Humanigen Inc (HGENQ)

[bobshmob]

Great call! Detailed summary below.

Dale Chappell is great...addressed most of the questions I've been wondering about. Audience questions were also (mostly) really good.

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[the few comments in brackets are my own thoughts]

Participants: Cameron Durrant, Dale Chappell, Omar Ahmed

Durrant---
~2:00
introduce Tim Morris: manufacturing and supply chain, corporate and business development, investor and public relations, and human resources.

~4:00
BET: market has not recognized the importance of lenz being selected by NIH as a high priority therapeutic from among many possibilities. NIH similarly picked remdesivir and then baricitinib. Not likely to select second anti-GMCSF.

~5:00 "natural history" of the disease: virus, viral pneumonia, CRS, death. Purpose of the lenz P3 study is to prevent CRS after the viral pneumonia

7:30 IL-6 inhibitors haven't been tested in RCT; tocilizumab has failed 2x in RCTs for covid-19. Sarilumab failed in two studies as well. Need to go upstream, as with lenzilumab, not just blocking a single cytokine.

9:00 competitor treatments are dropping out. Lenzilumab is farther advanced anti-GM-CSF in its progress through RCTs. Nor do they have the data that we do...Mayo EINDs and new data to share with you in the near term.

9:45 BET design: lenz + rem versus placebo + rem; 200 patients. Builds on NIAID ACT I study showed significant reduction in hospitalization time with rem. ACT II and others to follow. Maybe lenz + rem are synergistic, complementary MOA. Trial fully sponsored and conducted by NIAID.

Chappell--
12:15 planned interim analysis after n = 50 patients in each arm. Endpoints expected to be similar to those used in ACT I that gave rem EUA. Comparing just to rem will provide some clarity b/c current trial compares to SOC, which can vary.

15:10 compare lenz EINDs with rem in trials...their table 1's are similar [but lenz patients start from a worse position w.r.t. O2 needs and diabetes]. Small sample, not in same hospitals so treatment protocols may vary. No placebo control, but rem gives a standard for what is approvable. lenz seems to crush that standard in terms of time to recovery (5 v. 11) and % with clinical improvement at day 14 (100% v. ~60%).

17:44 graph of time to improvement shows clear advantage of lenz over "placebo" (i.e., lopinavir + ritonavir), remdesivir, and even mavrilimumab [which is a GM-CSFr blocker]. much bigger gap between lenz and rem than between rem and placebo.

19:10 plan to provide a data update on P3 study in near future

Questions--
19:45 Jim Burkinaw with Wells Fargo: what's the advantage of targeting the ligand over the receptor?
20:35 Chappell: pulmonary alveolar proteinosis (PAP) is a danger if you completely block GM-CSF signalling. GM-CSF is required for terminal differentiation in the alveolar macrophage, and if you don't get that, you get PAP, which causes difficulty breathing. If you target the receptor [on the cell], you prevent basal signalling, so you can get PAP, which has been observed in primate studies with some competitor compounds. We've done high-dose, longish-term studies with lenz in primates and have seen no evidence of PAP, no have we seen any indications of PAP in our human studies (two P1 and two P2) with lenz either. Targeting the ligand rather than the receptor allows a little time for signalling, so it is not entirely shut off. This raises questions about dosing issues...[due to the little gap between GM-CSF production and binding to lenz, there is more wiggle room for dosing and adjusting titers to meet conditions], and targeting GM-CSFr does not allow as much room or as much of a possibility for using large doses if needed (which we believe will be necessary).
22:35 Chappell: we are the only one out there with an anti GM-CSF in a P3 trial [except mavrilimumab? https://clinicaltrials.gov/ct2/show/NCT04447469], also the only to do P2 for pulmonary condition--severe asthma--and showed improved blood work in some patients. We've worked on dosing for CAR-T and are using what we leared there for covid-19. We think our competitors are significantly under-dosing for severe covid-19 [maybe because they need to worry more about PAP b/c targeting the receptor?] b/c basing their dosing (apparently) on what they've learned in RA or other chronic condition. RA doses are not sufficient for sufficient lung penetration to prevent CRS.

24:30 Jim Burkinaw: when can we expect to hear something about results from P3 and BET? what about the RCT "powering" [presumably, he means statistical power to detect clinically significant effect] and what do you expect in terms of effect vis-a-vis placebo?
25:00 Chappell: P3 expect data in Q4. Assuming some slippage in our P3 trial relative to the 5 days recovery in our EINDs and the 11 days recovery for rem.

26:00 Jim B: same kind of cytokine storm in covid-19 as with CAR-T therapeutics? Anything in the tocilizumab and sarilumab patients that leads you to question anything about the biology in the severe covid-19 patients?
26:45 Chappell: animal studies show you can knock out IL-6 or IL-1 or IFNg and it doesn't prevent cytokine storm. Knock out GM-CSF -> no CRS. There is anecdotal data for tocilizumab in CAR-T but no RCT data; we think it wouldn't work, especially since it failed in covid-19 RCTs. Not worried about what failure of IL-6s might say about lenz because we know for certain that covid-19 CRS is a myeloid cell driven pathology and GM-CSF neutralization significantly impacts myeloid cell activation, trafficking, and production of downstream cytokine. Our enthusiasm hasn't waned at all. and that dexamethasone has shown a mortality benefit clearly points to this being a hyperinflammatory pathology. lenz hits the "sweet spot" between something that is too immunosuppressive [dexamethasone and maybe GM-CSFr blockers] and things that are too narrow, like IL-6 inhibitors. lenz affects many downstream cytokines but not viral T-cell responses.

29:45 Durrant: we have much more experience studying GM-CSF antagonists for CRS than anyone else and are farther along in our trials---which is what NIH recognized when they selected us. More compassionate use data will be shared soon, along with some other insights that we have. strong position for EUA or conditional approval.

31:00 Louise Chen with catsoff fitzgerald [muddled]: the RCTs inclusions are restrictive, how do you see this working out in the real world? usage on top of rem?
32:00 Omar Ahmed: target population is hospitalized patients with pneumonia but not yet respiritory failure.
33:30 Durrant: 130000 patients expected, or maybe 237000 that meet those conditions.

34:15 Louise Chen: pricing?
Durrant: can't talk specifics yet but we know rem is $2340 in govt setting and $3120 for commercial payers. That's in context of hospitalization costs of ~$12000. lenz could be priced to cost of value...in US, cost of ICU is $10000-15000 per day or $15-20000 in covid setting. Lenz would be a significant cost savings.

35:15 Louise Chen: status of commercial preparations and supply capabilities?
Durrant: we have engaged companies and are making rapid progress, with target to be commercial ready this calendar year. bottleneck in manufacturing because biologic manufacturing capacities are being scooped up by, e.g., vaccines. too bad that so much of the manufacturing bandwidth has been taken up by chemicals with so little data [it must help to hook up with Gilead and NIH!] ; we will soon have a ton of data. We have manufacturing slots set up with multiple contrators and feel confident we'll be able to supply lenz this winter. We'll also try to increase capacity sooner.

37:15 Tony Butler (Roth Capital): RCT for P3 finish in sept and BET coming about the same time? Outcome measures the same?
Chappell: clinicaltrials.gov is slow. Expecting to enroll 300 patients in P3 with primary endpoint = time to recovery (through day 28). Haven't announced BET endpoints but will be similar to ACT 1 and ACT 2.
40:00 Tony Butler: in P3, it is lenz vs. placebo + SOC...
Chappell: ...and that SOC varies by site. May include rem sometimes, not other times.
41:10 Tony Butler: timing of data?
Durrant: we will release P3 data when it's available and not hold any back to wait for BET. NIH can recruit very rapidly, so maybe they can catch up.

42:40 Olga Smolitkova with Grime Guardian [muddled]: any long-term consequences of GM-CSF treatment?
43:30 Durrant: GM-CSF is a misnomer. It should be called myeloid inflammatory factor. Decades ago it was thought to be an obligate haematopoitic growth factor, but it is now known that that is not the case. Some of the theoretical questions about GM-CSF have proven not to be the case [questions inspired by the misnomer and the obsolete (mis)understanding of its role].
Chappell: no evidence of PAP or infections in our trials. In covid-19, we are intervening in a stage where the hyper-inflammatory immune response is really driving the pathologies, where patients are becoming hypoxic, they have inflammatory markers, they are progressing sometimes fairly rapidly to ARDS. In that setting, blocking myeloid cell activation...we know the pathologies are driven by the myeloid cell activation and their downstream inflammatory cytokines. We also know that part of the pathology is due to lack of T-cell response. The severe patients all have lymphocytopenia...this is one of the reasons that the virus may not be totally eliminated and why there might be chronic stimulation of the immune response that continues to go on. In our EIND data (and we'll show more soon), we see that when you blunt GM-CSF, you improve lymphocyte counts pretty quickly. Theoretical concerns about infection might actually work in reverse. Blocking the hyper-inflammatory response may improve the CD8 driven responses and help fight off the virus even better. This will differentiate lenz from the steroids, JAK inhibitors, and maybe even BTK inhibitors.

Durrant: (closing remarks). we're excited.