This is quite a synthetic chemistry accomplishment: the halichondrin derivative E7130 has been synthesized on an 11-gram scale by the Kishi group (open-access paper). I’ve copied that structure directly from the published paper, because there’s just not enough time this morning to redraw it! This would surely be the most complex natural product structure ever synthesized on such a scale; I cannot imagine that anything else even comes close.
The research team had to improve the halichondrin synthesis considerably to get to that point – the paper notes that the first bath of E7130 was 109 total steps (!) from commercially available materials and wasn’t very clean at the end of all that, either. A synthesis on that level can be described as a brutal, soul-destroying triumph, as far as I’m concerned; that is just a tremendous amount of work (mentally and physically). The improved synthesis is still 92 steps, but with far improved yield and purity. Even so, coming out the other end with 10-to-20-gram quantities after a climb like that is just hard to contemplate, as is the amount of work that had to go into improving the route enough to even make that possible. Holy cow, have there ever been people making loads of early-stage compounds for that effort; that’s a laboratory bucket brigade like few of us have ever seen.
Readers will remember the earlier approved drug developed by Eisai (in collaboration with Kishi’s research team), Halaven (eribulin), which has been approved in many countries for metastatic breast cancer and (more recently) for some liposarcoma indications. This one’s even more complex. And the only reason it makes sense to undertake such an effort at all is its extreme potency – the paper reports that human trials are underway in Japan at a dose of 25 micrograms/square meter twice a month. Using an average conversion factor, I would guess that each dose for an 80-kilo patient would be 50 micrograms, so 100 micrograms/month/patient. So if you have ten or eleven grams of E7130 on hand, you have enough material to get quite a bit of work done. Ten patients will use up 1 mg/month, so you could run, in back-of-the-envelope theory, at least 15 different one-year trials at such dosages with 500 patients in each dosing arm. That figure allows for some losses, but in truth, I have no idea how much to budget for when using such a substance!
So how is eribulin itself doing? It was first approved in 2010, so there are plenty of numbers to work with. Eisai’s annual report for 2018 doesn’t seem to be out yet, but the previous one came out in May of 2018, and we have the FY 2017 figures in it. The company’s total revenue was 600 billion yen, and almost all of the (553 billion) was their pharma business. Their oncology portfolio brought in 126.4 billion of that, and Halaven was 39.9 billion yen of that, their largest single product in the space and one of their biggest overall – Aricept (donepezil) for dementia is a bit larger. So it’s a big part of Eisai’s portfolio, and they clearly have hopes for E7130 as well.
It will certainly be interesting to watch its development – there aren’t many other compounds with these manufacturing complications. How many patients Eisai expects to reach will of course determine how much E7130 needs to be produced per year, and that will depend on its activity in the clinical trials which are just starting. Those results could read out as anything from “Not worth the trouble” to “How are we possibly ever going to make enough?”, so we’ll see where on that (very wide!) scale it lands. . .