Cytori (CYTX) OAK cell therapy (Phase2, N=94, wk 24 of 48). Note no 3-month improvement and significant placebo effect.
Interim top-line data:
1) Intra-articular application of a single dose of ECCO-50 appears to be safe and feasible in an outpatient day-surgery setting.
2) A significant placebo response was observed, similar to that demonstrated in other OA trials.
3) The pre-specified primary endpoint, pain on walking at 12 weeks, as measured by a single question from the Knee Injury and Osteoarthritis Outcome Score (KOOS) did not obtain statistical significance.
4) Key secondary endpoints ...Consistent trends were observed suggesting improvement in the cell treated group relative to the placebo.
Write the company and ask them to post the presentation to the website.
Singer is highly regarded in the field. They also had a PI present SPRING at a conference long ago. The stock did nothing. There will be no new data.
26 wk is not uncommon. Another HA/CS therapeutic (Cingal) had 26 wk results. Injections at more than 2/yr have compliance issues.
"Cingal delivered a 72% improvement (-42.4 mm, p=0.01) in WOMAC Pain Score relative to baseline at 26 weeks after injection. "
It will go below $1 if PIVOT fails. It might start going back up in late April as we approach expected results. I have no idea what it does between now and then. Nor does anyone else.
They could possibly help the price by using conferences to show Ampion results (including STRUT MRI data if there is any significant cartilage improvement). They aren't at the BIO CEO conference and no science conferences. Only Optina is being spoken about publicly. It is very odd.
Also reviewed CC recording. All 4 estimates were appraisals, not from pharma. Not worthless but worth less than a number from a partner/acquirer. (Time: 19:30 during the long non-answer to the contingency question starting at 18:48 and ending 21:40). Repeated again at 31 min. During this he also stated "Ampion works". Accepted, IMO. But 2 of the 3 important *trials" did NOT. That is what matters to the FDA and to shareholders.
He also stated he has numerous statements from physicians about Ampion success. Other than SPRING (and Phase I STRUT) why haven't those been made public? That could go a long way in validating the drug. Much better investment than videos IMO.
During STRIDE I looked at the MI HA trials vs saline and found that they were mostly in-line with the 30-35% SI values (peer reviewed meta-analyses). There is also a very large placebo effect with injections even beyond the true, temporary effect of saline itself. My guess (implied by a number of MM statements) is that the patients and clinicians were not "well controlled" in STRIDE. Hence the background checks, training, stricter enrollment criteria, including pre-acceptance observation period.
It actually makes common sense. If a patient is KL4 (67% were) and therefore in severe pain towards the end of the trial after the saline has worn off (about 10-12 wks) wouldn't they "cheat" and take medication to relieve the pain? Who's going to know (assuming it's not right before the final exam where blood samples can detect NSAIDs etc)? Either that or drop out (as with the saline arm of FX-006). Not saying that it was "the" factor, but it makes sense.
Personal medical choices are highly individualized. As the report (and it's repeated in other reviews) SC can work, but outcomes are variable. If it's not minimal manipulation, it is not FDA sanctioned. Doesn't mean it won't work. If the risk was low and I was in a similar situation, I might try it myself. In any case, Ampion is only for pain management, as are current therapies. I'd also look at TPX-100 outcomes.
Agree about the 3-comma comment. Since no one has gone back to see if he *explicitly* stated pharma/partner derived value, then it is highly questionable. I assume "recent discoveries" refer to the SC options?
Sending a large cash position to AYTU removes any possibility of another attempt and he failed to describe a contingency plan. His only answer was that they didn't need one as they were highly confident in PIVOT. They said the same about STEP. And about STRIDE. And they refuse to publish anything positive about STRIDE or STRUT. No physician comments. Not a single set of MRI's showing any improvement. There's lots of negatives, but the drug still likely works moderately better than saline IMO.
Clearly a concern but *if* SPRING results are repeated, there is still sufficient opportunity, though it's very unlikely to command the valuations it would had STEP or even STRIDE succeeded. MM referred to valuations (multiples of highest stock price). What we don't have confirmation is Who (an interested partner/acquirer or just a paid assessor) and When (pre- or post-STRIDE)?
"Emerging drugs for the treatment of knee osteoarthritis" Expert Opinion on Emerging Drugs (2015) 20:3, 361-378
This covers nearly everything (except Ampion). "A search for compounds in development was performed on the clinicalTrials gov clinical trials registry. The drugs in discussion were divided into Sections under 7.1 ‘Pain modification’ and 7.2 ‘Structural modification’. Within Section 7.2, Drugs are categorized into their targets in OA with ‘Inflammatory pathways’, ‘Cartilage catabolism and anabolism’, ‘Synovitis’ and ‘Subchondral bone remodeling’. Section 7.3 pertains to reformulation of current existing drugs used in OA, namely corticosteroid and hyaluronic acid."
Regarding stem cells (mesenchymal): "However, for cell-based therapies to be accepted, their mechanism of action must be elucidated. ... The technical approach is also contentious, as majority of MSC preparations are injected directly into the joint compartment without use of scaffolding. In addition, the optimal cell dose and number of injections are all undetermined factors."
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.
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
Since OHRP has had no news for some time, might as well look at what the competion has released recently.
OPHT today announced the completion of patient recruitment for its second Phase 3 trial of Fovista(pegpleranib) in combination with Lucentis (ranibizumab) for the treatment of wet age-related macular degeneration (AMD).
OPHT announced today that Genentech, a Roche wholly-owned subsidiary, has elected to exercise its option to participate in the financial arrangements relating to Novartis’ rights under the Ophthotech/Novartis ex-US agreement for Fovista (pegpleranib) to treat wet age-related macular degeneration (AMD). Roche’s option originates from a pre-existing agreement between Roche and Novartis. Ophthotech’s agreement with Novartis and its financial terms remain unchanged including potential payments to Ophthotech of over $1 billion in upfront and milestone payments, and future royalties on ex-US Fovista sales. Ophthotech continues to retain sole rights to Fovista in the United State
OPHT announced that the first patient has been dosed in a Phase 2/3 clinical study of Zimura (avacincaptad pegol sodium), an inhibitor of complement factor C5, in patients with geographic atrophy, an advanced form of dry age-related macular degeneration (AMD).
OPHT announced today that David R. Guyer, M.D., Chief Executive Officer and Chairman of the Board, will present an overview of the Company at the LEERINK Partners 5th Annual Global Healthcare Conference in New York City on Wednesday, February 10, 2016
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
How does it compare to Cingal? 70% pain relief/WOMAC at 26 weeks vs baseline. Clearly a different control arm (saline).
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.
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?
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.
CBYL stock collapsed yesterday on Phase III OAK failure to meet both endpoints for Hydros-TA (a HA/CS combo). The 2nd endpoint was to beat the CS alone at 26 wks. But, the control arm did better than expected (sound familiar?):
"patients who received the corticosteroid triamcinolone acetonide, or TA, showed a prolonged pain-reduction through 26 weeks, which was unexpected based on clinical experience and published literature. "
What is also surprising is that Hydros-TA is the same HA/CS concept as Cingal (even the same API), which had excellent Phase 3 results, is approved in Canada and currently under FDA review:
Apr 2015: Cingal(ANIK) "met the primary endpoint by demonstrating superiority over saline for the change in WOMAC Pain Score over baseline levels through 12 weeks after treatment in the Intent to Treat (ITT) population (-40.2 mm vs. -31.0 mm, p=0.01). The benefits proved long lasting as Cingal delivered a 72% improvement (-42.4 mm, p=0.01) in WOMAC Pain Score relative to baseline at 26 weeks after injection." Also, *all* secondary endpoints were met, substantiating the benefit.
So, along with the statistical fluke in Zilretta's last trial it is another example of how unexpected problems cause trial failure. The failures such as seen in STEP and STRIDE are not uncommon. Leerink (a specialist biotech investment house) downgraded CBYL to less than $2 from $15. They show $60M cash as of Dec 31, so are in a position to repeat the trial. Clearly, AMPE does not should PIVOT fail.
The 10K is more conservative in that it states Phase III will commence *after* the SPA is granted. Only "feedback" is required within 45d of submission. It seems improbable that all details haven't been agreed to, but the next 10Q, due soon, might (I hope) offer new info. From 10K:
" the submission of the Special Protocol Agreement (SPA) in November 2015, we intend to initiate the Phase III program upon completion of the SPA procedure, and begin enrolling patients in the first calendar quarter of 2016."
We'll see what the big money has been doing shortly. Some funds have to reduce risk as part of their strategy, take gains, etc. Hedging with options isn't usually viable with small caps.
Small cap biotech (Nasdaq NQUSS4573) is down 25% in the past 3 months. We're down about 40%. The 6mth chart does indeed look ugly (lower lows, lower highs). Wouldn't surprise me to see it run up to old highs on NDA acceptance, but anything is possible.
The only negative I can see is that CPP115 requires another Phase 1 (cost, time). The biggest clinical unknown are the remaining safety data. Remove those uncertainties without another offering and it's a new day.
The more recent Phase 1b results are more apropos. Clear increase in CNS Gaba levels, but somnolescence noted (another proof of efficacy but an undesired SE) so Phase II cannot start without another dose ranging study. The scope, expense and structure of that study is unknown. It is not entirely impossible to have a Phase II run-in. They have repeatedly stated Phase II will be partnered.
Dec 16 PR "Once we obtain the full results of this study, we intend to determine the steps required to make CPP-115 "Phase 2 ready," including a Phase 1 dose ranging study evaluating CPP-115 at lower doses."