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Quietly Another Drug Candidate Disappears

I wanted to note something today that won’t make many headlines outside of biopharma, but it’s just the sort of story that I wish more people knew about. Let’s start with this: there’s a terrible disease called IPF, idiopathic pulmonary fibrosis. Anyone with any medical background knows to beware the word “idiopathic”, since it’s a shorthand for “we don’t understand much of anything about this”. You’ll also know to beware the word “fibrosis”, for that matter, because it generally means a buildup of scar tissue that no one can do very much about. IPF happens in older patients, more males than females, and its features are progressive scarring of the lung tissue, driven by some ultimate cause that we haven’t quite been able to work out. The decline in lung function is progressive and irreversible, and most people who get the diagnosis are dead within a few years – short of a lung transplant, there’s really little to be done about the underlying problem. Pirfenidone and nintedanib are approved compounds for the disease, but in most cases they just slow down the inevitable a bit.

Now, this is part of a broader field of fibrosis diseases, affecting all sorts of organs and tissues (heart, lung, liver, kidney, etc.) Some of these we understand better than others, and we understand enough to know (simultaneously) that classifying so many things under “fibrosis” is an overreach, because such tissue effects are a symptom of something deeper (that “something” can be pretty wide-ranging), but also that the cell biology of fibrosis itself is often similar enough to make one hope for a relatively broad-based treatment of such symptoms. Which would definitely be an improvement over what we have now.

Back in 2012, Biogen bought a small company called Stromedix (founded in 2007) that had a candidate aimed at IPF. There’s a biotech-biz inside baseball angle to the story, because the founder of Stromedix was a former head of Biogen’s R&D (and has gone on to other ventures since), Stromedix came out of one of the well-known VC organizations here, Biogen had actualy developed the program initially, outlicensed it to Stromedix, and eventually came back around again, and so on. As with any technology hub, everybody either knows everybody or knows someone who knows them, and a lot of interesting stories get generated. But I’m leaving the human-interest and business angles aside, and focusing on the science and medicine.

The main compound involved, STX-100, is an antibody targeting the alpha-v-beta-6 integrin receptor. That’s upstream of TGF-beta, which has been shown to be a key player in fibrosis in general. (There’s one of those hopes for a general treatment). The integrin activates TGF-beta, so the hope was that targeting it would slow down or even halt the fibrosis process. Targeting TGF-beta directly is very likely a bad idea (it has just too many important functions), so there have been all sorts of attempts to bounce-shot the target by finding other targets that regulate its activity. The antibody had already been in trials for kidney fibrosis, but had shown some tox problems which apparently made it a better candidate for lung fibrosis – they’d gone into kidney patients first because there were easier to identify and monitor. And that’s where Biogen came back into the picture, buying the whole company and pushing the trials forward, because they’d looked at pulmonary fibrosis with it earlier and seen encouraging results.

STX-100 (now BG00011) went back into the clinic, with a trial ending in early 2017. But there wasn’t much news about that, although a Phase IIB went ahead in IPF patients last year. And (you probably knew where this was going), word has just come out that the study has been terminated with only about a third of its patients enrolled. That does look like the end of the line for this antibody, and it’s not particularly encouraging news for targeting alpha-v-beta-6 either (although there’s a small-molecule antagonist of it from GSK that’s in the clinic now (edit: now terminated as well). And there are, fortunately, many other mechanisms being investigated by many other people, with quite a few trials going. Fibrosis is a major unsolved problem, and the first people who make real progress against it will do very well, and help a lot of people who have, frankly, very little hope other than something new appearing from R&D.

And that’s what I wanted to highlight: here’s a big cause of human suffering that not many people are aware of outside the medical field. The first time most people become aware of fibrosis as a disease is after they or someone they know is diagnosed, and that isn’t good news at all. There are, though, a great many people in academia and industry who have been working on this from many different angles for a long time now, but if you’re not a biomedical researcher you will never have heard about any of that work at all. I would also add that a tremendous amount of time, effort, and money has gone into all this, by the time you add it all up, and so far (from a can-you-help-me-doctor perspective), there’s been little to show for it. We’ve gained a lot of knowledge and experience, and (as this latest news shows) closed off some ideas previously thought promising, but there is no fibrosis cure to announce. Yet.

You will not see any big headlines about the demise of STX-100, either. Drugs fail all the time, most of the time rather quietly, and all the work and money that went into them just sort of vanishes. But that work, and that time, and that money – all of them were very real. As were the hopes of the people working on the drugs, and the hopes of the patients taking them in the clinical trials. This is happening constantly in the background, all the time, and it’s one of the big reasons that I started this blog in the first place, because almost no one realizes it.

25 comments on “Quietly Another Drug Candidate Disappears”

  1. Eugene says:

    It is my understanding that some percentage of the clinical trial patients can show positive results on an individual basis. If you are such a person and the trial fails for whatever reason, what happens? Are you simply out of luck?

    1. DorothyL says:

      You get into murky statistical territory. They had a hypothesis that the drug would work in an already quite tightly specified population subset. It failed to show a significant difference between the placebo and drug-treated group. There are also individuals that show positive results in the placebo group for reasons unrelated to the drug (disease activity can wax and wane independent of any therapy). But theoretically there could be individuals that show a response. Pharma companies will aggressively try to identify these subject to the statistical caveats alluded to above. Even if they somehow meet these statistical hurdles the drug may not be commercially viable in such a small subgroup though.

    2. Sken says:

      You’re out of luck.

      I worked on a cancer drug that in the early stage trials had at least one case of a complete cure. (Awesome for the guy). But the drug failed in expanded clinical trials and eventually got canned as did most of the workforce.

      One question you have to wonder is how much was just random noise that a few people showed a great response while others didn’t or how much was luck that for whatever reason the drug was more efficacious with them and if there are biomarkers or something that we should have been looking for?

      1. HFM says:

        I’ve heard of a case like this where the mechanism was eventually hunted down. Back in the day, when Gleevec was newly released, it was tried (on a why-not basis) for many different types of treatment-resistant cancer. There was the occasional report of miraculous responses, but nothing repeatable…except in pediatric gastric stromal tumors, where it worked maybe half the time. As it turned out, there was cross-reactivity; the unexpected target, KIT, was a common driver mutation in this particular cancer, and also sometimes has a role in other cancer types.

    3. John Wayne says:

      A family member had a similar experience. He was a part of a clinical trial for cancer, had complete recovery and lived well past average life expectancy; the trial was considered a failure and it never became a drug.

      Why? Does this reflect our ignorance of biology, our ignorance of statistics, or some annoying combination of the two?

      1. Stephen says:

        They are called super-responders. They are of much interest to give clues as to why some drugs work and some don’t. E.g. see here for some info https://www.ascopost.com/issues/august-25-2018/unraveling-the-mystery-of-what-gives-exceptional-responders-their-superpower/

      2. Peter S. Shenkin says:

        Do we know whether the example you cited was in the placebo arm or the active arm?

        1. John Wayne says:

          From the side effects I guessed that he was on the real arm. Of course, I don’t really know; different folks respond to things in different ways. He and I were fairy close, which makes my perspective suspect.

          Control arm patient would be a pretty simple explanation; thanks for bringing it up.

    4. DanielT says:

      Does anyone know of an easy way of identifying these early stage drugs in the literature that cause a “rare miracle” cancer cure?

    5. Anon says:

      I seem to remember that if you respond to a experimental drug as a part of a clinical trial and wish to continue taking it, the drug company needs to keep supplying it to you (free of charge) even if the program is dropped. It’s part of the ethical guidelines.

      1. Tom Ames says:

        I don’t think this is a legal requirement. Would appreciate seeing a citation if I’m wrong.

  2. Mister B. says:

    I’m sad to see GSK348 being terminated too ! I had the chance to work on this programm during my IP year at Stevenage. Chemistry was really nice on this project !

    It’s quiet but sad news for IPF patients for all the reasons Derek mentionned.

  3. Kent Matlack says:

    How can a trial be terminated with only a third of its patients enrolled?

    1. Derek Lowe says:

      Got to be baaaad safety signals. . .

    2. Emjeff says:

      Most Phase 2!trials these days have a pre-specified interim look at the data. At this point , the probability of success is computed, and if it is less than the pre-specified threshold, the trial is stopped. Saves time and money. More importantly, it limits patient exposure to a drug which is doing nothing for them.

  4. aairfccha says:

    AFAIK there is ongoing research to make wounds heal scar-free. If there ever is a systemic treatment to achieve this, might it be also applicable to fibriosis?

    Of course, this is speculation on a treatment which at present is hypothetical to start with.

    1. FoodScientist says:

      I don’t really scar anymore to cuts now that my psoriasis has kicked into higher gear. I also have Wolverine like healing abilities to cuts. The research into the upregulation of growth factors is interesting. Though, if I didn’t heal quicker I would probably have a fewer percentage of skin. It seems like the destruction and regrowth are somewhat balanced.

  5. Luke T says:

    Exceptional responders could also be a result of a patient/s having a specific subtype of IPF that responds to a given treatment, where other subtypes don’t. Genomic studies indicate that IPF is likely several different diseases, each with unique molecular signatures, that present with similar symptoms. Clinical trials for several diseases are starting to stratify patient cohorts according to their disease subtype, recognising that each group will need a different treatment. Hopefully this will mean more trials are deemed successful – potential treatments successfully treating only small numbers of patients can still be a success, as long as most (if not all) belong to the same subtype.

  6. David E. Young, MD says:

    A 2002 phase one study on Combretastatin A4, done at Cleveland clinic for analplastic thyroid cancer had one individual who obtained a complete response and “was alive at 30 months” at the time of publication. This is an incredible result for a disease that is so aggressive that the average life span after diagnosis is about 3 months and major responses are almost unheard of. But further study of the drug (now called Fosbretaulin) showed no responses in a phase II study of about 26 patients, published about 7 years ago. My hunch is that the drug is all-but-finished in clinical studies. What was it about the one (rather young) individual who had such a good response?

  7. Mister B. says:

    I just read on LinkedIn that Galapagos (Belgian Biotech) is “committed to stand with them (EU-IPFF & the Pulmonary Fibrosis Foundation) in the race to combat IPF.”

    Do you have any insights on their on program ?

    1. WHM says:

      Galapagos has an autotaxin (ATX) inhibitor in Phase III, termed GLPG1690. Some 1500 patients to be enrolled. See their website. Boehringer Ingelheim payed $50 million upfront for an ATX inhibitor (BBT-877), which they apparently consider “best-in-class”; it’s in Phase I.

      1. Mister B. says:

        Thank you !
        I may not know how to look properly for such news and updates. Do the “press release” page efficient enough to be updated on this topic (clinical trials for one company) or do you know any feed that can sum up all the clinical trials running for one specific target ?

  8. Truth Teller says:

    This is funny since azithromycin+roxithromycin combo is known to work well for IPF. Our healthcare system maximizes industry profits, not health.

    1. Derek Lowe says:

      I would not call that “working well”, since everyone who takes it for IPF dies from IPF anyway, to the best of my knowledge.

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