate for an HIV cure”, which appears to be factual: it is a candidate for a cure, not a cure. We understand the difference in elections, why not here?

  10. RB Woodward says:

    Attaching the word ‘therapy’ to development modalities such as…’gene therapy’, ‘stem cell therapy’, ‘antisense therapy’, ‘regenerative therapy’, ‘protein degradation therapy’
    …has always been irresponsible. Let’s add in the irresponsible terms ‘cancer vaccine’ and ‘Alzheimer’s vaccine’. None of these things exist. They may never exist. But, just for pointing this out I’ll be criticized for limiting somebody’s academic freedom or stifling their intellectual freedom. Well, guess what… This is pharma. Science is truth. Get on the right side of it. RB

  11. Andrew Molitor says:

    I’ve seen enough Resident Evil movies to flinch when someone starts talking about “T cells” and “gene therapy.” Don’t these people know how that end?

  12. Patricia Snyder says:

    I’m “Joe Public” and after reading the article I realized the title was a come on. Possibilities are not certainties. Still, it’s one more iron in the fire of research and I wish them luck.

  13. zmil says:

    Mechanistically, I don’t see how this would lead to a true cure. HIV specific T-cells will only be able to target cells that are actively producing HIV, not the latently infected cells that make a cure so difficult. Additionally, it seems quite unlikely that it will be sufficiently effective to prevent the virus to evolve escape mutations; counter intuitively, the reason our immune system has so much difficulty controlling HIV has less to do with the fact that it infects immune cells and is more because of its incredibly fast evolutionary response. Our immune system is pretty good at controlling HIV, but not good enough to stop it evolving.

  14. Anon says:

    From the link: “AGT is developing a highly innovative treatment strategy that uses the tools of genetic medicine for immunotherapy that will address [remission after stopping anti-retroviral treatment] and potentially create a functional cure for HIV.”

    The key word is: “potentially.” I don’t feel mislead by what I am reading and I think that the strategy could be feasible.

  15. steve says:

    Unlike the commentators on this thread, I actually know these guys, though I have no formal relationship whatsoever with the company. They have really exciting data and honestly believe they have a cure. Unproven? Absolutely. Hype? Maybe. But their approach is new and exciting and very strong on the science. Time will tell.

  16. Emjeff says:

    I agree this should not be done; however, academics also do this, and are rarely called for it. Scientific exaggeration erodes scientists’ credibility, which is already pretty low.

  17. ron mexico says:


    1. Bob Evans says:

      Ron, your statement seems a little inflammatory given the patent portfolio, NIH connection, state of Maryland support and team of active scientists working in Rockville for this firm. None of the above guarantees success for sure, but do you have any evidence to support your claim?

  18. Mexico says:

    -Which patent? They do claim to own a patent for another condition but it doesn’t belong to them
    -Connection with NIH doesn’t really many anything.
    -State will want any business in their territory to succeed.
    -There are no active scientist.

    1. Bob Evans says:

      Sorry Mexico. I was hoping to have an informed fact based exchange that I might learn from. But claiming that they have no patents that belong to them and no actual scientists working on any of this simply renders anything you say afterwards as baseless. And no I don’t work for AGT, but I’m very interested in the approach and considering getting invested. It sounds like you might have an axe to grind though….

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