[s1artibartfast]

I dont know why you are being rude about a topic you know nothing about. As some who actually does this for a career, they are largely correct. Dose frequency and side effects especially are major reasons. I would add route of administration and patient convenience as well.

Anti-vegf treatments for blindness are a good example if you want to research. They all have basicly the same effect in terms of letters preserved on an eye chart if dosed as perscribled.

It's a 15 billion dollar per year Market that resolves on the basis of the longest dose interval and side effects.

You can look at the bevicizumab, to ranibizumab, to aflibercept, to brolucizumab, to faricimab drug programs. There are also dozens of failed programs in this area and perpetually new drugs and Gene Therapies looking to break into the market.

Perhaps an even more salient example would be pill based GLPs looking exploit the listed factors

[vibrio]

To add a somewhat cynical view, a significant part of the original motivation for the ranibizumab (Lucentis) development was due to pricing arbitrage across diseases. bevicizumab was priced based on uses in cancer indications with a “large” volume (many mls) used for systemic infusion. The same product injected into the eye, in say a 1:1000 volume, could be efficacious for AMD, but pricing per volume would be trivial amount at the bevi cost per volume. So they tweaked the active ingredient to a new product (exact same mechanism ) and raised the price per volume to a market standard cost per treatment. There may be some pk-type benefits to the derivative , but the pricing context is an industry case study.

[s1artibartfast]

Yeah, I think that's especially relevant here too and reinforces the phenomenon where US hcps will opt for the best independent of price, even if the marginal benefit is vanishingly small or hypothetical/not data driven.

Some providers did opt to self-compound avastin for off label use mostly in Europe but also in the US.

The idea that Pharma companies would pass on developing a product 1% better than keytruda, or that hcps would pass on buying is laughable

[bonsai_spool]

Not being rude, and I definitely know about medicine.

I explained in sibling that I understood the Lowe article to be about new research (as a researcher, I don't often think about how hard it is to make a GLP survive the stomach but I do think about how incretin biology works). I guess these VEGF agents you list feel like a very straightforward engineering question (can we make an antibody that targets VEGF, humanize its Fc etc) while Lowe brings up conceptual areas like PCSK9, HMG-CoA reductase.

I still maintain that the 1% better thing is not going to lead to incredible success because rational actors aren't going to change their prescribing patterns each time a new agent gets approved.

[s1artibartfast]

I dont think you have an accurate model of how US prescribers and patients operate.

They want the best, and are willing to sepnd 10x the price or switch treatment to secure that 1% survival, extra week of dosing interval, or the ability to inject at home via mail instead of some sweaty infusion clinic.

I used to think like you before transitioning from medical devices to pharmaceutical development.

The USA is the only real Market that matters for drug development. Unlike the with marginal benefit pricing and National negotiation, the US market is consumer Centric, with patients and their providers wanting the best, even if it is marginal. That 1% means that you can either take the market share or 10x the price.

> I guess these VEGF agents you list feel like a very straightforward engineering question

Each of those straightforward engineering questions takes about 100,000 labor-years and a billion dollars to get approval.

[s1artibartfast]

Oh fun trivia about those straightforward engineering problems was Novartis beavu. It had a few percent higher Side Effects than standard of care after lunch. This was enough to cause Novartis (a top 5 or 10 Pharma company) to essentially cease all ocular drug research and sell off much of their ocular portfolio.