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howdy, BorelFields. HGEN did change the primary endpoint for their P3 trial from mechanical ventilation + mortality to "time to recovery." At the same time, they boosted the planned sample size from 238 to 300 and tightened the enrollment criteria to push the cohort towards the more severe end of the spectrum. Despite the company spin of "making the endpoint more in line remdesivir's," I took the changes as a bad sign...the effect was not going to be clear enough without boosting the sample size and changing the primary endpoint. Also, Dale Chappell said there would be some "slippage" in results, away form the lovely "effects" reported for the initial 12 Mayo patients in the EIND preprint.
On the other hand, I think the recent data from Mayo are much more promising than the market seems to think, especially in light of the changed endpoint.
I bought some shares before the 08/03 conference call but had serious doubts w.r.t. the endpoint and sample size changes and about the the whispers of substantial share dilution in the not-too-distant future. I kept my shares, though, on the implicit "recommendation" the FDA gave by selecting lenz for BET. I still think it is a good bet for covid-19 success, but maybe I should have waited until next week to buy!
It"s grotesque. Excessive, premature, exploitative...adds to the negative public perception of the management as over-paid but under-performing, the company as over-hyped in service to SP in the short-term.
Au contraire....should have put more thought into picking the primary endpoint.
THAT is the most rational decision FDA could make, which makes it highly unlikely.
Yup. Big pharma HATES the idea of a allowing a right to use drugs that are safe but have not yet conclusively demonstrated clear and impressive efficacy. That sort of demonstration that big pharma and their buddies in the FDA want to see is very expensive and time consuming---an excellent filter for keeping potentially life saving drugs from small, new, would-be competitors (like CYDY) out of the market for longer, making it all the more difficult for them to succeed.
We need more effective therapeutics, and if something out there is safe and looks effective for some patients (like leronlimab, HCQ, convalescent plasma), why not allow patients and their doctors to make the decision for themselves? BP has a ready answer: "Because that opens the door too much to competition." And, yes, they might eloquently couch that argument in the language of "science must decide!", but what that really means is writing the rules to most advantage themselves. In the meantime, thousands upon thousands of patients die as safe and promising treatments like leronlimab flounder in a molasses-slow, BP-protecitng bureaucracy.
EUA essentially requires safety + reasonable expectation of effectiveness. Enough of the BP treacle. Get leronlimab out to the people who need it.
"2. Do you really, actually, had-to-bet-all-your-CYDY-stock think that the President's FDA/medical advisors/appointees would downplay or minimize Leronlimab's success because we are not in the big pharma 'club?' "
Absolutely. It's not that they say, "CYDY is not a member of the club, so let's minimize its success." Instead, as scientists, they are trained to be skeptical and ask questions. The game is one of eliminating doubt. When big pharma approaches the feds with results, they can afford to have put together an impressive data set wrapped in an equally impressive presentation. A long history of proven work in the past combined with long-held working relationships with FDA give their work a natural benefit of the doubt in evaluation.
CYDY? No way. They get the detriment of the doubt. A smaller study with bungled endpoint definition and less impressive presentation coupled with a CYDY management team that habitually generates doubts (about virtually everything) translates into great difficulty in removing doubts and getting approvals. This is an inherent problem in virtually any small pharma company, perhaps especially so with CYDY because of their hype-machine that always seems to be in overdrive.
The EUA standards are essentially: 1) demonstrated safety, and 2) reasonable expectation of efficacy. Leronlimab easily meets these standards but will have a tough time with the judges who will ask so, so many questions but want big pharma answers that CYDY can't provide without many more months of work.
Trump is aware of this phenomenon and tweeted about it the other day:
True.
The ever-credible five-ninety-five outfit, STAT, and big-pharma DO NOT LIKE the setup for the announcement.
Saturday Trump tweeted that:
Interesting article on new remdesivir results, Misi143.
One take-home quote:
Quote:
not true in general...only the ones who sell now after buying high
...and if her twitter weren't a long string of politics, politics, politics.
and your point is...?
The key for leronlimab in m/m patients is preventing disease progression. Leronlimab decreased the risk of disease progression or failure to improve within 3 days by 2/3 (29% vs. 10%), with a full 90% of leronlimab patients registering clinical improvement within 3 days....low risk of getting worse.
Of course, most m/m patients improve, but leronlimab substantially reduced the risk of no improvement (p-value = 0.02), which is exactly what a m\m therapeutic for covid-19 is supposed to do.
Can you imagine a social response equally as extreme to reduce accidents or 5x as extreme to reduce heart disease? Scary.
possibly a legitimate question for her doctor or for Scott Kelly, but definitely not a question for her or her friends from a hostile "reporter". Despicable.
20000/416000 = 98%? This must be some kind of new math that grownups don't understand. Can you explain? I get 0.048.
And it's 12 yr old data? Can you explain clearly the significance of NP's wife selling 4.8% of her stock 12 years ago? It seems utterly irrelevant to anything.
"inadverently"...LOL!
This one already jumped...up some 2000% since December...and has stayed up. Absent real results, what more do you want/expect?
truly bizarre board, this is. adios.
uh, look through my recent posts for an answer to your question.
HGEN has a good shot at $20+/share this year. Hang in there.
HGEN may (or may not) have a better shot at covid-19 than CYDY does, but covid is very much an after thought for CYDY. HIV (which uses CCR5 for entering the cell but is blocked by leronlimab) is #1, with metastatic triple-negative breast cancer looking promising. Other big indications are possible too because surprisingly often CCR5 is overexpressed, causing more problems than it solves.
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.
*******************************
[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.
nice article...exactly the kind of info I've been looking for. Thanks.
Hi Fezziwig2008, I don't see that quote anywhere in the paper you linked. Can you help?
agmcsf pointed out an excellent new paper on the conflicted roles of GM-CSF in the immune system, especially in the lungs. Here's my amateur's take on it.
On the one hand, GM-CSF is central in maintaining immune system homeostasis in lung alveoli. It is critically important for initiation of CD8+ cell responses in the lung. Reduced GM-CSF is associated with opportunistic infections (bronchitis, nasopharyngitis, pneumonia) due to impaired GM-CSF signaling. On the other hand, it is a key player in stimulating production of immune cells that produce pro-inflammatory cytokines and of stimulating production of the pro-inflammatory cytokines themselves, leading to the "cytokine storm" that is so damaging in severe cases. GM-CSF may be involved in a positive feedback loop with CD8+ (or other T cells), with GM-CSF stimulating CD8+ production, which in turn leads to more GM-CSF, which leads to more pro-inflammatories.
Blocking GM-CSF (or GM-CSFr) is an obvious possibility for treating severe covid-19 cases, and we've seen encouraging preliminary results for mavrilimumab (in Italy) and for lenzilumab (in EINDs in the US). The theoretical MOA (blocking GM-CSF signaling should lead to reduction in pro-inflammatories) is confirmed in the blood panels and reflected in improved clinical outcomes (hopefully---that's what the RCTs are for).
But what are the consequences of knocking out such a central player in the immune respose at a time when the body is fighting off a serious infection? Both the number of CD8+ cells and their status w.r.t. immune exhaustion (Diao et al. 2020, Weiskopf et al. 2020, Ganji et al. 2020) are important. What effect would/does lenzilumab have on CD8+? And what would be the risks of blocking GM-CSF either in the viral stage of the disease (before cytokine storm) or after the haywire immune response but before the virus is cleared? That's partly what the CRTs are for. And, maybe, that's partly what makes remdesivir a good fit for lenzilumab in a combo therapy.
Others are talking about administering GM-CSF itself (not a blocker!) to prevent "hyperoxia-induced lung injury by strengthening the resistance of alveolar wall cells to apoptosis and protecting against secondary bacterial infection." [But it wasn't been shown to work in an underpowered RCT that was canceled due to slow enrollment.]
very helpful paper, agmcsf. Thanks for the link.
Two things in particular stood out, and I'll talk about them in two parts. First is a brief rundown of the anti-GMCSF's mentioned.
I didn't realize there were so many groups working on anti GM-CSF(r) for SARS-CoV2. Here's a brief summary:
Frontrunners
lenzilumab (Humanigen)
2 trials: 1) pneumonia but no ARDS, 238 patients at 8 sites, began enrollment approx May 1; 2) NIH-sponsored combo therapy trials with remdesivir, 100 patients, begin August(?) 2020. EINDs looked good; seal of approval from NIH is a big boost of confidence.
otilimab (GlaxoSmithKline): treatment for RA, not yet approved anywhere; P2 trials for severe covid-19 cases to enroll 800 patients at around 40 sites in US (9), France, Japan, Netherlands, Poland, Spain, UK beginning (roughly) at the start of June. Primary endpoint is mortality + respiratory failure (high flow O2 or ventilator) at day 28. Inclusion criteria: severe cv19 w/ pneumonia and respiratory failure.
mavrilimumab (Kiniksa): developed for RA and trials have been going on for many years but abandoned; now working on GCA and CAR-T CRS. 4 trials for covid-19 were initiated this summer in US: 573 patients P2/3 (July), 60 patients P2 (August), 60 patients P2 (July), 60 patients P2 (June). Maybe not enough sites lined up to enroll 753 patients before the year 2022? [3, 1, 1, 2 sites for the 4 trials, resp.]. Primary endpoint for each is similar: mortality + O2 support at day 14. Big trial is divided into two cohorts: 1) severe but not intubated, 2) intubated. Inclusion for the other trials: severe (hospitalized). Company has several products and recently got BTA and orphan drug designation for rilonacept for pericarditis. Company has struggled for many but seems to be breaking through with revenue soon, several plausible INDs moving through the pipeline; good cash on hand and no debt, but still doing dilutions. Encouraging results from preliminary study in Italy.
gimsilumab (Roivant): One P2 trial for severe cases; to enroll 270 patients, beginning in April; been recruiting approx. 2/day. Primary endpoint is mortality at day 43. Inclusion: ARDS.
Hmm...
namilumab (Izana): no trial in US; no data yet from trial in UK (began in April)
TJ003234 (I-Mab Biopharma Co. Ltd)
One P1/P2 trial with 144 patients, starting in April. Chinese company that focuses almost exclusively on China.
Excellent help, agmcsf. Thanks.
I hadn't seen that mavrilimumab (a lot of these -mab names are awful-sounding, but this has to be the worst)...maybe because I had been thinking they were a little slow to the game? Slow to start, but they are careening along at a hellish pace now, with 5(!) new trials listed at clinicaltrials.gov, mostly beginning in July and August.
Their EINDs look fabulous too, just like lenzilumab, and with a similar MOA. This definitely speaks to the science in support of lenzilumab. What's the distinction between their respective actions? Is there anything to commend one over the other?
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And if you (or anyone who knows the politics/economics) have any insights about some other questions this brings up, do chime in! Specically, Lenz has a head start in trials, and the trial seems to be well-designed, but can HGEN keep up with Kiniksa (BTW, where do they get all their money?!)?
Also, I don't know a lot about the bureaucracy. What impact will having such restrictive enrollment criteria (that lenz has in the P3 trial) on approval and/or labeling?
-------------
And thanks for the further hints on the therapeutics antibodies. Do you know anything specific about Kd for lenz? Has there been any PK/PD work with lenz-specific parameters, or would that not be necessary? [Actually, I'd be more convinced by clinical results and blood panels than PK/PD, even though there's always a danger of slipping into "correlation implies causation". Best, of course, would be all three pointing in the same direction.]
And, as you say, they've observed clinical response at low doses in RA. But, still, covid-19 is quite different from RA...do you know any work that's been done on dosing for covid-19?
Thanks for the primer on HGEN history. I've been impressed with the new leadership. P3 trials, lots of institutional investors, partnerships. I think there's a great chance the covid-19 indication will work out in the next few months, but it looks like others are far, far out [correct me if I'm wrong].
As for CYDY, I don't think this is the place to discuss it. But I must say that I have been fascinated by their SPs recently---sometimes seem to be joined at the hip.
I'm disinclined to accept arguments by appeal to authority, but I'm even less impressed by ad hominems.
I think you are right. I just don't like remdesivir very much.
yeah, I'm impressed with Durant et al's networking and partnering successes. Over and over again.
As for convincing multiple egghead scientists? Color me duly unimpressed. I see a steady torrent of egghead scientists jumping on all kinds of bandwagons.
dloggold:
sigh. I'm not so interested in mechanisms of trading. Surely there are some nerdy science/medicine types here I can throw some rookie questions to.
yep. Preventing progression from m/m to s/c is key. Hamstringing GM-CSF seems like a promising approach to doing that. The inclusion/exclusion criteria for the P3 trials seem exquisitely chosen to demonstrate an effect...patients with pneumonia and very high risk of progressing to critical stage but no ARDS patients. Good results will impress FDA, and surely they won't require (will they?) the drug label to be so specific as the highly restrictive inclusion/exclusion criteria used in the trials.
Agreed. Remdesivir might have an impact on viral load if used early, and with lenzilumab preventing cytokine storm, it could be a winning combination. But, still, remdesivir makes me nervous, and I get a sick feeling in my stomach when I hear the word.
Thanks, agmcsf. Very interesting. The apparent effect of lenzilumab on downstream pro-inflammatory cytokines seems impressive in the EIND patients, and the patient recoveries seem almost miraculous. It looks like lenzilumab works great, at least in some patients. But 12 very not randomly selected patients and no controls leaves a lot of questions. That's what the P3 is all about, I suppose. But I want to learn more about how the thing works too.
Lenzilumab targets GM-CSF directly and not GM-CSF receptors, so if GM-CSF is rapidly "consumed" by cells, some (potentially large) proportion of GM-CSF would be able to bind to the cell and do its job before being disabled by lenzilumab. [Or can lenzilumab still bind to GM-CSF after the GM-CSF has been captured by the cell?] I would guess that fine-tuning the dosing and drug delivery are critical, which might help explain why it is delivered IV 3x/day.
A lot of different kinds of cells produce GM-CSF, but maybe Th17 (or Th1) are particularly important in severe covid-19. Temesgen's paper notes elevated levels of CM-CSF-secreting Th17 cells in severe cases (although the paper they cite to support that doesn't mention Th17 but discusses Th1 instead...no idea what the difference is, if any), but it does not report Th17 or Th1, so it's tough to tell.
Got it. Thanks. Let me re-phrase.
I'm a long-time investor in a biotech startup-that-shall-not-be-named. I'm trained as a scientist (PhD in ecology) but have been working as a statistician for about 20 years. Recently, I've started picking up shares of HGEN but need to learn more about the science of lenzilumab before I'm comfortable sinking much more into it.
The MOA is intriguing and seems promising. One nagging question that I've had recently is how wide will its applicability for covid-19 be? In particular...
Will it be effective for mild, moderate, severe, critical cases?
The current P3 trials are for patients who have pneumonia but no ARDS. Does anyone know the diagnostic criteria they are using to distinguish ARDS? Would it be effective in ARDS patients as well?
The first P3 patient began treatment on around May 5. Does anyone have any idea of the pace of enrollment in the trials since then? Are interim results going to be announced at some point?
Dr. Patterson at inCellDX has run blood panels on over 200 covid-19 patients and found that only about 20% have elevated GM-CSF. Would lenz be effective in patients without elevated GM-CSF? Are there any data that cast doubt on Dr Patterson's 20% figure?
Are there any "must read" papers (beyond the pre-print at bioRxiv) on the drug w.r.t. covid-19?
Is anyone thinking about CMML anymore?
What are people thinking about the BET trials in combo with remdesivir? It seems like remdesivir should be easy to beat...and to have NIH foot the bill for the trial is great (not to mention how great the vote of confidence from the feds is)! Any insights on why the market didn't seem to respond (beyond a morning spike that quickly faded)?