Biotech Values

[mcbio]

Re: IFRX vs CCXI

I follow the work of each company, and my view is that the difference is in the degreee of blockade of the C5aR by each company in the clinic. I think investors in the biopharma field under-appreciate the extent to which a receptor blocker actually achieves, considering that receptor occupancy is sigmoidal and hence complete blockade is difficult to achieve. It is also of interest that the classical neutrophil C5aR (the originally named CD88 protein) is considered to have a 'hair pin trigger'.

Thanks for the comments. I think the CCXI argument is they hit C5aR specifically (whereas IFRX hits C5a more broadly upstream) but certainly would be important to know how well CCXI's avacopan truly blocks C5aR.

The field of C5a small molecule antagonists has been an active one for many years, with a limited amount of chemical matter having drug like properties having been identified. The CCXI compound is considered 'bricky', with relatively poor drug like properties including solubility. The question to ask CCXI management is to what extent they have C5aR blockade, at both peak and trough blood levels. Also whether the drug hits the second C5a receptor (see below).

CCXI seems to imply avocapan does not hit C5L2. See slide 16 of: http://files.shareholder.com/downloads/CCXI/6019127124x0x968844/82BAAA9A-8A2F-4977-9C9C-FF93DF0FC5E9/CCXI_Corporate_Presentation.pdf . Is there a concern that IFRX drug would impact this receptor since it more broadly hits C5a and C5L2 falls downstream of this target?

As to IFRX, they have some fantastic C5aR biologists that had extensive training in Peter Ward's lab in the Dept of Pathology at the University of Michigan. They appear to have in IFX1 a novel C5 mAb that may block cleavage by the convertase, but also by 'rogue' plasma borne proteases. It is not clear to what extent this may be significant. They have shown compelling activity in HS, though much more needs to be done. My view is inflammatory skin disorders are where the action will be for C5 approaches, as in hydradenitis supportiva, lichen planis and the like.

Yes I dug more on IFRX data and see the P2 PoC data here: http://www.inflarx.com/Home/Investors/Press-Releases/09-2017--InflaRx-Reports-Topline-Phase-IIa-Clinical-Results-of-IFX-1-for-the-Treatment-of-Hidradenitis-Suppurativa0.html . Seems impressive that had 75% response rate (9/12 patients) at week 8 and 83% response rate at week 12 followup (week 20) given 9/12 patients were refractory to anti-TNFs.

I listened to IFRX Leerink presentation and thought there were some good points:

1. IFRX said only two other companies went into clinic behind IFRX targeting C5a specifically (ALXN and AZN/Medimmune). Noted that ALXN discontinued their own anti-C5a antibody, 107, after Phase 2 data recently. AZN/Medimmune discontinued several years ago after Phase 1 data. It would seem that IFRX is by far the leader in going after C5a but it would also be important to know why these others discontinued their drugs. Was it due to a drug-specific issue or is there read-through to IFRX drug as some class effect of broadly targeting C5a (as opposed to C5aR more specifically)?

2. Said they plan to move into oncology space soon based on promising approach. Not sure if they are planning on something similar to what IPH.PA is doing (https://www.innate-pharma.com/en/pipeline/iph5401-first-class-anti-c5ar-mab ) though IPH is doing similar to CCXI in going specifically after C5aR.

3. Did seem to at least provide some independent validation of the CCXI data in AAV. But, they claim their drug as an IV (vs. avacopan being an oral drug) could be better because it could act much quicker and provide quicker induction of remission compared to SoC. They also note that by blocking C5a and not its receptors it may allow the IFRX drug to avoid safety concerns arising from indirect off-target effects. I wonder if they are referring to C5L2 specifically here and not also C5aR (again avacopan only hits the latter according to CCXI). I would also want to better understand again why in hitting C5a upstream that the IFRX drug wouldn't have any impact on C5aR or C5L2 directly downstream.