Just a few observations: More friends and / or acquaintances are having knee replacements. A few of those include individuals in their 40's. Two years ago, I had an arthritic episode in one knee. For almost instant relief, the knee was drained. My doc then recommended a knee replacement (KL-3). Cautious about that big step (aware of and waiting for Ampion for about 4 years), I declined and became curious about stem cell therapy. It was available at only a few clinics, one was in the Denver area (Centeno-Shultz) and a couple out of the country. The procedures were pricey, about $5,000. Today there are more clinics, including Cendant Cellular Therapies and Denver Regenerative Medicine. Stem Genex, in La Jolla CA, has been open for some time. Most deliver processed cells at the site (knee, shoulder, etc.), while a few offer that plus delivery by IV, which apparently addresses multiple OA indications at once. Cell harvesting varies in method (bone marrow vs. adipose). Some are now offering lower prices ($3,000 for one knee or $5,200 for two). How does this relate to AMPE? Valuation models are based on a variety of factors, but an estimate of cash flow is one. So, is the AMPE opportunity window beginning to close?
a failed company - nearing end of critical stage with not much interest - volume sucks along with the stock price - you would think there would be some buying here at the $2 level - there's not
Yup I believe that it has been proven effective also, my concern isn't necessarily that Ampion will be proven ineffective based on control and design. my concern is the magnitude of its effectiveness and whether it will see us through the trial and the ramifications even if successful, it would have if Ampion was found to be less effective than originally thought, considering the possible well backed and effective near term competition.
One of the most thoughtful analyses this site has seen in some time. We seem to be in general agreement about the main points.
Having achieved good pain reduction with 2/3 KL4 in STRIDE and multiple independent samples (SPRING, STRIDE, STRUT) showing efficacy (vs baseline, especially at 20+ wks) I think the balance of evidence indicates an effect. But, while having the same reservations also believe PIVOT has a better than a 50/50 chance.
My thoughts are, that you are right, by the numbers, Ampio has a product that provides sustained pain relief to KL3s and KL4s over a respectable length of time, I would like to see better separation also but that can be chalked up to an over pronounced control arm, given the the fact the the numbers for Ampion are relatively strong themselves.
that said, Ampion is still slightly less effective than the current CS injections possibly coming to market, but likely has slightly fewer systemic complications. which makes it lack of effect on KL2s not only a concern for this current trial but for marketing going forwards as KL2s would seem to be a perfect fit for a slightly less effective drug with fewer complications.
But the reason I said supposed efficacy and not efficacy was based on the past trial failures, which seem possibly due to poor trial design and lack of control. That in and of itself is bad of course, but the flip side of that is that just as trials can fail based on poor tiria design and control products can also succeed based on the same. sometimes resulting in Phase I and II successes followed by Phase III failures. so with 2 failures and 2 successes I can't state with 100% certainty that Ampion works regardless of the numbers. so if and when Ampio finishes this well designed well controlled trial successfully i will move from supposed to actual efficacy.
For the record this is just my opinion and not fact so anyone can feel free to agree or disagree. but please try to be civil. And thanks bill for allowing for a civil discussion despite any points we may or may not agree upon.
Thanks for a meaningful discussion Rachel. A 2015 paper by Tufts compared 10 available OAK treatments and concluded CS and HA injections were most effective. Ann Intern Med. 2015; 162(1):46-54. Newer versions seem to offer clear improvement (duration, safety, some efficacy). The potency of Cingal impressed me (70% at 26 wks) so it only needs dosing 2x/year. That should reduce ASE and, possibly, reduced effectiveness of multiple treatments.
A review of IA OAK therapies discusses current opinion on even the older CS injections: World J Orthop. 2014, 5(3): 351.
"IA injection of CS has rare side effects. The infrequent reactive flares to IA administration may begin 6–12 h after injection and resolve spontaneously in 1 to 3 d. Early studies in rodents reported the possibility of cartilage destruction. However, subsequent studies showed that even multiple IA injections of steroids showed no significant evidence of knee cartilage degradation."
What are your thoughts on Ampion "proven efficacy"? It seems the statistics are strong enough to rule out chance, although there is a strong placebo effect from injections and 30-35% reduction just due to saline. Ann Intern Med. 2015;163(5):392-393. Certainly, lack of better efficacy than saline in KL2s is documented and remains my biggest concern in the current trial. (At least they don't have 67% KL4 as in STRIDE)
1) SPRING had a good p value vs saline (0.004, 12wk) although separation was small (ca. 10% WOMAC A ). The KL3 and 4 they followed for 20 wks validated it "in these same grade 3 & 4 patients, there was a statistically significant improvement in pain, WOMAC A, compared to the vehicle control both at week 20 (p=0.02) and over the whole period of 20 weeks (p=0.005)"
2) STRUT (40 in Phase II): 64% from baseline to 20 weeks vs saline (p=0.02, not great p value, but small sample)
3) STRIDE: week 20 vs baseline 59% K-L3 (p less than 0.001) and 31% (p less than 0.001) K-L4 with no major difference at week 24
I also agree that given the backing these companies have and their proven effectiveness, despite what ever systemic issues they have, they will remain at the forefront.
but also that Ampion can if it can make it through this trial, with the proper backing and marketing strategies find its way to the forefront also, having no known systemic issues currently and supposedly "proven efficacy"
The points to consider with any ASE are frequency and severity. Ampion also has ASEs, but most injection related and mild.
For FX006/Zilretta (last phase 3): "The frequency of treatment-related adverse events across the three groups (FX006 40 mg, FX006 20 mg and placebo) was comparable, and no drug-related serious adverse events were observed in the trial. Adverse events thought to be at least possibly related to study drug as assessed by the investigator were less frequent for FX006 than placebo."
So, *less frequent ASE than Saline.
For Cingal, studies with repeat injection also found the same AEs as Ampion (injection related). No ASEs. From 2nd injection study PR:
A low number of subjects (6.2%) experienced an adverse event (AE) related to the study injection. Observed AEs were typical of those associated with viscosupplements (arthralgia, injection site pain, swelling, and erythema), and over 95% were considered ‘mild’ or ‘moderate’ in severity. All AEs were transitory, resolving naturally without treatment.
The AE rate associated with CINGAL was found to be consistent across both first-time and repeat injection studies. There were no statistically significant differences between the AE profile of participants in the CINGAL 13-01 study (single injection) and those in the CINGAL 13-02 study (repeat injection)
So, given what we currently know about how effective (strength of pain reduction, duration of action, broad patient population (KL1-3)) these new formulations are they seem likely to remain near the front-line, standard of care. Long-term safety still needs to be analyzed, but the fact that only 2 doses/year are needed for Cingal is quite encouraging.
There is a very good (albeit dated) review of ANIK and the OAK injection market. Query anik_f14.pdf
and of course there are still issues with local side effects such as decrease bone density at the injection site, crystallization and so on
I was referring specifically to slow release localized injections, the list of side affects is still long although muted. despite slow release due to low solubility and decreased absorption rates out of the injection site.
the goal of the companies is to eliminate systemic side affects but the reality is that they are just limiting systemic exposure reducing the side effects which is great but still not eliminating them.
"FX006 was very well-tolerated and the systemic exposure produced by FX006 was substantially less than that of TCA IR"
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Actually, CS dosed locally and with sustained release has shown to have NONE of the side effects with identical CS administered differently. That is in the clinical data for all the companies and the entire purpose of these products. It's not just the API or salt form. Formulation and dosing regimen are key to avoiding side effects.
Longer term there would have to be a trial comparing the products to fully evaluate. If Ampion succeeds, it isn't the panacea some propose. Still, it does work as a less potent anti-inflammatory and has a stellar safety record. It will certainly have some market share, but less so than it would have had 2 years ago.
With no money left for another attempt, 1/3 "dead weight" patients and multitudinous chances for unpredictable err, PIVOT is very high risk.
While true none of them use opiates, ANIK at least, use triamcinolone hexacetonide, which behaves as any other cs, even at relatively low doses. It has a long list of drug and medical condition interactions which are different from the adverse events reported in standard efficacy and safety trials. Though FDA approved it is far from ideal particularly due to the high number of OA patients who are co-morbid. So you still have a best of the worst type situation with these cs derivatives and combos. So if, and right now it's a big IF, ampio can complete this trial succesfully and move ampion to market they still have a lot of market potential... that's assuming of course ampion doesn't have a similarly long list of interactions, after longer term studies are eventually done. But for now it's interaction list is quite non existant.
That said, none of what bill there said is wrong, but only so much info can be passed in a blog so one picks what is said, the info on cs above is general knowledge and if it had to be stated every time a cs was brought up it would become cumbersome. A lot of good info has been shared best to use it improve our understanding, even if we don't necessarily agree with the statements.
Who is using fentanyl? Certainly not ANIK or CBYL or FXLN or other competitor I've listed. Completely irrelevant.
You do understand that different members of the same chemical class behave dramatically differently from a PK/PD perspective?
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In my estimation, the cost of a manufacturing facility / clean room(s) is dependent on a multitude of factors, including but not limited to: square footage of the facility; number, size and Class of the clean rooms; complexity; cost of the equipment and supplies for the manufacturing process; production and storage capacity; and environmental requirements. In the case of AMPE's facility, the last cost estimate that I recall was $10.4 million, in leasehold improvements that took about 6 months. At the moment, the company is burning about $900K per month for non-clinical trial G&A. Your $30 million valuation is irrelevant without the data to compare one facility to another.
BW thank you for at least admitting that trials and many of them fail to meet the sold called endpoint for many reasons. They can show ampion worked, they can show the placebo was out of whack, they know much more now then before which to me makes the drug much more powerful in terms of marketability and further development. Also, this is the only treatment that I have found that does not have side effects. Your points are valid but often you neglect to leave out important details.
Fentanyl has many side effects, including:
Weakness and fatigue.
Feelings of elation (euphoria).
Constipation, which may be severe.
The fact that CINGAL is already being sold in Canada and has 2 ALREADY FDA APPROVED API's as it's formulation means that YES they do have their own lab. It doesn't take much research to find that out. Yes, the same for HA applications in other joints. Really Allen, you should try to do a better job at researching before posting. You are one of the more rational ones. Try not to drink too much kool-aid friend.
Agree about exclusivity,but exclusivity is IRRELEVANT to market share. A single Cingal injection drops pain 70% over 6 months. Injections are painful. That does not exclude Ampion which lowered 40% for 12 wks SI. Doctors and patients will select the most efficacious, cost-effective, safe treatment. Patent position is not a consideration.
Still, competition isn't relevant unless PIVOT works. The entire point of the post was that trials fail for unexpected reasons. It doesn't matter how closely they are monitored or how careful the design or who is running them. Even the most experienced developers have issues. Just less often. CBYL has the cash to repeat. AMPE does not. It is indeed do or die.
still missing from these companies and their studies is the simple facts. Ampio has a lab that is a rare find if you do some research you will find out that it costs 30million and much more to run the lab itself, do for example these companies your talking about have their own FDA approved lab? Do these drugs work for other indications other than the knee? soooooo much more than what your reporting bill. I have no worries at all that the study will be solid and they will package it per the CC with another few short studies and frankly the value of this find will be huge. 12 year exclusive patent vs a patent anyone can steal. That my friend is solid. You may want to look into patents and the legality of them. Many can be easily violated with the right legal team. Ampio is good. just sit back and relax.