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11 Oct, 17 tweets, 3 min read
Bicycle Therapeutics $BCYC has just fired a shot-heard-round-the-world, threatening to disrupt a huge technology platform in the biotech industry.

Here's a play-by-play on David vs. Goliath, taking on antibody-drug conjugates!

Thread below🧵
First, a little about Goliath:

Antibody-drug conjugates (ADCs) are antibodies (Ab) that target a specific cancer antigen on one end and are connected to a toxic payload (e.g. chemo) on the other end, acting as a biologic homing missiles. They work. Several are blockbusters.
Despite this cleverness, ADC's have tough side effects from toxin -> healthy cells. They are also bulky molecules. Central problem:

Bulk + low dose => poor tumor penetration

1. Activity limited to tumor surface
2. Spilled toxins concentrate outside tumor (innocent bystanders)
Enter David.

$BCYC uses small molecule drug conjugates that use loops to stabilize their conformation: Bicycle Toxin Conjugates (BTCs)

1. They are small, penetrating deep into tumors
2. Thus, spilled toxins fall primarily on neighboring tumor cells (helpful bystander killing)
This means BTCs target based on (1) antigen specificity, AND (2) physical proximity to antigen-defined targets, even killing tumor cells that lack the antigen (evolved to hide it, patchy expression, etc.)

$BCYC found a way to turn bystander killing into a powerful ally!
Since ADC activity gets focused at tumor surface, BK (1) causes worse tox as it hits junction of cancer/healthy tissue, & (2) doesn't kill many antigen-negative cancer cells. Newer ADCs can eliminate BK, but they'd need to solve tumor penetration to embrace it. As $BCYC has.
$BCYC has taken on a bold attempt to improve efficacy and safety vs ADCs. On last week's update, Phase 1 clinical data now supports both claims.

1. Nectin-4: BT8009 vs Padcev
2. EphA2: BT5528 vs MEDI-547 (& DS-8895a)
1. Nectin-4 targeting Urothelial Cancer: BTC vs ADC with same payload (MMAE)

In crosstrial comparison, BT8009 first two dose tiers (not optimized dose/frequency) already comparable ORR to fully optimized Padcev. Dose-responsive => better efficacy to come, if safe
On safety:

Padcev dose escalation was limited by neuropathy (49%) and 4 fatal toxicities (2%) with 34% severe treatment-related AE's (mostly non-heme), also noting skin tox (~40%) and ocular (12%).

BT8009 had 4% neuropathy (Grade 2), no skin/ocular tox, no Grade 4/5 heme tox.
We have room to escalate dose, and BT8009 has shown exciting dose-response!

Grade 3 toxicities were minimal: low K, high BP, fatigue (n=1, 4%).

Grade 3 heme tox (Hb 6.5-8, ANC 500-1000) in 3-4 pts out of 27 is very manageable, and should improve with every 2 wk dosing.
2. EphA2 was previously undruggable, not only by ADC (MEDI-547, stopped quickly for severe coagulopathy) but even by monoclonal Ab DS-8895a (65% TRAEs, 35% SAEs, 1/37 ORR).

BT-5528 has targeted EphA2 with the best clinical profile to-date by far. It adds POC to platform.
It is tragic that two patients died from renal failure on this study. Increased vigilance can be paid to TLS/AKI with what we know today, & with dialysis and TLS-preventing therapies in our toolbelt, I think there is realistic hope that such events do not repeat themselves.
It remains unclear whether BT-5528 has a risk/benefit profile that will be clinically useful.

If not, this is likely a shortcoming of the target rather than the tech. AE's akin to mAb (DS-8895a), yet w/better benefit. Better than ADC? Maybe? No coag = differentiated, at least
Overall, the cleanest comparison is on Nectin-4, and all clinical data is supportive of the hypothesis that $BCYC offers a positively differentiated clinical profile to ADCs.

David has lined up his shot. Can he hit?
$BCYC BD strategy focuses on fully-owned oncology assets with clear path to profitability while using grants and intelligent partnerships to fund drug development/trials of exploratory uses of the tech, generating cash & improving IP and revenue sources without cost to investor
Value Drivers:

1. BTCs targeting Nectin-4 and EphA2
2. TICAs use same targets but connect to NK cell to induce immune killing (instead of toxic payload). Similar to $AFMD NK cell engagers.
3. A slew of non-onc & partnered assets (w/ $IONS, $AZN, $RHHBY, $OXUR, etc)
4. Platform
I absolutely love the daring scientific vision here.

I have paid my highest respects by deferring all bicycle-themed dad jokes.

This summary is meant for bulls, bears, & biotech aficionados. Counterpoints are welcome/encouraged! as are comments!

Disclosure: Long/bullish.

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