I've been messing around with
epidermal growth factor (EGF) lately, having a look into it. There's a lot to EGF, with a lot yet to be learned about it and how to use it therapeutically.
I started with the presentation that accompanied the webinaire, much of which forms part of the current corporate presentation. In the presentations, the discussions of Cresence and the EGF programs referenced a paper released by
Prof. Ferdinando Nicoletti in 2019. Dr. Nicoletti was present on the webinaire.
I was also prompted to look further into EGF when DrDR stated that CRES101 crosses the blood-brain barrier and that it was a small molecule. I took some issue with the "small molecule" statement, especially with it being mentioned within the context of crossing the BBB. CRES101 is described as a recombinant peptide so I doubted it was a small molecule.
First of all, I wanted to have a look at
Nicoletti's paper but I had to pay US $35 for a single day and I wasn't going to do that. However, there was a Cresence advisor present on the webinaire by the name of
Prof. Giuseppe Scalabrino. In 2020 he issued
a paper that summarized many aspects of EGF functions and possible benefits. In the paper he references many other papers including that of Nicoletti from 2019.
EGF has many possibilities with respect to neurodegenerative diseases, one of the most interesting being its remyelinating effect in MS and other diseases where the
myelin sheath that surrounds nerve axons has been damaged, causing short-circuiting of nerve signals. It looks like EGF, through a complicated process, has restorative effects on the myelin sheath.
EGF is produced both in the brain and in the periphery (liver, salivary glands and other places). According to Prof Scalabrino's paper, "EGF levels are significantly lower in the cerebrospinal fluid and spinal cord of patients with multiple sclerosis (MS)." The work done by Cresence has been to determine if administered EGF can help MS patients and others who have demyelinating diseases.
This is where it gets interesting for Bioasis investors. EGF created throughout the body (endogenous EGF) and released into the blood stream can cross the BBB, and combined with EGF produced in the CNS, work together in the CNS to maintain healthy myelin sheaths and other structures. EGF produced in the periphery and released into the blood stream crosses the BBB via its own receptor, the EGF receptor, EGFR. It does not appear to cross by virtue of its smaller size.
So it would seem that injecting a man-made (exogenous) EGF, which is what CRES101 is, could augment the low levels of EGF in the CNS and not only prevent demyelination but could also cause restoration of myelin.
However, it appears that not only EGF uses the EGF receptor on the BBB. This receptor is multi-functional and is described as being easily saturated. This means that no matter how much EGF is administered to a patient, either not enough can get across the BBB, or high levels of EGF on the EGFRs may cause saturation of the receptors, and in the process may inhibit other critical processes that use this receptor.
And this may be why Cresence needed xB3. xB3 may be able transport EGF across the BBB without interfering with the EGF receptor, leaving EGFR unsaturated and able to handle other processes.
Bioasis's description of CRES101 as having the ability to cross the BBB is correct but it does not cross because of its size. CRES101 is not a small molecule, as near as I can determine, despite what DrDR says. To Bioasis investors, a small molecule has a molecular weight of less than 400 to 600 Daltons, small enough to squeeze through the tight junctions between BBB endothelial cells. Further, the small molecules must be lipid soluble and not water soluble. About 98% of small molecules cannot cross the BBB.
So, what is CRES101? CRES101 is described by the company and Cresence as a recombinant peptide, meaning that it has a man-made structure. (Exact human forms of proteins, peptides, etc cannot be patented.) Natural EGF is a peptide consisting of 53 amino acids. With a quick look, I discovered two companies advertising recombinant EGF, with both versions having 53 amino acids. Perhaps Cresence found a way to make their version smaller, but I doubt very much that they got it down to small-molecule size, not as we understand small molecules. The molecular weight of EGF is about 6400 Daltons, ten or twelve times the size of a small molecule. I suspect that CRES101 has a molecular weight similar to EGF and that it can't cross the BBB other than via EGF receptors. Natural EGF and the recombinant versions I found are all water soluble, further inhibiting their ability to passively cross the BBB.
To me, it means that CRES101 has little chance of being a viable drug on its own. The upcoming clinical trial, however, could very well prove that whatever amount that can be administered and that can enter the CNS, may have efficacious qualities, but because of possible interference with EGF receptors and limited delivery quantities, that prolonged use and efficacy may be questionable. The fact that it was sold to Bioasis at such low cost supports this question.
And that, of course, is where xB3 comes along. CRES101 and the other CRES drugs could have immense value if delivered with xB3. So, Bioasis gets to immediately call itself a clinical stage company, while at the same time proving that recombinant EGF (CRES101, etc) could be valuable payloads for xB3, thereby creating thoroughly unique and valuable xB3 drug programs for demyelination diseases.
One other interesting thing popped up. At first I considered the possibility that EGF passively crossed the damaged BBB in people with some of the demyelination diseases. All of these diseases appear to cause damage to the BBB by opening the tight junctions between the endothelial cells of the BBB. And then I discovered that EGF crosses the BBB via the EGF receptor. But it turns out that EGF has an interesting effect on the BBB. It appears that EGF causes the tight junctions of the BBB's endothelial cells to tighten up, helping to heal the damaged BBB in sufferers of these diseases. This could turn out to be another valuable use for xB3-EGF.
So, Bioasis gets to call itself a clinical stage company, a very important consideration for serious investors. And then, taking the company's word that xB3 is still performing as always hoped, the company is creating a great story, advancing to the clinic in the short term and possibly having business development deals poised to validate xB3, where the real value lies if xB3 comes through.
Finally, I have to comment on DrDR's way of describing things. I don't believe CRES101 is a small molecule as she stated. To investors it can cause the wrong perception, that CRES101 can cross the BBB by virtue of its size, which doesn't appear to be true. At best it's a smaller payload than xB3 is usually called upon to deliver. EGF, at 6.4 kD, is small compared to Herceptin (xB3-001) at 148 kD. Enzymes, some of which are xB3 payloads for LSDs, are 10 kD and higher.
I worry that Bioasis would not be bothered too much if it was thought that CRES101 had a clear path to commercial viability. But, also, I wouldn't think that Bioasis would want its "clinical stage" characterization to be questioned because CRES101 may not be of much value without xB3. Smart investors may think that the Cresence deal was a stunt by Bioasis to call itself clinical stage, when, in fact, the upcoming trial is very important for the advancement of EGF as a therapy, whether alone or assisted by xB3.
Asa I have previously discussed, the press release announcing the Cresence deal failed to assure many investors that xB3 was still a part of Bioasis's future. I got a lot of calls about that one. DrDR needs to more carefully consider how lay people might interpret her words, words that I am sure are completely understandable to her.
About CRES101 and all the little EGFs, time will tell if I am interpreting what I have read in accurate ways. I have never sent anything I have written to Bioasis for approval. I have raised some questions here. You can always check things out by calling Bioasis or IR all by yourself. Post the answers you get because they can't tell you anything that they can't tell everybody else.
jd