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IPF - PLRX, FGEN and others (BI):
Ozempic face is, apparently, a thing. Increasing demand for facial fillers?
https://www.nytimes.com/2023/01/24/style/ozempic-weight-loss-drugs-aging.html
Surprisingly articulate user. (EOM)
Yep. The problem is almost certainly that, like other viral diseases, the mortality risk is substantially elevated for months after recovery. Eg flu increases MI risk for several months after an infection. And COVID is much worse in that regard. US Military, Insurance Companies and UK NHS have all, separately, noted this large effect in the young, and the excess mortality started big climb in 2020 (ie prior to vaccine).
This is a good summary of post recovery heart risks:
https://heart.bmj.com/content/heartjnl/early/2022/09/21/heartjnl-2022-321492.full.pdf
Probably the most interesting thing is a number of celebrities dying from unexpected/odd events within a few months of bad COVID infection.
A ‘panic’ is when too many ppl have the same time horizon (very short). And otherwise people can have very different time horizons for reasonable reasons - eg need money for event x, capital gains durations, taxes, can’t stomach big binaries, … .
Thanks. I too think softer sell is better, but for more than just ‘patient disappointment’ reasons. Eg FDA may force a change, which will be unpleasant especially if very public. And they have an important sBLA in review by the FDA, so pissing them off seems unwise.
RVNC - Yeah, their marketing material seems a risk. They have a big advantage in duration (between 60 and 75%) and it seems odd to push past the boundary of the FDA approved secondary endpoints (which use loss of either patient or provider assessed benefit counts as loss of benefit - whereas company, and published papers, use maintenance of either as 'still meet criteria').
Comment: I don't know legal/regulatory history on this, but it was a little surprising they don't use return to baseline, which is actually a prespecified secondary endpoint in ClinicalTrials, seems to actually be longer and is also in a published paper?
TCDA - the interesting thing is if, in fact, there is a latching effect for Metabolic Acidosis then even if the company managed to raise $ and run another trial… the market isn’t large wo chronic dosing.
Of course, it’s also true that the failure may be Eastern Europe related and they should know that in the next few days (altho it may not be released for weeks).
TCDA - trial failed due to fact that actual serum bicarb didn’t separate. That’s a particularly odd failure, but probably due to the fact that they changed the protocol in this trial from previous trials. This trial was a discontinuation trial of responders from a Part A of trial. The responders latched.
Don’t change protocols dramatically from phase 2. It’s generally a bad idea. Sometimes very bad.
SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Oct. 24, 2022-- Tricida, Inc. (NASDAQ: TCDA) announced today the top-line results from its VALOR-CKD renal outcomes clinical trial, designed to evaluate veverimer’s ability to slow CKD progression in patients with metabolic acidosis and chronic kidney disease (CKD).
Primary Endpoint Analysis
The VALOR-CKD trial did not meet its primary endpoint, which was defined as the time to the first occurrence of any event in the composite endpoint of renal death, end-stage renal disease (ESRD), or a confirmed greater than or equal to 40% reduction in estimated glomerular filtration rate (eGFR), also known as DD40. One hundred forty-nine veverimer-treated patients versus 148 placebo-treated patients experienced a DD40 primary endpoint event, representing a veverimer to placebo hazard ratio of 0.99 [95% CI, 0.78, 1.24; (p=0.898)] over the 26.7 months median duration of treatment.
Primary Endpoint Event Analysis
Veverimer
(N = 739)
Placebo
(N = 737)
Hazard Ratio
(95% CI)
p-value
Number (%) of Patients with Primary Endpoint Event
149
(20.2%)
148
(20.1%)
0.99
0.898
Annualized Primary Endpoint Event Rate
9.9%
9.8%
The VALOR-CKD Trial Design
The VALOR-CKD trial was an international, randomized, multicenter, double-blind, placebo-controlled trial of patients with CKD and metabolic acidosis. To qualify for enrollment in the study, patients were required to have two eGFR values, taken at least 2 weeks apart, in the range of 20 to 40 mL/min/1.73m2, that were not more than 20% different from each other and three serum bicarbonate values, each taken at least 2 weeks apart from the others and all three within a 6-week period (the Screening Period), in the range of 12 to 20 mEq/L. The entry criteria for the study also required that patients be on a stable, maximum-tolerated, labeled dose of an angiotensin converting enzyme (ACE) inhibitor and/or angiotensin II receptor blocker (ARB) for at least 4 weeks prior to and during the Screening Period. Both patients taking oral alkali supplements and those not taking them were eligible for enrollment; however, a patient’s use and dose of oral alkali was not to be changed during the study and those taking oral alkali were required to be on a stable dose for at least 2 weeks prior to and during the Screening Period. There were no prohibited drugs.
Eligible patients were enrolled into a single-blind active-treatment period of 4 to 8 weeks (Part A) that was followed by a randomized withdrawal into a double-blind, randomized treatment period (Part B). Patients in Part A who experienced a greater than or equal to 4 mEq/L increase from baseline in serum bicarbonate and those whose serum bicarbonate increased into the normal range of greater than or equal to 22 mEq/L at Week 4 were randomized in a 1:1 ratio either to continue treatment with veverimer or to treatment with placebo for the double-blind, Part B, portion of the trial. Patients who did not achieve the required serum bicarbonate response to veverimer after 4 weeks in Part A continued to receive veverimer for an additional 4 weeks. After 8 weeks of veverimer treatment in Part A, those patients who experienced a greater than or equal to 4 mEq/L increase in serum bicarbonate and those whose serum bicarbonate increased into the normal range of greater than or equal to 22 mEq/L were randomized in a 1:1 ratio to either continued treatment with veverimer or to treatment with placebo in Part B. Those patients who did not achieve the desired serum bicarbonate response after 8 weeks in Part A discontinued treatment with veverimer and exited the study.
In total, 2,198 patients received single-blind treatment with veverimer in Part A. Of these, 1,480 patients were randomized into Part B. The randomized patient population had a mean baseline eGFR of 29.2 mL/min/1.73m2 and a mean baseline serum bicarbonate of 17.5 mEq/L. The majority of patients randomized in the trial had one or more co-morbid conditions, such as hypertension, heart failure or diabetes. Approximately 12% of patients in the trial were taking oral alkali at baseline. The table below provides selected demographics and baseline characteristics of veverimer- and placebo-treated patients.
Selected Demographics and Baseline Characteristics
Veverimer
N = 741
Placebo
N = 739
Mean Age (SD) – years
65.0 (11.87)
65.2 (12.30)
Male – N (%)
433 (58.4)
421 (57.0)
Mean eGFR (SD) – mL/min/1.73m2
29.2 (6.35)
29.1 (6.33)
Serum Bicarbonate (SD) – mEq/L
17.4 (1.39)
17.5 (1.32)
Hypertension – N (%)
726 (98.0)
724 (98.0)
Diabetes – N (%)
423 (57.1)
399 (54.0)
Heart Failure – N (%)
230 (31.0)
241 (32.6)
Oral Alkali Use – N (%)
83 (11.2)
87 (11.8)
Serum Bicarbonate Analysis
Based on the results from the veverimer arm of the previous TRCA-301 trial, the Part A run-in period was designed to achieve a large separation of serum bicarbonate levels in veverimer-treated subjects and subjects in the placebo group over the duration of treatment. Accordingly, Tricida expected the treatment effect in Part A would be an approximately 6 mEq/L increase in serum bicarbonate and that 74% of subjects treated in Part A would achieve the necessary increase in serum bicarbonate to proceed to randomization in Part B. Based on results of both TRCA-301E and the Phase 1/2 trial, TRCA-101, Tricida also anticipated that after withdrawal of veverimer at the end of Part A in patients randomized to placebo, serum bicarbonate levels would rapidly decline to near baseline levels, while continued treatment with veverimer in those randomized to the active arm of the trial would result in maintenance of serum bicarbonate levels achieved in Part A.
In the VALOR-CKD trial, at the completion of Part A, 67% of subjects achieved at least a 4 mEq/L increase in serum bicarbonate or a serum bicarbonate increased into the normal range of greater than or equal to 22 mEq/L and were randomized into Part B. Of the 1,480 patients randomized into Part B, the average increase from baseline in serum bicarbonate was 5.9 mEq/L, increasing from 17.5 mEq/L to 23.4 mEq/L. After 3 months of treatment in Part B, the average serum bicarbonate in the veverimer- and placebo-treated groups declined to approximately 22 mEq/L and 21 mEq/L, respectively, and these levels were maintained for the majority of the treatment duration. Furthermore, at each of the 3-month timepoints between Month 3 and Month 30 in Part B, approximately 60% of the patients in the placebo group had a level of serum bicarbonate above 20 mEq/L. Thus, the difference in serum bicarbonate levels between the two groups was insufficient to evaluate the effect of veverimer on slowing CKD progression in patients with metabolic acidosis and CKD.
“Unfortunately, due to the higher than expected serum bicarbonate values in the placebo group, we were not able to compare an untreated acidotic population with a veverimer-treated population and were thus unable to assess veverimer’s ability to slow CKD progression. Given our past clinical experience with veverimer, and the VALOR-CKD trial design, we were surprised that there was not a greater separation in serum bicarbonate levels between the two groups,” stated Gerrit Klaerner, Ph.D., Tricida’s Chief Executive Officer, and President. “In light of the disappointing results from the trial, and our cash runway, we are evaluating next steps.”
Analysis of Secondary Endpoints
Given the failure on the primary endpoint, our prespecified hierarchical analysis did not permit statistical testing of the secondary endpoints, however, the nominal p-values for all of these endpoints were non-significant.
Safety Analysis
The overall safety profile of veverimer observed in both Part A and Part B of the trial was consistent with that expected for the general population of patients with Stage 3 to 5 CKD. The incidence of all-cause death (14.2% vs. 14.0%) and cardiovascular death (5.7% vs. 6.0%) was balanced between patients randomized to veverimer and placebo. The percentage of patients reporting serious adverse events (SAEs) (26.7% and 27.8%) was also similar in the two respective groups. There were only 2 treatment-related SAEs. Adverse events resulting in discontinuation of randomized study drug treatment were reported for 6.6% of the veverimer group and 6.0% of the placebo group. The majority of adverse events were mild to moderate in severity and balanced between the two groups. The most common adverse events (i.e., those reported in at least 5% of the veverimer group), in the veverimer and placebo groups, respectively, were hypertension (8.8% vs. 9.6%), hyperkalemia (7.4% vs. 5.8%), COVID-19 (5.3% vs. 7.3%), headache (5.3% vs. 5.0%), and anemia (5.1% vs. 4.9%).
“Administrative Halt” is a weird animal, for which I do not know the detailed protocol. So it’s hard for me to interpret dates in ClinicalTrials.
FWIW
TCDA
RVNC
TCDA -
Not actually a bad idea. Potentially legal? Do a FOIA, if something bad is there then go short or buy puts. Then have two other ppl do FOIA’s (at which point the FDA posts it). (I knew someone who did something similar for satellite service providers - scraped the publicly available orbital parameters, made available via US Govt, every day. Then went short if he saw a problem. Then let it be known the provider was having problems.)
RVNC - All the items except the 2nd (the bridging study) seem pretty straightforward. Either paperwork processes or pushing faster on qualification of a working cell bank. But the scope of a bridging study is unclear. Very redacted (and note that the redaction means that the company knew the FOIA was coming) and bridging studies can be either large or small.
FGEN AKBA Moutons post doesn’t mention that AKBA missed its non-inferiority vs a black box arm. Whereas FGEN made their non-inferiority vs **placebo**. So it’s possible there is carry over from Vada to Roxa, but it doesn’t seem highly likely.
(Note: I’m sure Mouton knows the difference between Roxa trials and Vada, but just didn’t recap. But others may not know that difference)
Convalescent plasma
CTMX - I used to follow them, but became disenchanted because the technology doesn’t seem to really deliver. The only person I know who follows them is PGS - but it’s a “hate follow”.
If I had to pick a weird technology company to follow it wld be PIRS. if they got an aggressive CEO there might some interesting stuff that wld shake free. (Otherwise they are just an interesting science company)
OT - Amusing study that death rate drops when doctors on strike (from Israel in this case, although there have been similar studies, with similar results, in US). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1127364/