Novo Nordisk is finally starting to make moves.
With a semaglutide, Novo Nordisk not only took the lead in breaking through the first-class drug track and became the leader, but also became the most powerful contender for the new drug king "Keytruda" as the first approved drug for obesity or overweight and other complications.
But semaglutide is also under extreme pressure.
It was followed by Eli Lilly's GLP-1 GIP dual agonist, tirpatide, which was superior to semaglutide in all respects. And that's not all,Eli Lilly also has the world's fastest progress GLP-1R GCGR GIPR three-target agonist, Retatrutide, in the GLP-1 track
There are also Pfizer, Amgen, Roche and Novartis all taking the path of GLP-1 receptor agonists, and for a while, the ** track has become a red sea.
**The medicine track has found a new way
How does Novo Nordisk break through?
Although the GLP-1** track has been flooded with a large number of players for a while, there are still two bottlenecks that have not yet been solved. One is that losing weight will lead to muscle loss at the same time; The second is that after stopping the drug, the weight is obvious**.
In order to solve these problems, each company has also started to differentiate, trying to break the bottleneck and find a breakthrough, so as to achieve corner overtaking on the first-class medicine track.
Not long ago, Bioage conducted a phase clinical trial with Eli Lilly tirpatide to evaluate the effects of BGE-105 in combination with low-dose tirpatide** in obesityWith the name of "fat loss and skin preservation", it has opened up a new idea of the competitive landscape of GLP-1, and has also successfully made it attract gold in the D round of financing$700 millionRelated reading links: Suck 1700 million US dollars in financing, behind the dark horse of the first-class drug track, AI technology is the key
Eli Lilly is the first to take the lead in the drug track, passing in the direction of fat loss and muscle gain to 19The $2.5 billion acquisition of Vertanis and the investment in Bioage Labs continue to bet on the way to get the first step into the new era.
On the other hand, in the bottleneck of drug discontinuation, NLRP3 inhibitors have also begun to emerge. Researchers from nodthera said that under theMice treated with NLRP3 inhibitors were able to maintain weight loss after discontinuation of the drug。After discontinuation of GLP-1RA, weight can be stabilized by taking transcerebral NLPR3 inhibitors, thereby preventing body weight**. In this way, the combination with GLP-1 drugs also provides a new direction for finding the differentiation of the first-class drug track. （Related Reading Links: Beyond GLP-1? *And not** New targets are born
On this road of differentiation, Novo Nordisk introduced an NLRP3 inhibitor Vent-01 from Ventus for a total amount of $700 million as early as 2022, but it did not make further moves, which makes people anxious. In the face of the encirclement of a number of ** drugs, how can Novo Nordisk break through?
pick1、psd-95
Novo Nordisk breakout chance
It has been proven that Novo Nordisk has been on the road of stopping the drug and maintaining the weight loss effect.
Recently, researchers at Novo Nordisk have taken a different approach to analyze the open UK biobank using human genome-wide association studies (GWAs) to analyze the open UK biobank with long-term effect and fat loss as key indicatorsProteins that interact with C-kinase (PICK1) and postsynaptic density protein (PSD-95) were found to play an important role in weight regulation.
Source: Literature [1], the same below.
In animal experiments, daily subcutaneous injection of a dimeric peptide-based PSD-95 inhibitor (UCCB01147) was able to reduce body weight and food intake in DIO mice in a dose-dependent manner. To further ensure that UCCB01147-induced weight loss is not driven by off-target effects, the research team introduced two alanine mutations in the pentapeptide to produce a peptide with a similar chemical structure but essentially no binding to PSD-95 (UCCB01-144AA).
The results showed that the use of UCCB01-144AA** did not affect body weight or food intake, indicating:The ** effect of UCCB01147 is mediated by inhibition of PSD-95。On the other hand, the effect of nerinetide (NA-1), a weaker monomeric peptide-based PSD-95 inhibitor, was also demonstrated. In dio mice, equimolar doses of Na-1 reduced body weight and food intake, but were not as effective as UCCB01147.
In summary, the above results are highlightedPharmacological inhibition of PSD-95 is a promising weight-loss strategy
On the other hand, in order to study the functional role of pick1 in energy homeostasis, the research team developed a lipid variant of a selective dimer pick1 peptide inhibitor (MPD5), which is supported by the research dataMPD5 dose-dependently reduced body weight in obese mice, and a dose of 56 mg kg was determined to be well tolerated in chronic studies
To further confirm the target specificity of MPD5, a 7-day weight loss study was performed on Pick1 knockout mice fed with a high-fat diet. The study found that it was observed in dio wild-type littermate miceThe weight and food intake reduction effects of MPD5 were completely disappeared in Pick1 knockout mice, which just indicates that the appetite suppression and ** effects of MPD5 are mediated by Pick1.
To evaluate the long-term metabolic effects of MPD5 and UCCB01-147**, the research team conducted an additional 13-day study**, followed by a 29-day weight recovery period.
Consistent with previous studies, both compounds had a significant effect over a 13-day period, which was reflected in a reduction in body fat mass. It is worth noting that inAfter 4 weeks of cessation**, the body weight of MPD5-treated mice still did not catch up with the control group, suggesting that pick1 interference may have a lasting effect on body weight
In another follow-up study, MPD5 evaluated the sustained** effect of the GLP-1 receptor agonist liraglutide. After cessation**, mice with MPD5** maintained weight loss for approximately 8 days. In contrast, mice with liraglutide** began to regain their body weight immediately after cessation**。Up to day 35, the weight of liraglutide-treated mice was comparable to that of the control group, while the weight of MPD5-treated mice was significantly lower than that of the control group.
Pick1 and PSD-95 were previously identified as potential targets for neuropathic pain and stroke drugs**, respectively, and were demonstrated in this studyDimeric peptide inhibitors of Pick1 and PSD-95 can selectively reduce body weight and fat mass, and sustained weight loss after cessation**
References. 1]doi: 10.1126/sciadv.adg2636