Therapeutic windowWe are in the dark but the pessimistic take atm is effectively the therapeutic window is non-existent based on the present dosing schedule. 1a says go too high a dose and you have unacceptable toxicity. Go with the 1b working dose and you have unconvincing efficacy. You have some individual efficacy signals in 1a, it would be nice to know they have some in 1b as well, but at the population level it's not enough.
They should know something about drug exposure so they should be able to come up with a "better" dose but it's less certain they know exactly what the problem is so to me it's uncertain whether the "better" dose will fix the problem. Based on the present drug design they could be looking for a pretty narrow sweet spot of acceptable toxicity and efficacy, it also may not even exist.
I can understand not wanting to give up on Sortilin as a cancer target but a redesign might be necessary. I can imagine scenarios where either the payload or the peptide or both could require a redesign. This takes you back to step one and is commercially unattractive and investment-wise uninteresting.
Hunting for a "sweet spot" might be risky/uncertain/futile but if you can get a relatively quick answer and you can afford to splash a few more millions it is maybe commercially more attractive.
They are in a pickle.