email reply from phylogica management

Hi BioExec,

I just received an email reply from Phylogica Management in relation to a few of the comments you made in your earlier post.

Here is their reply.

Regards,
Tony



BIOEXEC

since Tat is from virus and has been around for 25 years and everyone and their brother has worked on CPPs for a long time with little to show for it, so their are a lot of doubters, like it or not.

PHYLOGICA MANAGEMENT

We do not agree with this assertion. Since 2000 there have been over 20 phase I and II clinical trials performed where cell penetrating peptides have been used to deliver peptide, protein or oligonucleotide cargoes. These POC trials confirmed the first generation of CPPs (eg TAT) are therapeutically active and non-toxic. This has subsequently led an explosion of interest in the new field of CPPs, which is now recognized as one of the hottest areas in drug discovery, as it provides a means of accessing the 80% of potential targets which are inside cells. Less than 10% of such targets are amenable to conventional small molecule intervention. Delivery of biologics via CPP’s therefore, presents a major opportunity for the pharmaceutical industry. Phylogica is as the forefront of these developments as evidenced by the fact that 2 of the 4 of deals the company has done with large Pharma are focused in this space – a clear endorsement for the potential of the platform.

BIOEXEC

Developing a system to find peptides that get out of the endosomal pathway and to cytoplasmic targets is a very nice technology, especially since their cell selective peptides all appear to hit extracellular proteins specifically to those cell types that recycle into cells via endosomal pathway ((not surprising since viruses and bacteria are usually engulfed that way)).

PHYLOGICA MANAGEMENT

We agree. As part of the collaboration with Janssen, Phylogica is developing a unique second generation screening platform designed to i) specifically capture CPPs that have escaped from the endosome and into the cytoplasm and ii) improve the hit-rate for cell-selective CPPs. By so doing we can overcome many of the limitations of competing CPP discovery platforms and hence clearly differentiate ourselves from our peers.

One of the approaches we are using to achieve this goal is to further enrich our libraries to include natural virulence factors from pathogens that have evolved for cell penetration – a unique property of the Phylomer libraries that enables us to leverage off billions of years of evolution.

The ‘BioExec’ poster also notes that a number of the Phylomer CPPs function by binding to extracellular receptors in a cell-specific manner. This is a very powerful feature that is not typical for the classical class of TAT-like CPPs, which are non-specific. Non-specific CPP’s such as TAT typically need to be added at much larger concentrations, as they are distributed throughout the entire body rather than just at the tissue type associated with the disease. At these high concentrations, they can show side effects and may not meet dose thresholds for a feasible cost of goods of the ultimate drug.

BIOEXEC

Important to note that cyclosporin A and Tat do not go through the endosomal pathway, and some peptides do directly penetrate via passive diffusion.

PHYLOGICA MANAGEMENT

This statement is not consistent with the current (incomplete) understanding of the mechanism of uptake of cationic CPPs such as TAT. Current thinking is that at high concentrations (ie. 10µM), TAT-like peptides are able to translocate directly across cell membranes after initially making contact with negatively charge heparin sulphate displayed on the cell surface. At lower concentrations (ie, <10 µM, which are therapeutically relevant) the evidence clearly shows that TAT prefers to enter cells via a range of classic endocytotic pathways (macropinocytosis, clathrin and caveolae dependent), after initially interacting with negatively charged components of the cell surface via heparin sulphate proteoglycans. Notably, these pathways are not specific for particular cell types as they are not receptor-mediated. Phylogica is working largely on receptor-mediated endocytosis, which can be tissue specific, and several of its CPP's are negatively or neutrally charged, emphasising that they are not like TAT.

BIOEXEC

So you can't buy everything they are saying in their slides cause they are just focusing on the part of the story they want to sell, which is business. Some of the posts on this page act like these guys have come up with something no one has ever thought about, and it just couldn't be farther from the truth.??If you read between the lines on Nick's comments, they really haven't started much work on their internal pipeline, he said waiting for sustainable revenue before attempting new programs. I have no doubt they are focusing all efforts on the Jansen project right now, as they should be, and/or trying to convince Roche to do something with those previous BEN peptides. ??I think Tony said CD40L program was worth $400M at one time on a post here. I applaud Tony and Wayne for diving into the science and trying to figure out what a company you are invested in is really doing and where their position is. I think that is fantastic. But with that, you would be wise to review some of these fields or therapeutic spaces they are going after, for example you would find that CD40-CD40L was one of the hottest targets 10-15 years ago, many inhibitors identified, many looked fantastic in mice models, all failed in humans, cause 1. mice didn't model humans at all for inflammation/immune disease, and 2. CD40-CD40L interaction is important for B cell development and alot of important functions, making its targeting very difficult (side effects). You would see that numerous antibodies failed, even though through mouse data, the data was fantastic.

PHYLOGICA MANAGEMENT

Evidence from animal models (rodents and primates) generated at the time of the initial clinical trials of the pharmaceutical industry did indeed strongly support a causative link between CD40L inhibition and a positive therapeutic outcome for a range of indications. However the assertion that the clinical trials ‘all failed’ to show any therapeutic benefit is not supported by the scientific literature nor the views of key opinion leaders we have discussed the matter with – including ex-members of the Biogen team involved in the early clinical programmes.

By way of a brief history:

Between 1998-2003, a number of Phase I and II clinical trials were initiated using 2 different humanised anti-CD40L antibodies – BG9588 (Biogen) and IDEC-131 (IDEC). Indications ranged from systemic lupus erythematosus (SLE), psoriasis, idiopathic thrombocytopenic purpura (ITP), Crohn’s and transplantation – reflecting the key role played by CD40L in many inflammatory-based diseases.

For BG9588, a Phase II trial in lupus-related nephritis involving 28 patients was halted prematurely after 2 patients experienced thromboembolic complications (myocardial infarctions). Importantly, of the 18 patients who could be evaluated a number showed significant improvement in key measures of disease that suggested the antibody was having some therapeutic benefit. As a consequence of the thromboembolic events, all other Phase I/II clinical trials involving BG9588 were prematurely halted. Given the lack of data, it is not possible to draw any conclusions regarding efficacy in humans.

In contrast to the Biogen antibody, evaluation of IDEC-131 in a range of Phase I/II clinical trial showed it was very well tolerated although a single thromboembolic event was recorded in a Crohn’s disease patient. As a consequence, all ongoing anti-CD40L clinical trials using this antibody were also prematurely halted pending the outcome of studies aimed at better understanding the mechanism of action of these antibodies (see below for further details). Reasons for the lower frequency of thromboembolic events observed with the IDEC-131 antibody compared to BG9588 include i) the former targets a distinct epitope on CD40L and ii) the maximum dose used was approximately half that of the Biogen antibody.

In terms of potency, a phase II open label trial in 85 patients with mild to moderate SLE failed to show any efficacy following treatment with IDEC-131 whereas a phase I trial in 5 ITP patients showed that antibody treatment suppressed a number of key measures of diseases suggesting that IDEC-131 was potentially efficacious.

To conclude, the vast majority of clinical trials involving the CD40L antibodies were prematurely halted due to thromboembolic complications and NOT to due to lack of efficacy, which remains to be determined. The fact that Biogen have re-initiated Phase I/II clinical trials using a new generation of antibody fragments, which avoid the complications experienced with the antibody-based therapies, confirms the continued interest from Pharma in developing therapies against CD40L.

BIOEXEC

You would ask yourself, how is a big peptide any better than the past molecules, which were excellent.

PHYLOGICA MANAGEMENT

The answer to this question underlies our rationale for choosing CD40L as a therapeutic target. As noted above a number of clinical trials that were initially undertaken using anti-CD40L antibodies were halted due to thromboembolic complications. Subsequent studies confirmed this was caused by antibody-related cross-linking of platelets, mediated by the conserved Fc domain found in all immunogloublins (ie. Abs). By using a truncated form of the antibodies (Fab’s), in which the Fc portion has been removed, researchers were able to show the clotting effects could be avoided. Importantly as Phylomers lack any Fc effector function they can similarly avoid the complications experienced by the antibody-based clinical trials – hence providing a competitive advantage.

In addition, peptides (unlike antibodies) have been successfully delivered by the intranasal route rather than by injection (eg. calcitonin, vasopressin, GNRH). Intranasal delivery can greatly expand the market for biological over injectable drugs.

BIOEXEC

No one will touch CD40-CD40L with a ten-foot pole now unless you took it into humans yourself.

PHYLOGICA MANAGEMENT

This statement is simply not supported by the facts. Phylogica is actively engaged with several large pharma companies interested in licensing PYCs CD40L program. As part of these discussions we have been provided with the benchmarks required to compete with the new generation of anti-CD40L therapies that have recently entered Phase I/II clinical trial and have been tailoring our internal programme to meet these thresholds accordingly.

Moreover, Biogen/UCB are currently evaluating a Pegylated anti-CD40L Fab in Phase 1 clinical trial for systemic lupus erythematosus (SLE) and a Phase II clinical trial for Amyotrophic Lateral Sclerosis (in conjunction with the ALS Therapy Development Institute) confirming that CD40L is still an attractive therapeutic target.