CU6 - General discussion, page-513

AMPLIFY TRIAL (COBRA 2.0): WHAT'S NEW AND WHY IT MATTERS

[Below - is how I see things (personal opinion), read together with the FDA approval of Illuccix (documents added to the bottom of this writeup)]

AMPLIFY is the planned registrational (pivotal) Phase 3 trial of 64Cu-SAR-bisPSMA in biochemical recurrence (BCR) prostate cancer. The trial protocol was approved by the FDA.

Effectively, this is COBRA 2.0, but with a gear shift from safety to efficacy.

Key Differences vs COBRA

What's New?

• AMPLIFY shifts earlier in the patient journey:
  Targeting BCR patients before systemic therapy begins, opening the door for earlier intervention and broader market.

• Biopsy tightening up (slightly):
  Still optional, but participants must be willing to undergo biopsy of any PET-positive lesion, where feasible.

• No Conventional Imaging or other PSMA imaging?
  The protocol summary (as read) doesn’t mention needing negative or equivocal conventional imaging first (COBRA did)! Itf thisis the case, it might well streamline trial entry and focus purely on PET performance.
  FDA precedent? YES! The 2 trials that were required as a bridge for the Illuccix approval, lacked reliable data related to the conventional imaging, but the FDA specifically stated that this did not negate the efficacy of the product!

LESSONS FROM THE ILLUCCIX (Ga68 gozetotide) FDA APPROVAL

1. Unmet Need Argument Was Specifically cited by the FDA!

• The FDA recognized that existing imaging modalities (MRI, 18F-fluciclovine, etc.) are inadequate, with many cases of recurrence and failure to localize disease. They acknowledged the imperfections of Ga68 PSMA agents (low sensitivity, esp on pelvic lymph nodes.

• Inference for 64Cu-SAR-bisPSMA: The same arguments still apply today. There is no good enough imaging agent, and the FDA acknowledges that prostate cancer patients need better options: Surprise surprise? Fast Track Designations = a strong clinical need PLUS clear advantages over existing options: logistics (half-life, centralized production), efficacy!

2. Trial Design Limitations Were Tolerated - due to significant benefits!

• The FDA explicitly noted that the studies presented had significant limitations, yet still concluded that the drug's benefit outweighed those issues because of its value in guiding therapy (avoiding unnecessary surgery, selecting systemic therapy, etc.)

• Inference for 64Cu-SAR-bisPSMA: Is this where the Co-PSMA trial comes in? Normaly, the FDA does not require a head to head - but not requiring it does not minimise it! Clarity will present the data, together with whatever other data becomes available from AMPLIFY and CLARIFY! How soon is this going to be approved? Who knows?

3. Approved Despite Known False Negatives and False Positives

• The FDA accepted limitations of false negatives (esp. pelvic lymph nodes), stating that all imaging modalities share these limitations.

• Inference for 64Cu-SAR-bisPSMA: This might sound like a cop out), but prescedence is important! The FDA is unlikely to require perfection; Cu64 might only need to show non inferiority in efficacy, with just operational/logistical benefits (e.g., longer half-life, centralized manufacturing, flexible scheduling) as good enough metrics qualifying it for approval.

4. Logistics

The FDA revieweres specifically say this: "Approval of the applicant kit is expected to increase geographic availability of PSMA-specific PET."

• Tthe FDA recognized availability and access improvements as a standalone benefit, even where the clinical performance was limited. This was explicitly cited in the risk-benefit balance, meaning logistics, manufacturing, and access considerations influence approval decisions for imaging agents!

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The BAR for approval is realy not High!

Here are the results that the FDA had from the bridging trials that were required for the approval of Illuccix! A Test Sensitivity of just 47% was avchiebved in the pre-prostatectomy trial, meaning that, that endpoint was not met. But that did not stop the approval for that indication!




THE BRIDGING TRIALS for ILLUCCIX







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KEY REFERENCES

NDA Multi-Disciplinary Review and Evaluation - NDA 212643, Gallium Ga 68 PSMA-11 Injection.pdf

NDA Multi-Disciplinary Review and Evaluation - NDA 214032 Gallium Ga 68 PSMA-11 Injection.pdf