Topic: PART 2 ARTICLE done... except for TABLE FORMAT & last minute changes
Do you see errors? Things that should be changed? Please let me know ASAP
I hope to publish this morning.
OMEROS COVID-19 NARSOPLIMAB DATA
PART 2: QUALIFYING CUP DATA APPLIED TO I-SPY PHASE 2 TRIAL
Alan Robert Ross
July 5, 2021
CUP - Compassionate Use Program
Narsoplimab - a monoclonal antibody, Omeros’ MASP2 inhibitor
CV19 - Covid-19
ARDS - Acute Respiratory Distress Syndrome
CPAP - Continuous Positive Airway Pressure apparatus
SOC - Standard Of Care, which in the I-SPY trial is what the control group gets
AE - Adverse event
Part 2 is about trying to use the already-collected Narsoplimab CV19 CUP data to predict how similarly ill CV19 patients would fare in the I-SPY Narsoplimab Phase 2 trial.
PART 1 RECAP
Biweekly treatment with Omeros’ Narsoplimab in the CUP led to:
- clinically significant improvement within two weeks
- discharge from the hospital of all 10 people who started out on CPAP breathing support
- 88% (15 of 17 patients) survival with a median of 33 days to discharge from hospital
But the patient population in the CUP was more severely ill than the average patient in the I-SPY trial.
PART 2 PREVIEW
Using the patient population, design, constraints & endpoints of the I-SPY trial, to
- construct a hypothetical I-SPY trial timeline for the Narsoplimab arm, based on CUP data recovery timeline for CUP patients that would be qualified to be enrolled in the I-SPY trial.
- estimate how well the Narsoplimab CV19 CUP patients eligible to enroll in I-SPY would have done in the I-SPY trial based upon their CUP data.
I-SPY TRIAL CHARACTERISTICS
The I-SPY trial is a controlled multi-treatment Phase 2 CV19 trial that has an “Adaptive Design”. This means that aspects of what is done can change as results are obtained. For example, the therapeutic treatments used as Standard of Care and/or the number of drugs being tested, may change. The official I-SPY trial listing can be found at : https://clinicaltrials.gov/ct2/show/rec … iew=record
The adaptive change that appears most relevant for Omeros (OMER) is that the rate of patient accrual will change based upon treatment efficacy. Drugs that help patients more/faster will be assigned more patients than the treatment arms with weaker less success.
Patient Population: At first glance, all of the 17 Narsoplimab CUP patients look eligible for the I-SPY trial, because I-SPY accepts male and female volunteers who test positive for CV19, if they are over 18 years of age, and rate 5 or higher on the WHO Ordinal Scale. (see Appendix of https://www.who.int/blueprint/priority- … 22020.pdf)
But 5 of these CUP patients would have been rejected because they have characteristics that are specifically excluded in the I-SPY trial protocol. Four of the 5 CUP patients would have been rejected for having been intubated for more than 120 hours before entering the trial. The fifth patient would have been rejected because s/he appeared to have more than a 50% estimated mortality rate over the next 6 months.
Table 1: It is obvious that the patients in the CUP, who would qualify for the I-SPY trial would have started to recover quickly and half of them were discharged in the time I-SPY’s endpoints allow for improvement. Only patient 6 had a long struggle, but it did end in discharge and no LongCovid symptoms when examined 6 months later.
Patient Assignment To Treatment Arms: When I-SPY enrolls patients, it randomly assigns each into a maximum of 1 Control and 8 Experimental Treatment groups. I-SPY increases the number of patients assigned to drugs that perform well and reduces the ongoing flow to those who do poorly, as part of their adaptive design. I-Spy has not publicly explained how many more or less patients are assigned, probably because it depends on the flow of total enrollment. I-SPY has increased the number of trial centers to increase the number of patients enrolling, so I’ve presumed that the number of patients added weekly for a drug with more than average efficacy would increase by 1 patient as long as relative efficacy was higher than average.
Patient Limits & Accrual: I-SPY set a minimum patient goal for each Treatment arm of 50 patients. When that minimum is reached it appears that the data for that treatment arm is subject to a more thorough interim analysis. Continued assignment of patients to groups may be ended at that point, or after, for futility or for efficacy. Testing can continue, but I-SPY sets a maximum of 125 patients per treatment arm.
Table 2: Note that the Endpoints are “UP TO”a maximum number of days. The maximum are not required. For example, If a patient is discharged in 30 days, to find out how many days the patient used a ventilator does not require 60 days. The 125 patients allowed by I-SPY rules would have already completed all the 28 day endpoints even at the maximum duration. All patients are scheduled to complete the maximum 60 day endpoints this month, but almost all of them are likely to have already been discharged and do not need the maximum of 60 days. In fact the maximum time for the Adverse Event and Ventilation endpoints do not seem crucial for patients likely to be discharged with a median of 28 days (see Table 1 for these data).
If all the patients needed the full 60 days to reach endpoints, data collection would be completed this month. This is quite unlikely, although the can be outliers like CUP patient 6.
Patient Treatment: The only treatment protocol we need to be concerned with is the one for the treatment arm using narsoplimab to treat patients. Treatment in I-SPY (twice a week) is the same as it was in the CUP.
Primary Endpoint: Patients have up to 28 days to hit the primary endpoint, which is: "Time to achieve durable change in Covid-10 to ordinal level 4 or less for at least 48 hours." WHO level 4 is less breathing assistance than "high flow oxygen". This would be a 1 stage improvement for people starting out on CPAP or High Flow, but a 2 Stage improvement for more severely ill patient who were intubated. Logic alone tells me improvement should be defined by a 1 stage change in the right direction. I think that could be what it is, but was not explained well in the trial listing. The data on this endpoint is in Table 3, below.
Secondary Endpoints: There are 4 secondary endpoints in the I-SPY trial.
A) “% of COVID-19 level 5 who never progress to COVID-19 level 6/7 [...Up to 60 days]”
B) “Ventilator-free Days [...Up to 60 days]”
C) “Total grade 3 or higher AEs” and “number of patients with grade 3 or higher AEs….
D) “Mortality at 28 days after study enrollment [...Up to 28 days ]
For some of the drugs being tested these endpoints may be a challenge, but for the Narsoplimab-treated CUP patients they mostly seemed to be easy to meet. All but 1 patient improved in 29 days or less. There were few days when the patients were being ventilated, no adverse events reported and no deaths occurred during the the trial, with all patients being discharged.
SUMMARY AND CONCLUSIONS
The 12 Narsoplimab CV19 CUP patients who would have been eligible for inclusion in the I-SPY trial all survived and were discharged from the hospital during the CUP and would likely have the same happy fate if enrolled in I-SPY.
To the extent the ISPY enrollment model is accurate, the recovery data for the 12 CUP patients should be reproduced by the patients treated with Narsoplimab in the I-SPY trial. All I-SPY Narsoplimab arm data should be completed by the end of this month (July 2021), or already be complete, because the longest lasting Secondary endpoints may be complete in much less than 60 days.
All available evidence indicates Narsoplimab should be a clear CV19 treatment success in the I-SPY trial, saving the lives of those treated.
We await those results.
Note: Hat Tip to WT and PC for valuable help in the various stages of this article.
The foregoing is not investment advice. I own shares in Omeros and no one has compensated me for writing this article. © 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.