B2B email open rates dropped from 25% to 15% (CTR 3% → 0.4%) — deliverability issue, audience fatigue, or something else?

I’m seeing a noticeable drop in email performance over the last few months and wanted to get perspectives from this community.

Context: I run targeted B2B outreach to ~1,000 contacts in large pharma and healthcare organizations across the US. Roughly 55% are existing customer accounts, and the rest are prospects. Emails are sent via ActiveCampaign with Outlook as the sending environment.

Historically, my campaigns averaged around 25% open rate and ~3% CTR. Recently, opens have declined to ~15% and CTR has dropped further to ~0.4%. This is happening across both customer and prospect segments, although the impact feels slightly sharper on prospects.

I’m trying to understand what might be driving this:

• Could this be audience fatigue or content relevance drift?
• Are there broader deliverability changes (Microsoft/Google policies, privacy protections, AI-based filtering, etc.) that others are seeing impact B2B campaigns?
• Has anyone observed differences when sending through CRM platforms paired with Outlook?
• What diagnostic steps would you recommend first—list hygiene, cadence adjustments, or something else? (domain reputation check done, and it's fine)

Would appreciate hearing if others in regulated industries or enterprise B2B spaces have experienced similar drops and what helped recover engagement.