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OCUL
What is your guess on this (i.e. probability)?
I wonder what feedback they received on the question of whether SOL-R design will be accepted as pivotal?
Recall that OCUL stated during the investor day that they were holding off on finalizing the second comparator arm till meeting with the FDA. Can we assume from the fact that the posted the trial on clinical.trials.gov that they had the meeting? If so, I wonder what feedback they received on the question of whether SOL-R design will be accepted as pivotal?
It's not clear to me from the clinicaltrials posting what the role of the second comparator is; as you know, management stated repeatedly during the investor day that it was solely for masking. The Piper Sandler take is that the active arm will be compared to the Eylea HD every 6 month arm as well as to the monthly arm, which seems bizarre. You would have an active being compared to Eylea 2 mg monthly (per package insert) AND to Eylea HD (administered off label, roughly half the frequency of recommended). It would be very unlucky to be noninferior to on label Eylea but inferior to Eylea administered half as frequently as recommended.
Additional details re second comparator arm
https://x.com/Quantumup1/status/1811750181647393110/photo/1
OCUL
Study to Evaluate the Efficacy and Safety of Intravitreal OTX-TKI (Axitinib Implant) in Subjects With Neovascular Age- Related Macular Degeneration
(Sol-R)
https://clinicaltrials.gov/study/NCT06495918
MRK closes acquisition of (private) EyeBio:
https://www.businesswire.com/news/home/20240712972802/en
Looks like some of the momentum guys are starting to bite into the bio sector.
Looks like some of the momentum guys are starting to bite into the bio sector.
About time.
Though I would think regular use would increase risk there is actually not that much data. Here is a meta analysis I found. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085407/
FWIW I think the recent article has a lot of flaws. As a couple people pointed out the severity of comorbidities was lot taken k to account. I think the use of a single top academic practice causes severe referral bias. (Cross section of people within ten miles but wealthier patients from the whole country who might travel to Harvard and have better care and control of their comorbidities). Most patients with NAION do not need referrral to a top eye program. Many ophthalmologists practice solo or small groups and collecting cohorts representative of the national population would not be easy. In the US a Kaiser or similar captured large population might best provide evidence or lack of evidence of an association.
Is regular (i.e. daily or multiple times per week) use of PDE5 drugs necessary to incur a meaningful risk to the optic nerve? Does the risk vary with PDE5 dosing linearly, or in some other manner? TIA
They cause optic nerve head hypoperfusion
OPT - if the phase 3 results are statsig but median is not that clinically impressive, will the drug still sell? I would have thought yes, with a multifactor/heterogeneous disease like AMD. Clinicians can try it for a particular patient; if the results are meh, it's a relatively small waste of time/money and you stop treatment. If the patient is one of a large group of better responders, they stay on it.
OCUL would disagree with the claim that OPT has the only product seeking improved vision v. current standard of care treatment. At least, OCUL management repeatedly makes the claim that long-term (longer than the follow-up period of their trials), pulsatile dosing has significant adverse effects, fibrosis, etc. It's the equivalent, they claim, of repeated concussions.
Mufaso’s compilation in #msg-174727339 lists all three of them
No I thought doc 328 said PDE use is associated and I then suggested there could be an imbalance with use of these meds with increased use in the glop-1 group bc they may have had more neuropathy from diabetes which can cause ED
So the causation is in the "opposite" direction—i.e. PDE5 usage per se would not be expected to increase the incidence of PAION (which is what I thought 'Doc328' was suggesting).
DM is associated with ED so it stands to reason worse DM more ED more use of PDE5
I have the paper and I don't think that the "propensity matching" takes into account the degree of obesity (e.g., BMI), just as it fails to account for the severity of T2D. Thus, there is the possibilty -- indeed, likelihood -- that the patients receiving Ozempic were more obese and that this increases the risk of NAION; you would not jump to give Ozempic to someone with BMI of 25.1, I assume.
To achieve balance between cohorts (prescribed semaglutide or not) for each study population (T2D, and overweight or obese), 1:2 nearest-neighbor propensity score matching (caliper = 0.05) was used to account for demographic factors (sex, age); comorbidities related to NAION (systemic hyperten- sion, T2D, obstructive sleep apnea); indications for use of sema- glutide (T2D and obesity) and contraindications of semaglutide (personal or family history of multiple endocrine neoplasia type 2, thyroid cancer, chronic kidney disease, pancreatitis)8; covarying factors related to T2D or to overweight or obesity (hyperlipidemia, coronary artery disease); and use of drugs as- sociated with NAION (phosphodiesterase type 5 inhibitors,9 amiodarone1 0 ). No patient with NAION had received a-interferon.11 After matching, all standardized mean differ- ences (SMDs) for covariates were less than 0.1, and all SMDs and 2-way interactions among confounding factors were less than 0.15, which in the context of this study using propensity score matching indicates adequate balance between cohorts. Table 1 and Table 2 provide the characteristics of the T2D co- hort and the obese or overweight cohort, respectively, with fre- quency distributions and measures of variability.
Ozempic and NAION risk:
How does that thesis gibe with the study’s findings in the non-T2D study group?
NVO is not infallible—FDA issues CRL for weekly insulin, Icodec:
https://finance.yahoo.com/news/novo-nordisk-receives-complete-response-214500201.html
Novo Nordisk today announced that the US Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) covering the Biologics License Application for once-weekly basal insulin icodec for the treatment of diabetes mellitus.
In the letter, the FDA has requests related to the manufacturing process and the type 1 diabetes indication before the review of the application can be completed. Novo Nordisk is evaluating the content of the CRL and will work closely with the FDA to fulfil the requests. Novo Nordisk does not expect to be able to fulfil the requests during 2024.
...there are also medical (PDE-5 use)…that were probably not matched.
How does that thesis gibe with the study’s findings in the non-T2D study group?
Re: PFE’s oral weight-loss pipeline
PFE is playing from behind, and they may not have the best molecule to boot, but they do have another undisclosed MOA in the clinic so if they can pair the two together this could open a window for success.
Re: PFE’s qD-Danuglipron
The text you excerpted from today’s PR — “a safety profile consistent with prior Danuglipron studies” — is perplexing insofar as the prior studies in question were conducted with BID-Danuglipron, which had very bad tolerability. In the phase-2b trial of BID-Danuglipron (#msg-173334861), 73% of Danuglipron patients had nausea; 47% had diarrhea; and 50% dropped out of the trial. (Oddly, 40% of patients in this trial’s placebo arm dropped out.)
Here is the transcript of a cc in which I found Dolsten off putting:
https://s28.q4cdn.com/781576035/files/doc_downloads/2022/09/PFE-USQ_Transcript_2022-09-07.pdf
For example:
there's one question that I forgot to ask when we were talking about vaccines, was the pneumococcal vaccines. And GSK,
the other company, made an acquisition of Affinivax, which offers higher number of serotype targeting, they would claim, raising the bar again
Well, I recall that company made an attempt earlier to break in with their 10-valent. And I think it's a hardly used vaccine. I think it's a very late
entrant, with Pfizer being by far the leader with our 20-valent. Merck being a long-term player as a second company there.
We have monitored this technology that you referred to, and we didn't think it had the technological sophistication that was interesting to us. And
I think you need a very deep knowledge base on how many different serotype you can put into one single vaccination campaign, to design and
get the data that allow you to establish a new vaccine as the preferred standard.We're working on numerous follow-on vaccines. This is a game where you never can relax in a comfortable chair like this. You always need to lean forward and push the frontier. And believe me, I think there's little room for the company referred to. And I wish them the same luck as they had in the COVID.
Andrew Simon Baum - Citigroup Inc., Research Division - Global Head of Healthcare Research and MD
So it's tough to benchmark because, of course, GSK hasn't shared the data. But they seem to be intimating, for the equivalent of 3-plus symptoms,
somewhere around the 80% mark, which would put them in a certainly competitive, if not stronger position than you. But obviously, we need to
see the data, and we can't make judgments there.
One might imagine that the presence of the adjuvant may result in 2 impacts. Number one, a greater level of protection in the older, whether
they're immunosenescence. So I was curious as if you could share a little bit of information about how many patients in your trial were above the
age of 65, 70, and whether you saw the same VE as you did in younger patients.
And then second, that may also translate into the duration of protection. And obviously, we can't comment yet, but data will on that will emerge
in the fullness. Again, any thoughts there?
Mikael Dolsten - Pfizer Inc. - Chief Scientific Officer and President of Worldwide Research, Development & Medical
Well, we will share more data at conferences. And I can only say that the data I've looked at looks really strong. I would have been having difficulties
to imagine a better outcome than what we saw (really? Many vaccines are >90% efficacy across the board w flu being more the outlier). And I think it will be seen as a premier vaccine, all the older adult population, particularly that's
the most vulnerable (PFE had subpar efficacy in the "most vulnerable", and GSK has said this has been one of the biggest reasons for the relative success vs PFE thus far in the older pts w comorbidities). And then we are the only one that have a maternal vaccine. I think the company referred to failed in that area.
I tend to say that having an adjuvant is a liability if not needed. And we did study some adjuvants and found that our 2 RSV pre-fusion F antigens
did so well by themselves (the truth is they tested an adjuvant but it didn't improve immune response at all - I am sure if it did they would have carried it forward), and our tolerability is phenomenal (this is true). If you can avoid adjuvants, you are usually on a positive side because with each
adjuvant, you elevate the risk for rare adverse events, particularly immunological rare events (well as it turns out PFE has more immunological events. they tried to hide once case of GBS in their data set and were called out at ACIP on that - separately listing the GS variant miller fisher syn) , that may be seen as you accumulate more patients
on your product.
Now we also view
that, over time, we will see a lot of combination vaccines evolve in this space. We don't know exactly when would be a nice
rhythm to revaccinate for RSV. But we certainly know there will be annual vaccinations, probably very likely, for COVID, for flu. And in some way,
RSV will likely be integrated. Having quite strong adjuvants as the other company will hamper your ability to build a comprehensive combination
franchise as we see has been so important in adult and infant vaccination schedule.
So this was part of our overall strategy. But of course, you may think differently if you have success in pneumococcal, in COVID, in RSV, than if you
have more of a lonely stand-alone effort. But that's really the strength of Pfizer. We go in all in and we want to offer patient-friendly solutions to
deal with the total burden of respiratory infections here.
. And clearly, small
molecules, where we have probably the largest in the world knowledge base about structure activity. We have a leading structure-based drug
design, virtual screening, AI-powered technology, all of that were example behind PAXLOVID. (really paxlovid was AI powered, or are you throwing in AI bc it is in vogue?) They are example that helped us to design I think
the only in-house pharma oral GLP-1, that's a true small molecule based on that unique small molecule capability. (um what about LLY?)
6We are blessed to have 2 different drugs. Many of you may be familiar with danuglipron that have been shown in repeat Phase 2 studies to have
a very nice effect on both lowering of HbA1c and body weight. As we refined our drug design, we have been able to move a second one with the
Pfizer #1532, which has, beyond what danuglipron has, a once-a-day, very optimal half-life with a sustaining, a very nice active dose over the entire
24 hours in patients.
And that 1532 is now entering Phase 2b studies. We will share later at conferences how we were able to normalize studies of only 4 to 6 weeks
titration studies. We will normalize fasting plasma glucose, have a remarkable effect on HbA1c and robust short-term effect on body weight
reduction. So that looks to me as a potential, really premier, best-in-class oral small molecule.
Why is that so important? Well, the GLP, and to come, the GIP/GLP class, is the most powerful antidiabetics, and today by far, maybe the only really
persuasive anti-obesity medicines.
But still, they are used among patients that need -- in just the low number of percentage. And whether you have diabetes or obesity there, you
could say, in diabetes, they have still moderate market share because they are injectable and not oral. In obesity, they have a higher market share,
but very few patients are treated because they're injectable and not oral.
So we see a tremendous opportunity, based on 1532 and danuglipron as an alternative over the next year, maybe 1.5 years, to cherry pick the dose
and move swiftly with 1 of them into pivotal studies. And our vision here is really to, within the oral segment, be by far the most efficacious drugs.
And within the segment of any diabetic obesity drug, be as good, but the most convenient opportunity for patients to really capitalize on the great
story so far, how these drugs have, near-term, improved glucose and weight control; and long term, really good vascular outcomes.
I think there will also be on cardiovascular outcomes, powerful drugs or other diseases, such as NASH. So it's one of our big next efforts. We kind
of now label it Lightspeed project, and we're bringing all our knowledge we had from many other Lightspeed programs. It started, of course, with
the way we develop Comirnaty and PAXLOVID (again bringing up covid success to show their capability, when in fact paxlovid was a happy accident that a drug for prior sars agent happened to be effective for covid, and comirnaty was a brilliant stroke by PFE, but the R&D was virtually entirely BNTX. "project lightspeed" is kind of like talking about "AI", just a nice buzzword that sounds great but means nothing IMO) . And you will see a tremendous focus from us in building what we think would be one of the big
next oral drug segments
"Just over four million people are expected to use GLP-1s this year, according to Needham analyst Mike Matson, who used National Library of Medicine data to reach his estimate."
This quote appeared in an article about Resmed (a maker of CPAP machines) being a buying opportunity:
https://www.msn.com/en-us/money/companies/glp-1-concerns-clobbered-this-healthcare-stock-it-s-time-to-buy/ar-BB1pMsf7?ocid=finance-verthp-feeds
If successful when is the earliest they could bring this drug (qD-Danuglipron) to market?
The question is are they withholding more data bc the results really are mid (as the kids like to say), or bc of competitive reasons. Perhaps a bit of both
PFE is playing from behind, and they may not have the best molecule to boot, but they do have another undisclosed MOA in the clinic so if they can pair the two together this could open a window for success.
1)https://www.nature.com/articles/s41591-024-03084-6
2)I believe the rationale presented by
@d_stock07734
underscores why big pharma can’t afford to buy out $NWBO #DCVAX. This company has achieved something remarkable: they have patented a platform technology and its manufacturing process with #Flaskworks that harnesses billions of years of evolutionary refinement. By leveraging the body’s innate immune system to precisely target specific cancers and diseases, #DCVAX represents a groundbreaking advancement that will revolutionize treatment paradigms hence #Franchising 💯 https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174566808
If successful when is the earliest they could bring this drug to market?
PFE is moving the qD-Danuglipron program forward and has selected a formulation. However they didn't release any real efficacy or tolerability data other than to say the selected formulation had "a safety profile consistent with prior Danuglipron studies."
Pfizer Advances Development of Once-Daily Formulation of Oral GLP-1 Receptor Agonist Danuglipron
NEW YORK--(BUSINESS WIRE)-- Pfizer Inc. (NYSE: PFE) today announced that based on results from the ongoing pharmacokinetic study (NCT06153758), the company has selected its preferred once-daily modified release formulation for danuglipron, an oral glucagon-like peptide-1 (GLP-1) receptor agonist. Pfizer plans to conduct dose optimization studies in the second half of 2024 evaluating multiple doses of the preferred modified release formulation to inform the registration enabling studies.
“Obesity is a key therapeutic area for Pfizer, and the company has a robust pipeline of three clinical and several pre-clinical candidates. The most advanced of them, danuglipron, has demonstrated good efficacy in a twice-daily formulation, and we believe a once-daily formulation has the potential to have a competitive profile in the oral GLP-1 space,” said Mikael Dolsten, MD., PhD., Chief Scientific Officer & President, Pfizer Research and Development. “Following a thorough analysis of our previous Phase 2b data and trial design, we believe that with the preferred modified release formulation and future trial design optimization, we can advance a competitive oral GLP-1 molecule into registration enabling studies, with the goal of addressing the present and persistent medical needs of people living with obesity.”
The ongoing open-label, randomized study is evaluating the pharmacokinetics and safety of immediate- and modified release formulations of danuglipron administered orally in healthy adults 18 years or older. To date, study results have demonstrated a pharmacokinetic profile supportive of once-daily dosing. with a safety profile consistent with prior danuglipron studies including no liver enzyme elevations observed in more than 1,400 study participants.
OPT
Market doesn't seem to be very impressed with their prospects, not sure why. Large Phase 2 results look good and the two phase 3's are completely or almost completely enrolled.
I'm so glad they chose the biocompatible option.
Update on COSM’s weight-loss program, LOL:
https://www.accesswire.com/viewarticle.aspx?id=887452&lang=en
Cosmos Health Inc., a diversified, vertically integrated global healthcare group engaged in innovative R&D, owner of proprietary pharmaceutical and nutraceutical brands, manufacturer and distributor of healthcare products, and operator of a telehealth platform, announced today the successful completion of the pilot production and scale-up phases of CCX0722, a biocompatible hydrogel made from natural ingredients for weight management.
OPT - my favorite subject, I see that both of their large phase 3 trials make ample use of sham injections. No discussion or questions about that.
OPT - my favorite subject, I see that both of their large phase 3 trials make ample use of sham injections. No discussion or questions about that.
One of the KOL's mentioned long-lasting TKI treatments and how OPT would work with that, basically your take below.
Market doesn't seem to be very impressed with their prospects, not sure why. Large Phase 2 results look good and the two phase 3's are completely or almost completely enrolled.
LGVN—(+60%)—receives FDA RMAT* designation_for mild AD:
https://www.globenewswire.com/news-release/2024/07/10/2911026/0/en/Longeveron-Announces-U-S-FDA-Grants-Lomecel-B-Regenerative-Medicine-Advanced-Therapy-RMAT-Designation-for-the-Treatment-of-Mild-Alzheimer-s-Disease.html
Caveat emptor. An FDA RMAT designation does not imply that the drug—an allogeneic cell therapy called LOMECEL-B—will succeed. Indeed, LOMECEL-B’s track record for is not great—see #msg-172966621 and #msg-165430604.
Even after today’s pop, the stock is down 54% from its 2021 IPO (#msg-172966621).
*Regenerative Medicine Advanced Therapy
The NPV of Bourla's pension may comprise only a modest proportion of his net assets.
The NPV of Bourla's pension may comprise only a modest proportion of his net assets.
PFE is due to report the qD-Danuglipron data any day, so let's discuss the pipeline when those data are made public. I'm not optimistic about this program—see #msg-174337046—but a success can't be ruled out.
Either Bourla is lying or is an idiot. Nobody should put all their pension into any one stock.
“All my pension I put into Pfizer stock,” Bourla told Barron’s Editor at Large Andy Serwer on Monday, in a recording of At Barron’s on the sidelines of the World Economic Forum. “I’m all in.”(See #msg-173633673)
OPT - listened to “KOL conference call” and amusingly they said approximately same things i did:
A) 3 letters better is ‘meh’ (so focus with patients should be on higher percent people getting 15 letters etc)
B) intent is to pair their drug w whatever existing treatment is being used. (Reminder: all existing treatments use a loading dose (multiple months of monthly dosing)
Were i getting treatment i wld do exactly as being described by the KOLs. I.e. Get the OPT treatment with loading, then “treat and extend” per label of the non-OPT treatment. It might get a little tricky with very long lasting treatments like OCUL’s, but given the very unpleasant process of injections… .
Amusing note: one of the KOLs looks and sounds like George Clooney!
PFE - Dew, as you said, PFE's balance sheet is great, but what do you think of the pipeline? It does seem that that is a real and lingering problem.
Dew,
There is a decent history of Pfizers upper group all moving on in their 60's. I think McKinnell, Kindler and Read all left in their mid sixties, We'll see how long Bourla stays around.
Thanks, jbog, for weighing in. We know Dolsten is not retiring—the PR would have said so if he were. Is Dolsten leaving PFE voluntarily to work somewhere else? Unlikely; if this were the case, he would not hang around at PFE for six months or more. So, what's left? A “soft” firing because somebody has to take the fall for PFE's mediocre R&D track record during the past 15 years.
I never had a thought that he was being forced out, He's staying in his position and assisting the search for a replacement which they estimate will take into next year.
Having $50+ mil in your back pocket could entice anyone to walk away.
Comments from anyone on PFE’s ousting its longstanding CSO, Mikeal Dolsten?
OPT—One interesting component...is that the wAMD type that they are targeting is 'Asian' enriched...
OPT and VEGF-C/D relevance:
a) The TKI AMD treatments, unlike the mab treatments, tend to be pan-VEFGR inhibitors. Vorolonib (used by EYPT), for instance, is actually a better inhibitor of VEGFR3 (VEGF-C/D receptor) than of other receptors. And that isn't working out too well. (Axitinib, used by OCUL, is more equal across VEGFR-1/2/3).
b) However the OPT ph2b look good - so maybe there is another path or they, by being targeted, are more potent? But in any case the improvement in the ph2b was 'only' 3 letters, which is under the typical Non-Inferiority margin often used in wAMD. Given Vabysmo's uptake rate and my own personal experience with an EXTREMELY diligent friend's reaction to bimonthly injections of something VERY uncomfortable - I doubt 3 pts additional improvement is enough to pull big market away from Vabysmo etc.
c) However^2... OPT seems to know this and is trying to target a population that got much better improvement (vs SOC) in order to get a stronger response. (One interesting component of this is that the wAMD type that they are targeting is 'Asian' enriched since, apparently, Asians (I assume they mean E Asian because Australia doesn't have the same weird categories as US?) have a much higher prevalence of this form of wAMD)
All told... it's will be an interesting trial - and a risk to OCUL etc, but probably mostly marginal?
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