Member Info for Tp23

https://twitter.com/joeblynam/status/1243633111797248000?s=21
The ECB orders banks to stop paying dividends to shareholders
Not sure how this will effect Lloyd’s?

We must also be realistic over possible time lines? ‘My’ interpretation of the process is the meeting on May 3rd will be the opportunity for the company to discuss the issues raised in the CRL and how these can be addressed? The result of the meeting will also identify what type of resubmission of the NDA will be required ie Class 1 (2 months) or Class 2 (6 months) which, will obviously impact on how much time and finance the company will require to progress to approval?

Thanks Ivy,
It does seem that most of the issues identified during the Assist trials were addressed by the change from weight to fixed dose?
Regarding the limited patient population and identifying the potential for DILI in the wider population, I can’t find any additional trials or study conducted by Paratek for their FDA approval of Nuzyra (omadacycline)? I assume the FDA would have required similar data?

Ivy, Having looked at the comparative data I’m not sure that the raised AST levels present any greater issue in the identified dosing regime than the others which have been approved ie vancomycin, omadacycline, Linezolid etc?
Without further details from the company at the moment we can only guess but I agree with your earlier observation that it may be to do with a wider population DIli issue? what are your thoughts re the previous EMEA observation re the treatment for severe complicated cases which would generally require treatment for longer than the 14 days as used in the trial?

Ivy, also worth remembering that following the Aprida submission the “The FDA Advisory Committee focused on the dose-dependent increase in QTc in the clinical trials; Unlike the EMEA, however, there was no specific focus on possible hepatotoxicity signals with the IV infusion.” So not previously considered a major issue by the FDA?

Not sure which way to interpret the following taken from a Motif Bio presentation dated 14th Feb 2019:

“Complete response letter received February 2019; Motif to request meeting with FDA ASAP to discuss
• Intended follow-on indications
• Hospital-acquired bacterial pneumonia (HABP)
• S. aureus lung infections in patients with cystic fibrosis (Orphan Drug Designation granted in U.S.)”

No mention of discussion re evaluation of liver toxicity?

http://phx.corporate-ir.net/External.File?item=UGFyZW50SUQ9NzAzOTk0fENoaWxkSUQ9NDE2MTc2fFR5cGU9MQ==&t=1

Vas, following the Assist trials the FDA advised to move to a fixed dose regime rather than a weight based dose. That was the study conducted by David Huang et al to identify the appropriate fixed dose of 80mg to be used during the Revive P3 trials.
They also refer to the following trial in the Clinical protocol document which was the reference for establishing the proposed lower dose.
“Open label, parallel, single dose study to investigate the pharmacokinetics of iclaprim in subjects with hepatic or renal dysfunction and in obese subjects. Study Iclaprim-HKI-004. Harrison Clinical Research GmbH, Munich, Germany. 05 February 2007.”

Vas, like yourself and the rest I’m just looking for possible answers but, am limited to what they publish? We can see that they identified the need for a lower dosage for participants with moderate hepatic impairment but cannot see from the published results exactly how many if any were treated as such?

I briefly compared the ALT/AST results published for Iclaprim and its FDA approved comparator vancomycin and also the results from the, now FDA approved, Omadacycline phase 3 trials with the approved linezolid and Moxifloxacin and as you can see from the published results there must be more to it as the Iclaprim data seems the same if not better than the others?

Iclaprim
Revive 1 Iclaprim - 293 participants ALT 2.0% AST 2.0%
Revive 1 Vancomycin - 297 participants ALT 1.7% AST 4.3%

Revive 2 Iclaprim - 299 participants ALT 1.7% AST 2.0%
Revive 2 Vancomycin - 302 participants ALT 2.3% AST 1.7%

Omadacycline
Trial 1 Optic Omadacycline - 382 participants ALT 3.7% AST 2.1%
Trial 1 Optic Moxifloxacin - 388 participants ALT 4.6% AST 3.6%

Trial2/3 Oasis Omadacycline - 691 participants ALT 4.1% AST 3.6%
Trial2/3 Oasis Linezolid - 689 participants ALT 3.6% AST 3.5%

Liver function tests check the levels of certain enzymes and proteins in your blood. Levels that are higher or lower than normal can indicate liver problems. Some common liver function tests include:
* Alanine transaminase (ALT). ALT is an enzyme found in the liver that helps your body metabolize protein. When the liver is damaged, ALT is released into the bloodstream and levels increase.
* Aspartate transaminase (AST). AST is an enzyme that helps metabolize alanine, an amino acid. Like ALT, AST is normally present in blood at low levels. An increase in AST levels may indicate liver damage or disease or muscle damage.

Vas, I refer you to one of my previous posts from Sat of how and why the 40mg dose was calculated:
“An iclaprim dose of 40 mg administered over 2 hours every 12 hours (q12h) is selected as the dosing regimen for patients with moderate hepatic impairment (Child-Pugh Class B [Appendix E]). An open-label, parallel, single dose study to investigate the pharmacokinetics of iclaprim in subjects with hepatic or renal dysfunction and in obese subjects showed a 2.5-fold increase in AUC and a 1.4-fold increase in Cmax. Since iclaprim clearance was reduced by 50%, a 50% reduction in dose will be used for patients with moderate hepatic impairment [7].”

The reasons I questioned the lower dose were:
“might the issue relate to the proposed 40mg lower dose for participants with mild liver hep Child-Pugh score B?
IF my interpretation from the published trials are correct then all 298 participants Revive 1 and 295 from Revive 2 received the 80mg does??
https://clinicaltrials.gov/ct2/show/results/NCT02600611?view=results
https://clinicaltrials.gov/ct2/show/results/NCT02607618

If no participants received the lower dose then by assumption:
1. How could the lower dose be evaluated?
2. I cannot see a dosage adjustment for the comparator vancomycin?
3. If no participants received the lower dosage then the trial population for Iclaprim comprised of Child Pugh Class A only?

If point 3 is correct, the FDA MAY consider these exclusions worth further trial data?
Example From an FDA publication:
“Patients with organ dysfunction are frequently excluded from clinical trials. For example, Patients with kidney or liver disease may, even after dose adjustment, have effectiveness or safety effects different from patients without that condition, but those patients will not be assessed if they are not included. Exclusion from clinical trials leaves an evidence gap regarding the potential benefits and risks in these populations.”

Within the Omadacycline P3 trials 6 specific participants 2 x Child Pugh A, 2xB and 2 xC were identified and specifically treated to identify the effect on patients with existing liver damage?

As Ivy correctly identifies we don’t know if all the data has been published so these assumptions may be useless!

Link to the Feb 19 conf call:
https://edge.media-server.com/m6/p/jjvp5uks

Hi Ivy,
Agree it’s not clear but from the R1 and 2 trial results I posted earlier the indication as I read it is that all the participants received the 80 mg dose. That was all I was highlighting as if none of the participants were Child-Class B then the lower dose would not have been used and subsequently not evaluated? Just a thought.

Vas, page 26.
The 40mg (half) dose was identified as the appropriate dose to give any participants of the Revive trials that demonstrated mild hepatotoxicity Child-Pugh class B. (Those participants with Child-Pugh class C were excluded from the trial. My question to Ivy earlier was from the Revive 1 & 2 results I posted earlier it does not appear that any participants were treated with the lower 40mg dose hence a possible question from the FDA as has the lower dose been proved safe for those with Child-Pugh class B?

From the Revive 2 Clinical protocol document:
“An iclaprim dose of 40 mg administered over 2 hours every 12 hours (q12h) is selected as the dosing regimen for patients with moderate hepatic impairment (Child-Pugh Class B [Appendix E]). An open-label, parallel, single dose study to investigate the pharmacokinetics of iclaprim in subjects with hepatic or renal dysfunction and in obese subjects showed a 2.5-fold increase in AUC and a 1.4-fold increase in Cmax. Since iclaprim clearance was reduced by 50%, a 50% reduction in dose will be used for patients with moderate hepatic impairment [7].”
https://clinicaltrials.gov/ProvidedDocs/18/NCT02607618/Prot_000.pdf

Vas, I believe Iclaprim’s usp has always been for people with kidney problems not liver? The reason why they changed to a fixed dose was I believe to reduce the hepatoxic effect?

Ivy, might the issue relate to the proposed 40mg lower dose for participants with mild liver hep Child-Pugh score B?
IF my interpretation from the published trials are correct then all 298 participants Revive 1 and 295 from Revive 2 received the 80mg does??
https://clinicaltrials.gov/ct2/show/results/NCT02600611?view=results
https://clinicaltrials.gov/ct2/show/results/NCT02607618

Morning Ivy, completely agree and believe any issues will be minor and probably dealt with as a class 1 resubmission (2 months from resubmission). I also note from that document in my last post that “applicants receive approval after they agree to obtain additional data about the adverse risks of their drugs at a future date, after the drug was sold on the market.”?

N4, it’s also worth noting that “drug applications may receive approval despite confirming an affirmative link between drug and potential health risk. The FDA does not require a drug to be perfectly safe - it requires a drugs benefits to outweigh its risks”
Pages 11/12 http://www.mondaq.com/pdf/clients/371622.pdf

DT67, have a look at the link in my previous post for the detail provided by Paratek for omadacycline? To a novice like myself they detail what appear to be more serious adverse effects than were encountered during the Revive trials??

Ian,
Paratek referenced the ast/alt levels in their ‘Prescribing Information Document’ for Nuzyra. Can’t see why Motif can’t do the same? Page 9 Table 5
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209816_209817lbl.pdf

Morning Ivy,
I believe Paratek encountered higher AST/ALT levels during their P3 trials with omadacycline and received FDA approval?