I'm certainly not an expert on chemistry or drugs. However, I've...

I'm certainly not an expert on chemistry or drugs. However, I've done a bit of research, (e.g. ttps://go.drugbank.com/drugs/DB15601 vs https://go.drugbank.com/drugs/DB06045 and others) and found the following information that I thought interesting. Some of the below is cut & pasted from these sources.

Trofinetide is a novel synthetic analog of glypromate, also known as glycine–proline–glutamate (GPE), a naturally occurring protein in the brain and the N-terminal tripeptide of insulin-like growth factor 1 (IGF-1). GPE is an N-terminal tripeptide product of the cleavage of insulin-like growth factor 1 (IGF-1) found in the brain. Molecular weight: 315. Believed to act by modulating IFG-1 signaling on neurons and glia. There are many studies indicating that Trofinetide exerts its effect by improving synaptic functions, restoring synaptic structure, reducing the effects of neuro-inflammatory substances in the brain, enhancing antioxidant responses, attenuating injury-induced apoptosis, normalizing the synthesis of essential proteins, restoring normal homeostasis in the brain, and augmenting the concentration of IGF-1 in the CNS."

NNZ-2591 (cyclo-L-glycyl-L-2-allylproline)1 is an investigational synthetic analog of cyclic glycine-proline (cGP), a breakdown product of human insulin-like growth factor 1 (IGF-1), that has been chemically modified to increase its half-life, stability, and oral bioavailability. Molecular weight: 194.

So they are not identical certainly, but if you read Neuren's own website https://www.neurenpharma.com/science/science-behind-neuren-s-products is pretty clear they're targeted at achieving the same thing. Neuren states "Trofinetide and NNZ-2591 are improved synthetic analogues of peptides that occur naturally in the brain and are related to IGF-1, which is a growth factor stimulated by growth hormone"

One of the biggest advantages of NNZ-2591, as I understand it, is it's bioavailability and blood-brain-barrier permeability, which means a much lower dose is required to achieve the same levels in the brain of the desired end products. It's possible the benefits of NNZ-2591 don't come so much because its mechanism of action is different, but rather it's simply better at getting into the brain and staying there. The biggest problem with IGF-1 type drugs in the past, I believe, was they were very hard to get into the brain and had a short half-life. IGF-1 has to be injected (oral route doesn't work) and the I believe the half-life of glypromate (which Trofinitide is based on) less than 30 minutes.

Margaret Brimble's big breakthrough, as I understand it, wasn't proposing IGF-1 or glypromate as a drug candidate (this idea has been around since the 1980s). Her achievement was finding small molecule formulations that dramatically improved bioavailability and stability, making a drug feasible. Doing this was very hard and something noone else had achieved.

Comparing the dose & half-life of both drugs:

Trofinitide: Dose 500mg/kg (24g for patient 50kg). Half-life 1.4 hours

NNZ-2591: Dose 12mg/kg. Half-life: >2 hours?

So the dose for NNZ-2591 is ~42x lower than Trofinitide.

The only data I could find on the half-life of NNZ-2591 was from a 2009 study in rats. The blood half-life was 2 hours and the cerebrospinal fluid (CSF) level remained the same between 0.5 and 2h. The paper said "The maintained CSF level to 2 h suggests a sustained central transfer of NNZ 2591 from plasma and that central uptake of NNZ 2591 compensates for the drug's elimination through CSF absorption".

Does this mean NNZ-2591 has a longer half-life? Maybe. Am sure they will have measured this in the recent Ph 2 Phelan-McDermid trial (half-life is an important metric), so the actual value in humans (not rats) will eventually be published. "What is the half-life for NNZ-2591" might be a good question for someone to ask on the next Neuren call. If NNZ-2591 does have a longer half-life, even by a small amount (see below) that could be a big advantage too.

Even if the half-life of NNZ-2591 is the same as Trofinitide, the fact the dose required appears to be ~42x smaller could make a huge difference already, particularly when we're talking about drugs with such short half-lives.

Note that 500mg/kg (24g a day) is enormous. Most drug dosages are in mg, not g. A half-life of 1.4 hrs is also very low.

The ideal half-life of oral drugs is 12-48hrs. This means you can take a daily dose and after 24hrs still have active amounts present in your body. If the half-life is short you have to take giant doses so a high enough dose can be maintained long enough to have a sustained benefit (or you have to take it continuously intravenously, or develop a slow-release formulation). Having to take a very large dose runs the risk of side-effects of course.

With a half-life of just 1.4 hrs and twice daily dosing, the difference between peak and trough levels of Trofinitide will be an enormous 380x (2 ^ (12/1.4)). In theory this means you have to give 380x the ideal dose to ensure the trough level still remains effective. It's possible they are not giving 380x the effective dose, but are instead accepting there will be a significant period when the drug is present at lower than optimal dose. This may be a tough balancing act.

For comparison, if you had a half-life of 6 hrs, then the peak-to-trough will be just 4x. So you only need to give 4x the effective/ideal dose to maintain a continuously effective dose.

With the above in mind it's this may be the reason why we see such significant side-effects with Trofinitide (and not with NNZ-2591). The side-effects of Trofinitide may not be intrinsic to the drug, but rather due to very high doses required to achieve a sustained effective dose.

In fact, in terms of effectiveness, its possible even at the recommended dose they're still not reaching a continuously optimal dose. Neuren may have had to balance side-effects vs effectiveness.

The main benefits of NNZ-2591 may simply be it's bioavailabilty. However, this could make a big difference to effectiveness also, because instead of compromising on dose level to minimize side effects you have more room to increase the dose to maintain an good enough trough level.

For example, it could be that at recommended dose Trofinitide is still only maintaining an effective dose level for 6 out of the 12 hours. If NNZ-2591 is 100x the bioavailability of Trofinitide and has the same half-life this could allow Neuren to double the level achieved in the brain (without causing side-effects) so as to ensure an effective dose is present 12 out of 12 hours, thereby maybe 'doubling' the effectiveness of NNZ-2591.

Of course, without understanding the exact way the drug's mechanism behaves its hard to say. Some drugs only work when they are present at or above the effective dose, others only need to be present for a short period to 'trigger' some process that then continues for a while before returning to normal. Some drugs have a linear dose-response effect (lower amounts still have some benefits), for others its non-linear where below a certain threshold the effects become zero. I'm sure the Neuren scientific staff have a much better grasp of all this. Either way, a much more bioavailable drug will make it much easier to achieve and maintain an optimally effective dose i.e. it has the potential for great effectiveness all else being equal.

I note the above suggests a potential way to reduce the side-effects for Daybue. For example, if you used two hourly dosing then you'd theoretically need 1/300th the dose to achieve the same trough level. You'd still need a big evening dose before 8 hours sleep. However, there may be more to this of course, I'm sure Neuren & Acadia have looked at all this.

Finally, I don't know how much it costs to make Trofinitide or NNZ-2591. But a 50kg Retts patient currently needs 8.7kg of Trofinitide a year(!). This is a whopping amount. I can't help thinking that must be pretty expensive. By comparison, you only need 200g a year of NNZ-2591. So that can only be an advantage. All things being equal NNZ-2591 could be 40x cheaper to make per dose. I don't know much about the costs & difficulties of manufacturing drugs, but NNZ-2591 also appears to be a smaller with a less complex chemical structure, which may also make it cheaper to manufacture.