# Novo Nordisk Buys British ‘Smart’ Insulin Diabetes Biotech in deal worth €702M



## Northerner

*Novo Nordisk acquired the UK biotech Ziylo, which develops glucose-responsive insulin treatments for diabetes that act in response to changes in blood sugar levels.*

The Danish big-pharma, which is already a big player in the diabetes space, acquired the full rights to Ziylo’s technology in a deal worth up to €702M ($800M). Novo will use the technology to develop so-called ‘smart’ insulin treatments for diabetics, designed to be taken once a day, that are only active when a patient’s blood sugar levels are too high or too low.

Smart insulin could lead to safer diabetes treatments by reducing the risk of low blood sugar or ‘hypos’, one of the main side effects of insulin therapy. Like conventional insulin, the technology is designed to keep high blood sugar, the hallmark symptom of diabetics, in check. But unlike normal insulin, it is designed to ‘switch off’ when blood glucose gets too low, or switch on when it gets too high. 

https://labiotech.eu/medical/novo-nordisk-smart-insulin-diabetes/

This must be almost ready, they've been talking about smart insulin practically since I was diagnosed, and that was 10 years ago....


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## mikeyB

That’s good news. As you say, it must be almost ready but Ziylo isn’t big enough for the big roll out. Can’t wait


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## khskel

Fingers crossed, that's the one I'd like to see come to fruition.


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## Northerner

khskel said:


> Fingers crossed, that's the one I'd like to see come to fruition.


Yes, it's long been the one I've had the most interest in  Such a shame so much other money went into inhaled insulin that nobody really wanted and never came up to expectations even though it made it onto the market.


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## Lisa66

How great would this be! Exciting times


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## Matt Cycle

Medtronic and the other pump makers won't be happy about this.  If it works with a once a day injection then pumps would become redundant.


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## novonord

lot more information on this on the unit dx website
will be at least 4 years before this becomes available, if it works at all and passes all the toxicology and efficacy, and even if all goes well.


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## novonord

do think the biomimetic glucose receptor developed by Professor Davis and team at the University of Bristol after a lifetime of 20 years of dogged research is absolutely brilliant and, if it could be harmonised with Novo's world leading expertise in insulin analogues to develop a glucose responsive insulin that, say, kept the glucose below 7, and involved only one injection a day,  would be worthy of Nobel prize recognition.


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## mikeyB

Indeed, we also live in hope that when it appears, the NHS will pay for it. I have my doubts under the current government, if they ever get back to doing any governing instead of fighting like a sack of ferrets.


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## novonord

another interesting article is howgego's 'sensing the sweet spot' in chemistry world: the question will be whether this can get through the toxicology and whether the on and off switches are sufficiently sensitive to control glucose within a reasonably physiological range or at least 4-9 say....still at least 5 years off.


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## trophywench

As a long-term and current user of NN's insulins (so I'm biased LOL) I have to say it sounds good to me - it would make insulin pumps redundant without the initial up front investment in the hardware and also the added ongoing cos of the consumables - which is shedloads more expensive than MDI, so as pumps come up for renewal and don't need to be, that would free up money so that smart insulin could be offered to more diabetics.  I mean - nobody knows what price it would have to be sold at so we can't at this stage assess/guess the costs.

Having experienced the change  from  animal insulin through 'human' to the current analogue et al, that process hit the diabetic in the street over about 10/12 years I think, so I'm probably unlikely to see it come to fruition - or probably won't care when it does LOL.

But who on earth wouldn't rather only have to have one jab a day than MDI or all the extra fiddling about with a pump!


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## novonord

suspect I'm in the same boat as you trophyw being too old (or already dead) to benefit, probably, if this comes to fruition though agree with your other comments, it might be trialled at NN's Oxford facility.
as a sufferer also from Addison's for nearly 40 years, always amazed at the cost of hydrocortisone 10 mg- 30 tablets cost £80 or thereabouts so yearly cost of this alone to the NHS is around £2000, lifetime cost about 100000, cost of manufacture is about 2p per tablet, I would guess. Then there is the cost of fludrocortisone as well.
looks to me that Novo has been researching glucose responsive insulin for years, as their other insulins are going off patent, and has until now always been stymied by the lack of specificity of their own glucose sensing molecules.


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## novonord

correction: it seems that the NHS cost of hydrocortisone 10mg is just over £1 a pill not as above- still v expensive.
further research on the internet shows that Merck, Sanofi, Eli Lilly all have programmes for smart insulin though Merck's first effort based on boronic acid was pulled in clinical trials for lack of efficacy- still think Novo the most likely to get there, out of all of them, first, if any of them can do it, and if the Univ Bristol glucose receptor they will be using is stable and can be conjugated reliably to turn off insulin when the glucose level drops... listening to desert island discs today, the subject there, an eminent economics prof at UCL seemed to be arguing that the state should direct research in areas like this-I don't think so! NN did buy the univ Bristol spin-out co but paid through the nose for it!


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## mikeyB

Yes, Novo may have been researching this for a while, with no success, so instead they buy a company that has had success, or at least a very promising line of research. I think this may appear earlier than folk may think. As Novonord says, Novos insulins are running out of patent so they will be chasing the Holy Grail as a top priority. 

The main problem is in rejection of the proteins they have to mix the  insulin with. If they can’t conquer that, the efficacy will disappear rapidly.


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## novonord

Guess you're right Mike, the conjugate is based on lectins, proteins that when introduced to subjects many of whom already have a tendency to autoimmunity as dm type 1 or type 1.5 with or without other autoimmune conditions, eg thyroid disorders, pernicious anaemia, addison's, coeliac, rheumatoid, lupus, might provoke a further strong immune lupus like reaction to the foreign protein.The FDA takes a particularly careful line on adjuvants and this sort of thing; the Stability of the lectin in the systemic circulation is also unknown until tested in clinical trials.


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## mikeyB

Or, in my case, Ulcerative Colitis, asthma, chronic pancreatic plus whatever is eating away my motor neurones, so how I would react to foreign proteins is a point of interest.


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## novonord

much discussion in the press today over the soaring hike in costof T3 treats some forms hypothyroidism.... many on here are sufferers.
seems, from the article in Nature Chemistry, the glucose sensing molecule NN has purchased is likely to be stable and non-toxic in the circulation so the remaining questions are over immunogenicity and whether it can be reliably conjugated to switch off bound insulin rapidly when glucose drops say below 6 or 5.5
lot of interest in the article in  Nature Chemistry, it's on the 98 centile of all published at the time...


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## novonord

another article on the unit DX website; seems this smart insulin being mainly targeted at type 2 though could also be applicable to type 1.
NN claims to be making progress with stem cells for type 1 - it's likely a long road though.


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## novonord

looks as though the main collaborations are with Cornell, for encapsulation, and UCSF for GMP stem cell production for stem cells in type 1...


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## mikeyB

You’ve hit on an interesting aspect to all this, novonord. There is more money to be made treating T2 than T1, so the focus will always be skewed in terms of money for research.


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## novonord

NN claims that stem cells may be ready for testing in 2 or 3 years; would think the authorities would be extremely wary of allowing stem cells to be introduced to the peritoneal cavity without exhaustive studies in other large mammals first- looks as though dogs and mice have been trialled so far. authorities would need to be completely satisfied that all of the cells could be retrieved on every occasion at the end of their useful life or the end of the trial. If it works it would represent definitive treatment for type 1 and 1.5 but the NHS does not have the capacity to perform all the laparoscopic surgery involved- would need to train diabetes physicians and CNS' s to perform the surgery, there are 300 000 type 1 in this country. On the other hand 10% of the NHS budget is presently spent on diabetes, much of it on complications.

as regards the glucose sensing molecule, it looks quite a large entity in relation to insulin. Insulin is about 50 amino acids, this molecule has many benzene rings and 0-, NH2 groups.


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## mikeyB

The techniques to do the laparoscopic insertion are pretty common and low tech, though. But the problem lies in getting it out again if things go awry. I don’t know where the implants have been inserted - do you?


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## novonord

each insertion/removal is not quite straightforward requires a general anaesthetic plus insufflation of the abdomen; don't know how the implant would be positioned in the peritoneal cavity. Don't know, if it works at all, how long it would last- they seem to suggest up to 24 months, possibly but that would mean a lot of operations particularly for those diagnosed at a young age.


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## novonord

not sure how practical stem cells at present would be;
not only would the NHS find it unaffordable but I read somewhere that the Novo Nordisk solution would require a 6 ft ribbon impregnated by stem cells and covered in gel to be implanted to control sugar in an adult male..


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## novonord

reports of a mit/novo/harvard joint venture soma ingestible insulin pill aimed at delivering basal doses/type2.. self-orientating millimeter applicator pill, still many years off probably.


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## Northerner

novonord said:


> reports of a mit/novo/harvard joint venture soma ingestible insulin pill aimed at delivering basal doses/type2.. self-orientating millimeter applicator pill, still many years off probably.


Is that the same as this?

https://forum.diabetes.org.uk/board...oise-could-replace-diabetic-injections.79559/


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## novonord

yes... you spotted this first!

on a different tack it seems carbometrics are recruiting.
just been looking on carbometrics website the other university of Bristol spin-out company sister to ziylo under the same inventors, Destecroix, Davis et al,
seems their glucose binding molecules are produced by a 'streamlined scalable synthesis and are readily derivatised for bioconjugation and chemical synthesis'... they are also 'stable, versatile, offer unparalleled selectivity for glucose and function in the most complex biological mixtures' -  presumably they mean blood.
looks promising after 7 months of collaboration between Novo and Ziylo.


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## Matt Cycle

novonord said:


> 'streamlined scalable synthesis and are readily derivatised for bioconjugation and chemical synthesis'



Eh?


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## HOBIE

Northerner said:


> *Novo Nordisk acquired the UK biotech Ziylo, which develops glucose-responsive insulin treatments for diabetes that act in response to changes in blood sugar levels.*
> 
> The Danish big-pharma, which is already a big player in the diabetes space, acquired the full rights to Ziylo’s technology in a deal worth up to €702M ($800M). Novo will use the technology to develop so-called ‘smart’ insulin treatments for diabetics, designed to be taken once a day, that are only active when a patient’s blood sugar levels are too high or too low.
> 
> Smart insulin could lead to safer diabetes treatments by reducing the risk of low blood sugar or ‘hypos’, one of the main side effects of insulin therapy. Like conventional insulin, the technology is designed to keep high blood sugar, the hallmark symptom of diabetics, in check. But unlike normal insulin, it is designed to ‘switch off’ when blood glucose gets too low, or switch on when it gets too high.
> 
> https://labiotech.eu/medical/novo-nordisk-smart-insulin-diabetes/
> 
> This must be almost ready, they've been talking about smart insulin practically since I was diagnosed, and that was 10 years ago....


Its 50 odd years since I have been hearing about a miracle . Something might happen ?


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## novonord

looking at Novo's capital markets day, they say that smart insulin will be in the clinic in 2020, rather earlier than expected when the partnership with Ziylo was set up, ie phase 1 trials so, if all goes well, will be on the market 3 years later in about 2023, will make millionaires of Professor Davis and his team at Ziylo and may be worthy of a Nobel prize if this gets to market and is a success as it will revolutionise treatment.


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## novonord

nn1845 novo nordisk 'smart' insulin in phase 1 in Germany as of September 30 according to Novo's 3rd quarter research update released today...still early days, have to hope this will be advanced to the next phases and, if successful, could revolutionise treatment....


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## grovesy

Do you have shares in and or work for Novo, as this is the second time you have posted this today?


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## novonord

I am interested in Novo but work in the NHS nearly retired...


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## pinsulin

novonord said:


> nn1845 novo nordisk 'smart' insulin in phase 1 in Germany as of September 30 according to Novo's 3rd quarter research update released today...still early days, have to hope this will be advanced to the next phases and, if successful, could revolutionise treatment....


NN1845 is not based on Ziylo's molecule. It use "diboron" as glucose sensitive group, not Ziylo's GBM (glucose binding molecules). If NN1845 can "cover" all diet meals, fasting period and protect patients from hipoglycaemia (with no need for extra bolus insulin) it would be revolution in a treatment of diabetes and Novo will take all "insulin world market". Does anyone know when we can expect NN1845 to reach the market, if all goes well? In preclinical study NN1845 showed about 5 time stronger potency on 20mM than on 3 mM....witch is very promising!


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## Amity Island

The bit that impresses me is the ability to know and limit the insulin to a specific blood glucose range. It's really amazing stuff. If they combine the smart insulin with a smart glucogon release agent too, that would be perfect.


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## pinsulin

Amity Island said:


> The bit that impresses me is the ability to know and limit the insulin to a specific blood glucose range. It's really amazing stuff. If they combine the smart insulin with a smart glucogon release agent too, that would be perfect.


You do not need "smart glucagon" when you have glucose sensitive insulin with no or very low activity of insulin when blood glucose is low. Glucose sensitive insulin protect patient from hipoglycaemia.


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## pinsulin

NN'S GSI


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## Amity Island

pinsulin said:


> You do not need "smart glucagon" when you have glucose sensitive insulin with no or very low activity of insulin when blood glucose is low. Glucose sensitive insulin protect patient from hipoglycaemia.


Hi @pinsulin

Thanks for your reply, do you know if that would mean one could excercise freely and not worry about hypo's, sounds amazing...so you wouldn't need to eat carbs to excercise?


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## pinsulin

Amity Island said:


> Hi @pinsulin
> 
> Thanks for your reply, do you know if that would mean one could excercise freely and not worry about hypo's, sounds amazing...so you wouldn't need to eat carbs to excercise?


You welcome....with GSI people with DM1 and advanced DM2 (on insulin) will live, work, excercize, sleep..etc free from hypos and from high blood sugar levels. The GSI will cover all fasting period (day and night), so, the main question is would GSI will cover all meals or some meals. GSI change it's potency about 5 times, so at low glucose levels insulin "work" with only about 20% of it's potency...


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## novonord

pinsulin said:


> You welcome....with GSI people with DM1 and advanced DM2 (on insulin) will live, work, excercize, sleep..etc free from hypos and from high blood sugar levels. The GSI will cover all fasting period (day and night), so, the main question is would GSI will cover all meals or some meals. GSI change it's potency about 5 times, so at low glucose levels insulin "work" with only about 20% of it's potency...


thanks for input on this thread: note that the phase 1 trial 68 subjects of NN1845 is complete, though was delayed somewhat by Covid complicating and delaying all trials: will have to wait a few months to see whether Novo will take the molecule further trial, phase 2, or start a phase 1 with the Ziylo construct or abandon the whole programme for the time being. Meanwhile, Eli Lilly has some interesting data on its Terzepatide for type 2.


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## novonord

looks as though Eli Lilly is also keen to develop a glucose-sensitive insulin that 'does away with the need for constant monitoring and multiple daily injections' as it has just announced the acquisition of privately held Protomer which is designing the linker...


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## novonord

pinsulin said:


> NN'S GSI


interesting graphs,could you explain them,presumably the second graph relates to NN's glucose sensitive insulin?


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## novonord

Novo third quarter report-  NN1845 safe and well tolerated in phase 1 demonstrating proof of principle for a glucose sensitive insulin, further work to optimise pharmacokinetic properties, programme continuing....does this indicate the present formulation is not sufficiently rapid in one or all of onset,durability or in switching off at low glucose concentrations?


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## novonord

just been watching novo nordisk's 2022 capital markets day r and d presentation powerpoint, which was held today.
seems the glucose sensitive insulin project NN1845 or NN845 is ongoing through the rest of 2022 in phase 1, looks to me that the pharmacokinetics are troublesome, over longevity of its action in the circulation though they are claiming proof of concept? so the whole formulation may need to be tweaked or the project abandoned,
will try to listen in to the other parts of the day's presentations, seems there are multiple other projects of interest ongoing particularly in the type 2 field. Anyone interested can gain access through the novo nordisk.com website....


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## everydayupsanddowns

It was always going to be a very tricky nut to crack. 

3 or 4 years down the line I guess there will come a time where they will have to decide whether or not the work done so far still has legs.


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## novonord

correction
they're claiming proof of principle for the glucose sensitive insulin NN1845/ NN845 which is less strenuous as a test than proof of concept which has yet to be determined by the looks of it but verdict will be reached by the end of this year on the latter, not altogether encouraging -think the most likely problem is duration of action in the circulation,
they have the ziylo programme possibly to fall back on though that may suffer from the same problem of response duration.


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## novonord

seems that Novo did a second phase 1 study on their candidate smart insulin NN1845 in 30 subjects in Graz Austria.
the control comparison was, surprisingly, levemir suggesting that the smart insulin is not particularly fast-responding and might therefore only represent a better basal insulin rather than a replacement for Fiasp or rapid-acting insulins? Also, the trial involves 6 hourly injections suggesting that durability in the circulation is not great. Results may be announced August 4 or by the end of the year.


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## novonord

meanwhile Vertex is trying to corner the market in stem cell therapies for type 1, having just acquired Viacyte, although Novo Nordisk is active in this field also.


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