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If one digs a little deeper, just out of nostalgia ...
[OT] >this may look as if i had too much time
as some people have been replying and it doesn't seem possible to reply without a paid account: all is ok! just not enough hours in the day.
if there were, I'd really use some to participate more in this excellent forum.
(@Dew: please delete this message if you think it's too off-topic)
The Ashton Manual / tapering schedules for benzodiazepines
this may look as if i had too much time, but imho this is an obituary everyone interested in the wellbeing of patients and not only money should at least skim
https://www.nytimes.com/2020/01/03/science/dr-heather-ashton-dead.html
no time to catch up, still behind other things, but:
no opinion on their lead drug, but definitely not impressed by their SITC 2019 results of the HER directed anticalin
reasons are:
- limited effect where the one PR could be a late responder to standard PD-L1 (compare this to results for ZW25 as mAb or DS-8201 as my benchmark for an ADC)
- poor half life (extrasavation problem as typical with smaller than mAb constructs)
- already some > 20% anti-drug antibodies, so potential for dosing up is limited
>Please provide ref to Roche slides.
the slides, ESMO vs. SITC? as I said, they were identical (a late-breaker, a small company probably wouldn't be invited for the next few meetings for doing that)
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=152118889 -> https://bit.ly/2lxRNHQ
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=152214580 -> http://bit.ly/30SRgiA
>Are you referring to the much different side-effect profiles of I-O versus chemo?
Yes, indeed. Of course this is nothing new for the people in the forum here, but imho in the real world this continues to impress in new indications and possibly for new compounds/mAbs.
Keytruda will rake in billions for MRK and if they are able to show clinically meaningfully improved results in combination studies (with a proprietary, ideally fully owned investigational compound) this streak will last at least a decade if not longer. Given the extremely high number of Keynote-studies imho this is actually even the more probable case.
However, I am somewhat unsure about the market perception of competition.
E.g. I do not believe nivo to take back much market share from pembro, still there was quite some very short term reaction of MRK's stock price to a BMY study that hit it's endpoints*. So imho if IMpower 110 shows similar or even slightly worse results but with a much improved safety profile that might not only take some market but imho affect the market perceptions not only short term, but could effect MRK's stock price a bit stronger/longer.
dM
*https://news.bms.com/press-release/corporatefinancial-news/checkmate-9la-phase-3-trial-evaluating-opdivo-nivolumab-plus-l
... I expect the reverse merger to close and millions of share-holder capital to vanish.
To show what a mess this is - a matrix printer company (!) has started some activist campaign for its bid of 1.75$ a few days ago:
https://www.newlinkmerger.com/
(no investment advice, anything that'll happen from now on is no longer driven by fundamental factors)
KDS at last ends ATIR-101 program
For a brief moment I was impressed by their grandesse to retract the MAA and even halt the ph3 and totally end their (in my opinion harmful) ATIR-101 program
[OT] no need for anything new in a late-breaker
... for anyone following this: obviously Roche did not present anything groundbreaking on Saturday.
Actually, they did not present anything new at all at SITC (only outside SITC there was good news for a Lupus nephritis trial and their SMA gene therapy with PTCT). The presentation - if I or they did not mix anything up - is absolutely identical to the ESMO presentation:
http://bit.ly/30SRgiA
(really nothing new, not even anything on the assays)
[Semi-OT] I guess I rather would have wondered if there was no combo study with pembro ;).
Jokes aside, after the HCV frenzy (Merck's takeover of Idenix, JNJ's more cautious investment in ACHN), then Nektar and perhaps Kite have marked some top of the awareness about IO/cellular therapies.
Nektar with some cooperation with an enormous upfront and virtually all freedom. Kite with offloading the commercially much less relevant autologous CAR-T at sky high prices ... just to let the management start their new company Allogene (which was only possible for lack of non-compete clauses).
Link to old IMpower 110 ESMO presentation
... in preparation for SITC I was digging into the adverse events stuff as well and was search for some more slides. Nicely enough the Roche researchers have a link on the slides (https://bit.ly/2lxRNHQ) linking to the full presentation.
If anyone still needs to understand the IO revolution, slide 18 really tells some often neglected part of the story.
P.S.: what might also be presented at SITC, from the final slide
Well, it must be an even worse challenge for clinicians.
On the positive side, perhaps the possibility of competition will lower the prices for the patients (in case the two treatments would show roughly equivalent).
>When the discussion does not explicitly state that the HR has been corrected for crossover, it's reasonbale to infer that the figure in question is the raw HR.
Thanks for your assessment! I googled Genentech's and Roche's site for some terms (hazard-ratio, cross-over, corrected) and couldn't find a single entry that contains both a raw and a corrected hazard ratio. To be really certain I'll probably need to look at some recent press releases and compare them to the corresponding journal article, to see if there some systematic pattern.
> Whether justified or not, there seems to be an underlying preference among KOLs for PD-1 agents versus PD-L1 agents.
This is what I perceive as well.
IMHO, any difference we see might even be traced back to the differences/sensitivity of the different assays. Someday. For that we'd need a systematic study comparing the assays for pembro vs. atezo.
IMpower 110 vs. Keynote 024
... well, to recall:
For KN-024
and they have hit OS (https://www.gene.com/media/press-releases/14807/2019-09-11/genentechs-tecentriq-atezolizumab-as-a-f).#ESMO19 IMpower 110 meets its primary endpoint of improving OS in PDL1 high NSCLC. Signal seen (to lesser degree) as PDL1 expression decreases. HR 0.59 in TC3/IC3 with median OS of 20.2 vs 13.1 months. #OncoAlert #LCSM pic.twitter.com/elp1EtAzTm
— Stephen V Liu, MD (@StephenVLiu) September 27, 2019
I more and more think we need some kind of baseball cards for the CEOs/CFOs/etc. of (listed) companies. I am not a fan of buzz words, but the G of ESG-investing principles may really have an added value.
FGEN ph4 study
I am not familiar enough with the complete set of company communication and the communication policies at FGEN/AZN. So I do not dare a guess at the moment.
Something I found in the meanwhile, there's a ph 4 study:
https://www.clinicaltrials.gov/ct2/show/NCT04059913?term=roxadustat
It does _not_ have any cardiac safety measure as endpoint. Insofar this is good. However, they are mentioned along the exclusion criteria:
"Cardiovascular risks such as: myocardial infarction, stroke, heart failure or a thromboembolic event (e.g., deep venous thrombosis or pulmonary embolism) within 26 weeks prior to Day 1."
So what I wonder is how much is this a boilerplate text vs. deliberately written.
FGEN / I see, I was incomplete in my reasoning:
This is AZN/FGEN where people should act as you describe ("Any phrase that appears where one would expect to see a claim of statistical significance is pretty strong evidence that there wasn’t."), opposed to a shady Chinese-/Israelan-listed biotech.
no idea, but they do not seem very far. Actually far, far away from placebo-controlled ph2 data in PTSD/suicidality and PD (= probably many further rounds of diluation, especially as they have so many compounds to be developed in parallel).
As well, I wasn't able to locate scientific references, papers, conference posters adhoc on the website. So it's really opaque.
My 2c
KDS does not even retract it's application at EMA
... for everybody who recalls these things:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=149661112
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=149694959
at last, the EMA/CHMP (after some "EU-adcom"/Scientific Advisory Group on Sept. 3rd which was behind closed doors, this being the standard in the EU) kicks Kiadis out:
I think that's the good part of this forum. Being able to have different opinions.
I am also a dissenter (my view: There is so much HBSAg, empty spheres, RNA-packed spheres and traditional DNA-packed HBV viruses. If the immune system is meant to single out infected cells and destroy them and the number of these gazillion particles has to be brought down. I am not sure if I read about this or phantasize here, but would extra-cellular HBsAg be an antibody sink?, preventing them to reach infected cells [if HBsAg is presented on MHC-I there])*
* from my answer you can deduce that I have no position in a HCB-focused stock at the moment
Re: FGEN Pooled data
This is a very valid question. Please scrutinize my line of reasoning / my view (jb_118, you might have a point):
- In my understanding the regulator demands a pooled analysis. See e.g. here https://www.crosnt.com/integrated-summaries-regulatory-requirements/ for a very brief summary of the role of the ISS/ISE. I have rather been criticizing companies that do _not_ provide a pooled analysis to investors, since that could be used to hide facts behind wide confidence intervals of the non-pooled individual studies. So pooling in itself isn't bad.
- When it comes to the question what FGEN will present and what they will "hide":
HIF-1 alpha, a primer by the noble assembly
Probably one doesn't need to know that for investing ...
https://www.nobelprize.org/prizes/medicine/2019/advanced-information/
but it's kind of funny when you read the following paragraph ...
FGEN "Roxadustat Global Phase 3 Results for Treatment of Chronic Kidney Disease (CKD) Anemia to be Presented at American Society of Nephrology Kidney Week 2019"
just on a note, the ASN abstracts are online already, here's the press release:
https://fibrogen.gcs-web.com/news-releases/news-release-details/roxadustat-global-phase-3-results-treatment-chronic-kidney
I was really looking for the like-button for this reply! (didn't find it, so this post :)
NLNK why not dissolve the company and return capital to the investors?
The NLNK part really sounds like dissolving the already restructured company:
I must admit that I closed my position and (currently) do not have any companies that develop a treatment for HBV in my portfolio.
RNAi-based compounds are simpy "too effective" in bringing down HBV RNA/DNA, i.e. too strong competition. Still, I am not sure if they are the final solution - IMHO it'd be ideal to have an compound to bring down HBsAg - the decoy/distraction to the immune systeme - while allowing some low HBV activity in cells so these cells can be identified and removed (if everything is perfectly silenced, infected and healthy cells are impossible to distinguish).
> Probably the most rewarding thing is to grab some pop corn and watch doing nothing (sigh).
Time for even more pop corn, argh!
Bellicum files a mixed shelf of up to 400mn (with a market cap below 70mn), just about at the trough of the stock price.
https://www.sec.gov/Archives/edgar/data/1358403/000119312519200072/d779555ds3.htm
EMA/FDA mutual recognition of on-site inspections
see https://www.ema.europa.eu/en/news/eu-us-reach-milestone-mutual-recognition-inspections-medicines-manufacturers
Paper "Severe Morbidity and Mortality Associated With Respiratory Syncytial Virus Versus Influenza Infection in Hospitalized Older Adults"
https://academic.oup.com/cid/article/69/2/197/5193205
haven't read it yet, but the title suggest there's a market in the elderly population
stumbled upon by a retweet from ReViral (a competitor of ENTA)
Medicare/Medicaid spending dashboards
P.S. I had posted this link somewhen in the past, perhaps useful, here Medicare Part B
https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Information-on-Prescription-Drugs/MedicarePartB.html
IPI / Let's hope it stays at a lesser scale.
I still recall the youtube-video of Gottlieb at Brookings where the "most favoured nations"-approach was first mentioned (and if I recall correctly I jotted down my notes here in a post).
Trump still names it a favoured nations clause**, but the official name now is international pricing index (IPI) and it's one of the more effective and therefore somewhat feared approaches (see e.g. *).
See also https://www.hhs.gov/about/news/2018/10/25/ipi-policy-brief.html for some info about the proposal and https://www.reginfo.gov/public/do/eoDetails?rrid=129248 and
https://www.reginfo.gov/public/do/eAgendaViewRule?pubId=201904&RIN=0938-AT91 for the procedure.
There is no exact date for this procedure, exept for "August". So I guess everybody incl. me was somewhat surprised by Trumps remarks (**).
Some further articles I bookmarked
https://thehill.com/policy/healthcare/449740-key-trump-proposal-to-lower-drug-prices-takes-step-forward
https://thehill.com/policy/healthcare/449382-grassley-announces-opposition-to-key-trump-proposal-to-lower-drug-prices
Please add further info or comment on the timeline if you have more insight (I am not a lawyer).
dM
*
None at the current time.
I still need to watch how this field further develops and gain more insight/make myself an opinion on the relative importance of future vaccines (or vaccine-like approaches) vs. therapeutic compounds against a current infection*.
What I mean: If there is a vaccine eventually, how broadly will it be used? If so, what will be the remaining role for therapeutic compounds, will they commercially suffer a similar role to many newly developed antibiotics?
For RSV I'd currently say a vaccine will grab much of the pediatric market, but less so of the elderly/immuno-compromised. As well any anti-RSV compound is highly specific and will be the first to treat that disease, so it will very probably not suffer the fate of many newly developed antibiotics that are "kept back" for the otherwise helpless cases.
My 2c
dM
* Besides ReViral's compounds I also watch MEDI8897 which has received both FDA BTD designation and EMA Prime eligibility.
https://www.astrazeneca.com/media-centre/press-releases/2019/us-fda-grants-breakthrough-therapy-designation-for-potential-next-generation-rsv-medicine-medi8897.html
I mentioned them earlier here
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=129203651
> Probably the most rewarding thing is to grab some pop corn and watch doing nothing (sigh).
So it's KDS -25.7% (reaction to news of SAG/"EU adcom" after close) and BLCM -4.7% (delayed effect of deletion from Russell? solidarity drop? no data yet published angst drop? another idea: doubts about commercial relevance due to Evaluate article I quoted?).
Things I usually do not watch, but on this special occasion: Notably KDS only opened 9:45h (instead of 9:00h) at AMS, since there was quite an overhang of market sell orders that would have erradicated all bids, meaning a drop into an abyss if there wasn't this wait. What I do not understand that there was still quite much "organic" buying during the first half of the day (i.e. not from puts sold back to market makers), but I guess that's mean reversion algos/traders and perhaps sadly some still too gullible investors.
They are using a quite elaborate model* which is beyond my knowledge of traditional statistical methods. So I cannot say much about a "95% credible interval (95% CrI), the Bayesian analogue of the confidence interval".
Yet, generally with respiratory pathogens I do expect quite a variable distribution over time (these things spread over the air, faster than STD or bloodborne diseases - just think of how differently influenza spreads eachs year, or more surprisingly how whole strains vanish, see a tweet I came across recently:
)In the ~20 years I've been reporting on health, I've written more about #flu than any other topic. I know #influenza constantly rewrites dogma, does the thing you don't expect it to do. But the disappearance of human H5 & H7 cases still surprises me. https://t.co/r4WwX5Njvd pic.twitter.com/bsBqudsVo2
— Helen Branswell 🇨🇦 (@HelenBranswell) June 28, 2019
Perch-Study / Etiology of Pneumonia in Children in developing nations
10 pathogens caused the vast majority (about 8 in 10 cases) [of severe childhood pneumonia in seven developing nations]:
RSV 31.1% (28.4, 34.2)
Rhinovirus 7.5% (5.3, 10.1)
human metapneumovirus (hMPV) 7.5% (5.9, 9.5)
Parainfluenza 7.4% (5.8, 9.3)
Pneumococcus 6.7% (5.1, 8.5)
Haemophilus influenzae 5.9% (3.8, 8.5)
tuberculosis (TB) 5.9% (3.9, 8.3)
Staphylococcus aureus (Staph) 2.7% (1.5, 4.3)
Influenza 2.0% (1.1, 3.2)
Pneumocystis jirovecii 2.0% (0.9, 3.3)
see http://perchresults.org/ and http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30721-4/fulltext
This is a study in developing nations, so the results cannot be transferred to the US or Europe. Still quite interesting how large the share of RSV (no vaccine/currently quite prohibitive prevention by mAb) vs Pneumococcus is (for the later probably everybody thinks of Prevnar here, I guess, or perhaps Merck's vaccine candidate).
Well, that's also my fear. There isn't even a 8K (yet), so I hope the part they already have committed to isn't too expensive.
If it goes to exercising the licensing option, getting an IND or running clinical trials, I am absolutely of the same opinion as you: they do not have the ressources for that.
Russell reconstitution
Perhaps not everything was a "panic sell". Seems I overlooked the Russell reconstitution. Along many, many names BLCM seems to have been deleted from an index, which might also be an explanation of the drop...
... and interestingly, RVNC has been added to the Russell Microcap index (see "Russell Microcap Index - Additions" here https://www.ftserussell.com/resources/russell-reconstitution), so there might be a little higher correlation with the rest of the market now.
Sarah Siegler seems to have it tracked down a little more:
Okay, it looks like it could be the anti-CAIX CD70 bispecific construct: https://t.co/Pk5jOqKgFA #CARTcells #techtransfer
— Sara Elizabeth Siegler (@sesiegler) June 27, 2019
Kiadis/Molmed/Bellicum (haplo-HSCT)
... for anyone following how my position of Bellicum is going to zero (cough, cough) or how haplo HSCT is attempted to be improved upon: quite a few things happened in the last few days and probably the next week.
- Molmed's Zalmoxis (conditional approval in EU, 1-4 doses, 149,000 to 163,900 EUR per dose *1) failed it's ph 3 study in an unplanned interim*2. The stock price did not really react, since it never really sold.
- Kiadis ATIR-101 had another (the third!) "list of outstanding issues" in this month's CHMP (see the agenda *3). Even worse, they will experience the EU equivalent of an adcom (see tweet by the European counterpart of tgtxdough *4), so the main Dutch stock forum (on iex.nl) is discussing the extent of the stock price drop on Monday.
- Bellicum Pharmaceuticals did not have any company specific news yet, but is expected to disclose topline results for their central "Rivo-cel"/BPX-501 study in a pediatric setting soon (actually 2019H1, but according to another tweet somewhat delayed *5). So they could fall on Monday, due to data not yet being released on Monday morning, they could fall due to solidarity to Kiadis, they could fall since positive or negative data might have been released ("sell the news"/time it takes until formal EU approval) or due to the G20 results. At least in the last few minutes today someone seems to have panic sold (and that wasn't me). Theoretically they could also rise (I am a bit sarcastic here).
For anyone interested, there's also an Evaluate article (but without the most current info on the "EU adcom" for Kiadis):
https://www.evaluate.com/vantage/articles/news/corporate-strategy/twilight-stem-cell-transplant-adjuncts
Probably the most rewarding thing is to grab some pop corn and watch doing nothing (sigh).
dM
*1
https://www.molmed.com/sites/default/files/uploads/press-releases/3225/3225_1513170251.pdf
https://uk.reuters.com/article/idUKL8N1PB20N
*2
https://www.molmed.com/sites/default/files/uploads/press-releases/3649/3649_1561653397.pdf
*3
https://www.ema.europa.eu/en/documents/agenda/agenda-chmp-agenda-24-27-june-2019-meeting_en.pdf
*4
$KDS EMA "AdCom" (SAG) in september for ATIR-101 but CHMP opinion only later in 2020 https://t.co/K8HDWFZJ20
— Bertrand Delsuc (@BertrandBio) June 28, 2019
$BLCM Rivo-cel pivotal data likely Monday based on response from company: pic.twitter.com/C9C25SGF9M
— BioValues (@BioValues) June 27, 2019
We need larger numbers
The high number of CR is definitely noteworthy (n=13, 34%).
The BORR (53%, n=20) is higher than in Keynote-006 (~ 36%), but NKTR's trial is 1L stage IV patients while Keynote-006 was not fully 1L, but only ipi-naive (~ IO-naive) stage IV patients (see * and **a). On the positive side, NKTR only had 62% PD-L1 positive patients vs. ~ 80% in Keynote-006.
Still, it's difficult to draw conclusions with n=38 (or ITT n=41). For example Keynote-001 also showed a high CR in a naive setting (see *b - BORR of 25% CR, 27% PR). Or as well, DVAX SD-101 (yes, the compound they no longer develop but would like to outlicense) showed a really high ORR of 18% CR + 58% PR for n=45 at the 2mg dose (not purely stage IV, but interestingly seemingly to work in PD-L1- as well having a 79%/n=14 ORR in these PD-L1-, see ***).
Well, I think the usual sentence on a poster would be "warrants further investigation", since n=38 (or ITT n=41) too low for final conclusions.
My 2c
dM
*