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Yes, pre-2014 and even in the past year.
IMO, the biotech market has become exponentially more illogical possibly driven by the sheer number of companies that has diluted the focus of serious investors. The depth and persistence of misinformation astounds me, and I think the volatility provides a hiding place for the more nefarious investors.
cost and efficacy. DNA plasmids to drive an immune response are formulated in saline solution and cost pennies to make. efficacy is enhanced by the continuous production and the lack of ADAs, because they are completely human and as was pointed out, proteins that go through the cell's machinery are usually not targeted for attack.
No silencing antibodies in this approach: Inovio recently announced the successful animal testing of its dMAbs targeting the immune checkpoint molecule CTLA-4, as reported in the prestigious journal Cancer Research. The breakthrough preclinical study demonstrated that highly optimized dMAbs targeting mouse CTLA-4 protein can be robustly expressed in vivo, and shrank tumors in mice. More importantly, Inovio’s dMAb constructs for anti-human CTLA-4 antibodies ipilimumab (YERVOY®) and tremelimumab, achieved high expression levels in mice (approximately 85µg/ml and 58µg/ml, respectively). These dMAbs exhibited long-term expression with maintenance of serum levels >15µg/ml for over a year.
This is CBER's version of breakthrough therapy designation. The FDA has reviewed the early data and sees promising data in a disease with unmet need. This provides accelerated meeting times and increased interactions with the agency.
"it failed the first time around"...to what are you referring?
Last time I saw this was with MEIP...... Worked out well for them.
My bad for typing HeFH, I meant homozygous FH. if you don't have a functional LDL gene, then it is difficult to increase the level on the cell surface.
You are mixing apples and oranges. ESPR is not going after the HeFH market in part because of the MOA of their drug..the causative issue in HeFH is a mutant LDL receptor that results in lowered recycling of LDL into the liver. Statins and PSCK9s have similar issues in that their MOA does not work well for HeFH. Madrigal's drug has a completely different MOA, which is why the drug could be a better fit for HeFH patients. however, we don't know what will happen with outcomes data for this new agent because LDL lowering does not always translate to CV risk reduction.
Personally, I hope both drugs come to market because with 81M patients being treated for elevated LDL, a little personalization could prove more effective.
Details from CLEAR harmony trial were released at the ECS meeting. New gout onset was 0.3% in the placebo arm and 1.2% in the bempedoic acid arm, p=0.03. So there is a slight increase in the risk of gout. That correlates with an increase in Uric acid of -0.06 in the pl arm vs. 0.73 mg/dL in the bempedoic acid arm, p=0.001. Baseline uric acid levels were balanced at 6.1 and 6.0, respectively.
Again, I don't find those numbers to be of any great concern.
There was no statistically significant imbalance in neopasms (0.9% for pl and 1.2% for BA) or deaths (0.1% for pl and 0.4% for BA).
Yes, the PCSK9 inhibitors are over-achievers when it comes to LDL lowering. However, we have seen time and time again that there is an inflammation component to CV disease and, if one believes the hsCRP is a biomarker for inflammation, then bempedoic addresses that piece. Clinical trials showed the lipitor lowered the CV risk more than pravastatin and many experts believe that this is related to the relative ability of each to lower hsCRP -- 21% for lipitor and 6% for pravastatin (these numbers vary depending upon the study). And in the Jupiter study, patients who achieved both LDL and hsCRP goals showed a 79% reduction in CV events. Given that bempedoic acid lowers hsCRP by as much as 40%, the combination of a PCKS9 inhibitor + bempedoic acid may be really interesting. What I like, is that bempedoic acid is metabolized in the liver...MDGL has the same benefit
The uric acid issue is nitpicking. Here's the reality: all drugs have side effects. Both MDGL and ESPR have great drugs. ESPR's drug has been tested in many, many more patients and so better vetted. What strikes me is the difference in market cap that is not consistent with the stage of development and what we know.
Where is your reference for the 7.7% increase in serum uric acid and what was the range of the increase?
Not sure what you mean by "wish objective medical journalist would get on the bandwagon"....
The "vector" is a plasmid, not a virus.
SGMO has been editing T cells, without the use of a virus, for years. Much, is not all, of HIV work was down using electroporation of isolated T cells. So this is not new or revolutionary.
Agree with everything you have written here. IDO and ARG play a role in regulating nutrient levels -- more specifically they deplete nutrient levels, and T cells need nutrients to thrive. So inhibiting those enzymes doesn't really stimulate the production of new Tcells, it just makes the environment better for those that are present. Seems like inhibiting PD1 already addressed this mechanism by allowing Tcells in the tumor microenvironment to survive. The science is pretty clear that tumors are cold because of a lack of Tcells. So what did they really expect IDO to add? The
The CEO's failure to mention the paper you referenced, is no different to your ignoring this publication:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904560/
Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO–induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO–induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.
thanks!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074546/
Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study
Reaches peak plasma level at 1 hr post dosing. Steady state was reached after 3-4 days. Steady state trough of 36 ng/mL at day 7 was reached 12 hrs post dosing with 2x/day30 mg dose. That's >94% coverage of the c5aR throughout the day.
I would agree.
Not at all. Neutrophil attack and influx is part of the disease pathology and one way to measure efficacy is by measuring the rate of neutrophil decrease. Both drugs decrease neutrophil levels; both drugs seem to be effective. Both drugs have pros and cons. At this point, there is no way to tell which will be the better drug.
what is important is the reduction in neutrophil levels driven by each drug and the biological role of that second receptor. Some studies have indicated that C5R2 (aka C5L2) is needed to drive repair and is required to recover from anaphylactic/septic shock. Also, many of these kidney diseases have protein deposits that are damaging. There are reports that Soliris actually increases these deposits as the antibody gets gummed up in the mess. For that reason a small molecule that binds to receptors on neutrophils may have an advantage.
the IC50 for avacopan is 0.2 nM and the IC50 for INFX's drug is 0.1 nM. A difference without a distinction.
I have no idea. In earlier posts someone suggested that they should see if that was causing the cholesterol/heart disease in the family. He said "they checked" but did not give the diagnosis.
Most cases of HoFH are caused by mutations in the LDL receptor. If you do not make enough LDL-R, PCSK9 inhibitors will not work. If this were my family, I would watch the RegenxBio study: https://www.clinicaltrials.gov/ct2/show/NCT02651675. This is a gene therapy to introduce a healthy copy of the LDL-R gene into the liver. The downside here is that liver cells turn over rapidly and classic gene therapy as being tried here might be a short term fix. However, if the approach works, I would expect a gene editing company to move into the space. And that would be a game changer.
The company also moved its incorporation from WA to DE. Old management was replaced with Frazier helping to reorganize.
The biggest difference that I see between the two is that dobutamine increases heart rate by about 8-12 bpm and omecamtiv decreases by 3 bpm. Will be interesting to see how this impacts a CVOT.
SGMO presented data on this exact application. Using electroporation delivery of mRNA to T cells, they can reliably knockout both copies of any gene with >90% efficiency. Using this technology in a single step, they have created universal T cells in which 76% of cells had GFP (as a reporter) inserted into the TRAC locus and are missing HLA-class 1 and CISH (checkpoint gene). Remember that the company has successfully harvested, edited and transplanted >100 patients in their HIV program. More than 5 years out there is no evidence of a safety concern and all patients are doing very well. In fact, all are seeing at a minimum a one log decrease in their HIV reservoir. No other therapy has shown this type of success. And while commercialization might be difficult in light of the low cost of HART, the results speak to the ability of this technology to provide a long and lasting T cell population.
I think that you are misunderstanding the intended meaning here. The author is saying that with gene editing, there is no need for retention of the virus. I would also point out that SGMO does not use viral delivery for its in vitro products and that they have developed a nanoparticle for delivery to the liver as an alternative to the virus.
That's the same price as two years of Soliris. Given that there are only about 1200 of these patients in the US and that 10-20 new disease carriers are born each year, it's not going to break the bank. The cost of Solvadi for HCV was much more devastating to the healthcare system given the number of patients.
A new item: If the duration of an oncology trial suggests that patients are surviving longer, than my drug must be the cause.
HI PGS, hope you are well, and hope you figure out how to pay the taxes on your grad student stipends once the tax reform is passed into law.
I have seen you many times comment that you like this approach over that for Omecamtiv by CYTK. That confuses me because it seems as if the two are targeting the exact same mechanism, except Omecamtiv increases the number of interactions between myosin and actin while Mavacamtem decreases those. What difference are you seeing here that causes concern for Omecamtiv over mavacamtem?
I don't do social media.
I think Andy is way off base.
The HLA data was good, but beyond that is the realization that the data is as good if not better than what CRISPRs have released. And while the CRISPR world touts the ease of use, the reality is that SGMO can design and test a ZnFinger just as rapidly. The academic world's issue with ZnFingers is that SGMO locked up the IP and so the price and knowledge is not amenable to academic research.
Can you break those responses out by education. Because I will guarantee that those who do the science would agree with my definition.
Not to pile on, but your definition of gene therapy is incorrect. Gene therapy is the introduction of genetic material into a cell to treat or prevent disease. The fact that a piece of DNA is used to drive CAR-T cell activity makes them a form of gene therapy.
The primary endpoint for the trial as defined by a SPA is progression free survival. OS will be less relevant as patients in the treatment arm are allowed to move on to Adcetris at progression. This is how first-line Hodgkin's lymphoma trials readout.
There is a scientific reason why PFE chose to partner the SGMO program. Look at the non-human primate data that SGMO presents. The expression cassette gives orders of magnitude higher factor 8 levels. A scientist at SGMO made it her personal goal to engineer the cassette and improve output.
Shades of Theranos and Elizabeth Holmes?