Skip to main content
Menu

Business and Markets

Zafgen: Will There Be a Third Act?

A few years ago on this blog, I wrote several times about a small company called Zafgen and their unusual epoxide-based chemical matter (beloranib) that was in development for the rare Prader-Willi syndrome. That’s a genetic disorder that includes, among many other problems, constant hunger (with the complications that you’d expect from that). Zafgen was pursuing inhibitors of the enzyme methionine aminopeptidase 2 (MetAP2) as a treatment, and thus their epoxide compound. Unfortunately, the company had a death in their Phase III trial, and the confusion and consternation about that hadn’t even settled down before a second death occurred.

Most observers wondered if that would be the end of the company – things like this have most certainly ended small biopharma companies before. But Zafgen carried on. Beloranib itself seemed to be acting through more mechanisms than just MetAP2 inhibition, as many compounds with two epoxides in them well might be, and they came back around with compounds that seemed to be more selective. ZGN-1061 went into clinical trials last year for diabetes, but the FDA put a clinical hold on the program last fall, citing cardiovascular concerns. Meanwhile, a further compound (ZGN-1258) was on the way to the clinic for another crack at Prader-Willi until earlier this week. Beloranib’s problems had been traced to effects on the vascular epithelium, and the latest compound showed no sign of trouble there.

Unfortunately, what it did show was toxic effects on muscle tissue, which had apparently not been observed with the 1061 compound. Zafgen announced after the close of the market Monday that the compound had been dropped because of this finding, which is absolutely the last thing the company needed. Their stock has cratered once again – you’ve needed mighty strong hands to hold on to ZFGN through all this – and the number of ways out of this situation would seem to have narrowed. There’s not much clarity on how (or if) the clinical hold on ZGN-1061 could be resolved, and it may in fact be unresolvable. The company says that it’s produced new assay data and is setting up a meeting with the FDA about the ZGN-1061 safety concerns, but who knows how that will go?

Sometimes a small company’s near-death experiences end up as a prelude to a dramatic comeback, but sometimes they’re just a prelude to, well, the company’s death. Zafgen’s executives will have to be extraordinarily persuasive to convince investors that this isn’t the case here, but they already lost their CEO and CSO last August and their Chief Medical Officer just resigned as the company announced the hiring of a new R&D head. So there’s that. I wish Zafgen luck, but they have quite a hole to climb out of at this point.

26 comments on “Zafgen: Will There Be a Third Act?”

  1. Paul Brookes says:

    Curious, what’s the mechanism (biochemical, physiologic) by which inhibiting MetAP2 would impact obesity? All the Wiki page says is “MetAP2 inhibitors work by re-establishing balance to the ways the body metabolizes fat”, which is not very useful.

    PubMed yields is a mouse paper from 2010 (https://www.ncbi.nlm.nih.gov/pubmed/20094042) and a very small clinical trial in 2013 (https://www.ncbi.nlm.nih.gov/pubmed/23512440). From that first paper, it would appear the mechanism is simply inhibition of angiogenesis by blocking endothelial cell proliferation. Sure, growing fat needs blood vessels, but hitting angiogenesis seems like an awfully blunt sledge-hammer approach! Who in the hell would even think that was a good idea to begin with?

    1. Derek Lowe says:

      Yep, angiogenesis in white adipose tissue does seem to be the target: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944999/

    2. milkshake says:

      The irony is, they initially developed analogs of fumagillin as anti-angiogenesis agents for treatment of cancer, it did not pan out in the clinic but they noticed a dramatic weight loss in the patients so they re-purposed for obesity. As if they did not know that cancer therapy agents have probably the lowest safety and efficacy bar, and anti-obesity agents have to have an extremely high margin of safety.

      Of course they did know. But it was probably a conscious business decision to save the soured investment in a failed project – by making other fools to invest in it and keep the clinical trials going . When the project failed again, it was already someone else holding the bag.

      1. loupgarous says:

        So, beloranib and its follow-on don’t actually treat PWS as such, merely manage its prime complication (morbid obesity). I agree with you, using a cancer drug to manage obesity seems warped.

        I’ve actually seen a kid with PWS in a residential setting where I worked as a caregiver while in college. His obesity was already advanced and ruining his health in his early teens. His condition was incompatible with a life of normal length, he could look forward to very early death from cardiac failure, kidney failure or early-onset type II DM. But the only management for his disease was dietary restriction, and not all of the other caregivers were strict with him on that. He was already in a group home owing partially to lowered cognitive function.

        So, yes, Zafgen’s drug candidates are remarkably toxic as obesity cures go. But PWS isn’t a forgiving disease process, and people with it will die early if their obesity isn’t managed. For those who can get it, human growth hormone can help patients gain more nearly normal muscle mass and may help patients control their compulsive eating, and caregivers who are motivated to help patients control what they eat are essential.

        Ghrelin may be a better drug target in PWS, as sufferers have more of it, and it’s directly associated with appetite, hypogonadism, and other common features of the syndrome. No idea how to inhibit ghrelin function, or how toxic that would be compared to blocking angiogenesis with a cancer drug.

        1. In Vivo Veritas says:

          Except how well have those ghrelin receptor antagonists worked out for……anything?

          1. loupgarous says:

            Not well at all, because hunger and satiety don’t work across a single hormonal axis. Roy Smith’s group at Scripps Florida has looked at D2 receptor agonists in GHSR knockout mice and found feeding behavior decreases significantly.

            Not that either the ghrelin antagonists or D2 receptor agonists are innocuous drugs, but it may be worth studying whether they’re less toxic than fumagillin analogs in PWS and have comparable or better efficacy.

  2. 2G says:

    Any clues about the structure of ZGN-1258? Still two epoxides as in the second act (ZGN-1061) or has the target died with this results?

  3. whodtheybribeatfda says:

    hmmmm, 2 deaths in phase III and there was really no indication of such potential problems earlier on??

    1. loupgarous says:

      Odanacatib was great for osteoporosis, the increased stroke risk only came to the forefront after Phase III had encouraging results and the controls were given the drug as well. Unsuspected toxicity issues do sometimes show up in Phase III, and not earlier.

  4. He will be more than on get off ride to new heights and make life hard for all who were involved in trying to make him look ridiculous. Then he breaks through the wall and wins all back and is better than any could imagine. Fact its happening so move out of the way or get rolled over in a hole

  5. Chairman Mao says:

    Anybody know of any drug that has an epoxide functional group? Artemisinin doesn’t count as its an endoperoxide. I’ll wait.

    1. Emperor Qin says:

      The antibiotic fosfomycin.

    2. KazooChemist says:

      Spiriva

    3. gippgig says:

      Besides the original fumagillin, some macrolides like oleandomycin & carbomycin.

    4. OldLabRat says:

      You can add epleranone to the list.

  6. Get Brett Weir I said! says:

    scopolamine, cerulenin, Desopan, Inspra, Bactroban, ixabepilone, natamycin

  7. LB says:

    The most profound and life-altering symptom of Prader-Willi Syndrome for patients and caregivers is chronic uncontrollable hunger. Although not strictly a clinical endpoint, the earlier iterations of the Zafgen drug did (at least in the eyes of the caregivers) have a meaningful benefit. I’m sad for the the PWS community that this program will probably be discontinued.

  8. biotechtoreador says:

    Third, fourth, and likely fifth….there are so many of this lousy little companies which, in an efficient market, would just go ch 7. Next step will be in-licensing a compound that previously failed to show efficacy (Phase 2 ready!) and run a study in a different indication. A name change might also help. So many of these btech zombies that are able to trudge on for years, if not decades (XOMA, VICL, CTIC, CYTR, HEB to name a few)

  9. Watson says:

    So has anyone tried fumagillin on such a cohort?

  10. Soleno (SLNO) is testing DCCR in PWS with early signs of success. The DSMB just gave them a green light at the first interim safety check in their Phase III. Stay tuned.

  11. MaoMaoMao says:

    Chairman Mao really backfired. Still love the bias of the med chemist who says you can’t have this or that in a drug. Then looks around to find them in all kinds of drugs.

    1. AlloG says:

      Dat Mao what does he know? He needed a different barber anyway. I put an oxirane on a tropane ring too and cranked out benzylecgonine methylester epoxied. Now you never need dopamine again! Of course you never can go to sleep again either.

  12. Samissung says:

    Another company needing a third act is Nvax. Failed on the primary endpoint for their phase 3 RSV maternal vaccine. The data was very unusual with some subsets and secondary endpoints showing good efficacy. Wonder if they can salvage something here. Company is running out of money and time.

    https://novavax.com/presentation.show

  13. mfernflower says:

    The 3‐[2‐(morpholin‐4‐yl)ethyl]azetidine‐1‐carboxylic
    acid fragment is rather strange – Does anybody know the purpose of it? Improved water solubility perhaps?

  14. Zach says:

    Zafgen is one of the most under appreciated company due to their checkered past. But their molecule has a new MoA (not a me-too), strong tutes support, they have drug that actually works as shown by Phase 2 studies, significantly improved safety profile over belo. The last box they need to check is convince FDA with this recently agreed upon invivo nonclinical study and then sky is the limit. Just watch the progress these guys will make in about a year from now!

Leave a Reply

Your email address will not be published. Required fields are marked *

Time limit is exhausted. Please reload CAPTCHA.