Executive Summary

Q4 2020 revenue rose to $5.70M, driven by collaboration revenue recognition, while net loss widened to $30.1M (EPS -$0.62) on higher R&D spend, including a $12M upfront for the SY-2101 acquisition .
The company initiated a registration‑enabling Phase 3 trial of SY‑1425 in higher‑risk MDS and outlined plans for a randomized Phase 2 AML triplet study in 2H 2021, reinforcing late‑stage pipeline momentum .
Cash, cash equivalents and marketable securities were ~$174M at 12/31/2020; guidance on runway was updated from “into 2H 2022” (Jan 11) to “into 2023” (Mar 4) following two financings, improving funding visibility .
Near‑term catalysts include Phase 3 enrollment progress in MDS, AML triplet study initiation, and SY‑2101 dose‑confirmation start in 2H 2021; these events are likely to drive stock narrative around execution and registrational pathways .

What Went Well and What Went Wrong

What Went Well

Initiated Phase 3 for SY‑1425 in RARA‑positive higher‑risk MDS (primary endpoint: CR; 2:1 randomization, ~190 patients), marking a key advancement toward registrational data .
Acquisition of SY‑2101 (oral ATO) expands hematology franchise; management expects the Phase 3 in APL to start in 2022 and believes oral ATO could quickly become frontline standard of care given heavy burden of IV ATO infusions .
Strengthened balance sheet via $90.5M private placement (Dec 2020) and $75.6M follow‑on (Jan 2021), extending runway into 2023 and supporting multiple clinical milestones; “We are entering 2021 in a strong financial position” .

Quotes:

“We plan to launch three clinical trials across our portfolio of targeted hematology therapies... indications where we have the opportunity to set new standards of care.”
“We are entering 2021 in a strong financial position... Together, the proceeds from these financings extend our anticipated cash runway into 2023.”

What Went Wrong

Net loss widened significantly YoY and QoQ in Q4, to $30.1M, primarily due to the $12M SY‑2101 upfront and increased clinical advancement costs (1425 and 5609), pressuring near‑term P&L .
R&D expense spiked to $29.0M in Q4 (vs. $17.7M in Q3), highlighting burn sensitivity to business development and late‑stage study preparations .
Lack of available S&P Global consensus estimates (tooling limitation) limits formal “vs estimates” comparison; investors must rely on intrinsic trends and qualitative milestones (see Estimates Context).

Financial Results

Core Financials (Quarterly)

Metric	Q2 2020	Q3 2020	Q4 2020
Revenue ($USD Millions)	$3.2	$3.8	$5.7
Net Loss ($USD Millions)	$(17.2)	$(19.5)	$(30.1)
Diluted EPS ($USD)	$(0.38)	$(0.43)	$(0.62)
Cash, Cash Equivalents & Marketable Securities ($USD Millions, period-end)	$108.7	$93.1	$174.0

Notes: Q4 2020 condensed statement corroborates these values (Company press release 3/4/2021) .

Operating Expenses Detail

Metric	Q2 2020	Q3 2020	Q4 2020
R&D Expense ($USD Millions)	$14.8	$17.7	$29.0
G&A Expense ($USD Millions)	$5.1	$5.2	$5.9

Drivers: Q4 R&D increase primarily due to $12M upfront for SY‑2101 acquisition and continued advancement of 1425 and 5609 trials .

Collaboration Revenue Mix (Quarterly)

Revenue Source	Q2 2020	Q3 2020	Q4 2020
Global Blood Therapeutics (GBT) ($USD Millions)	$2.5	$3.5	$3.6
Incyte ($USD Millions)	$0.7	$0.3	$2.1
Total ($USD Millions)	$3.2	$3.8	$5.7

Guidance Changes

Metric	Period	Previous Guidance	Current Guidance	Change
Cash Runway	Corporate	Into second half of 2022 (Jan 11, 2021)	Into 2023 (Mar 4, 2021 press release)	Raised
SY‑1425 (MDS)	2021	Initiate Phase 3 in Q1 2021	Status: Phase 3 open for enrollment; CR is primary endpoint	Maintained (executed)
SY‑1425 (AML Triplet)	2021–2022	Initiate randomized Phase 2 in 2H 2021; initial data in 2022	Reaffirmed timeline	Maintained
SY‑2101 (APL)	2021–2022	Dose-confirmation 2H 2021; Phase 3 start in 2022	Reaffirmed; asset acquired Dec 2020	Maintained
SY‑5609 (CDK7)	2021	Report additional dose‑escalation data incl. clinical activity in Q3 2021; expansion begin 2H 2021	On track	Maintained

Earnings Call Themes & Trends

Topic	Previous Mentions (Q2 2020)	Previous Mentions (Q3 2020)	Current Period (Q4 2020)	Trend
SY‑1425 Efficacy/Tolerability	High CR rates, transfusion independence signals in newly diagnosed unfit AML; frontline opportunity clarified	ASH focus; high response rates in RARA‑positive; translational data link to venetoclax resistance; combination safety	Phase 3 in MDS open; AML randomized Phase 2 triplet planned; CR as primary endpoint; broad potential in MDS/AML	Advancing to registrational
Companion Diagnostic (RARA)	DHRS3/biomarker PD context in programs	Biomarker enriches RARA‑positive responders vs negative; validates selection	CDx development progressing in parallel with clinical program	Execution progressing
SY‑2101 (Oral ATO)	N/A	N/A	Asset acquired; dose‑confirmation 2H 2021; Phase 3 in 2022; strong KOL enthusiasm	New program added
SY‑5609 (CDK7)	Phase 1 design and PD marker strategy; Q4 initial PK/PD data planned	ENA data: proof of mechanism; POLR2A PD increases; intermittent vs continuous dosing; cohorts expanded	Additional dose‑escalation data Q3 2021; expansion 2H 2021; tumor types and combination strategy refined	Data maturing
COVID-19 Ops Impact	No major disruptions; telemedicine/monitoring adopted	Not a call focus	Not a call focus	Stable operations
Financing/Runway	Cash into 2022	Cash $93.1M; into 2022	Two financings extend runway into 2023; cash $174M	Stronger balance sheet

Management Commentary

Strategic priorities: “Advancing a leading franchise of targeted therapies for hematologic disorders... building on our leadership in selected CDK inhibition... leveraging our foundational gene control discovery engine...” .
On SY‑2101 (oral ATO): “As an oral agent, we believe 2101 could dramatically reduce the intense burden of treatment... We plan to initiate a dose confirmation study in the second half of the year, followed by a Phase 3 trial... next year.” .
On SY‑1425 trajectory: “We believe 1425 has the potential to set new standards of care for targeted populations of patients with MDS and AML...” .
CFO on liquidity and uses of capital: “Together, the proceeds from these financings extend our anticipated cash runway into 2023 and allow us to invest along our three strategic priorities...” .

Q&A Highlights

AML randomized Phase 2 triplet (1425+VenAZA): Primary endpoint will be composite CR rate; expectation that VenAZA control may underperform in RARA‑positive monocytic phenotype, potentially favoring the triplet .
MDS Phase 3 design: ~190 patients, 2:1 randomization, CR primary endpoint informed by FDA feedback; powering specifics not disclosed; interim analysis plans not detailed .
5609 expectations: Proof‑of‑concept criteria include tolerable safety with PD/biologic activity; expansion cohorts will be more homogeneous, focusing on tumor types informed by dose‑escalation data (e.g., breast, lung, colorectal, pancreatic) and combinations (fulvestrant) .
Companion diagnostic: CDx development for RARA progressing in parallel; critical to launch strategy for 1425 .
Dosing considerations for triplet: Brief safety lead‑in planned; 1425 not myelosuppressive; hypertriglyceridemia largely a lab finding; dose strategy expected to proceed efficiently .

Estimates Context

S&P Global consensus estimates for Q4 2020 (Revenue, EPS) were unavailable via our tool due to missing mapping; therefore, comparisons to Wall Street consensus could not be verified. Values retrieved from S&P Global were unavailable for SYRS in this period using our tooling.
Implication: Without validated consensus, we cannot label beats/misses; however, revenue increased sequentially and YoY, and EPS loss widened on elevated R&D and BD spend (see tables) .

Key Takeaways for Investors

Late‑stage transition: SY‑1425 is now in a registration‑enabling Phase 3 (MDS), with AML triplet randomized study slated for 2H 2021—clinical execution is the core near‑term driver .
Hematology franchise expansion: SY‑2101 (oral ATO) adds a distinct, potentially faster‑to‑market asset targeting APL and could be a practical standard‑of‑care upgrade if Phase 3 succeeds .
Funding visibility improved: Post‑financings, runway extended into 2023, enabling multiple value‑creating readouts without immediate financing risk—an important support for sentiment .
Near‑term P&L trade‑off: Elevated Q4 burn (R&D +$12M upfront) is consistent with late‑stage build; monitor quarterly opex cadence vs milestones to gauge capital efficiency .
Clinical narrative could re‑rate: Clear biomarker strategy (RARA), non‑overlapping safety profile, and potential to address VenAZA‑resistant AML create a differentiated path—trial starts and early data will be watched closely .
Trading setup: Expect headlines around enrollment updates and trial initiations; pullbacks on opex spikes may be opportunities if execution stays on‑track.

Citations:
Earnings call transcript Q4 2020
Earnings call transcript Q3 2020
Earnings call transcript Q2 2020
8‑K/Strategic priorities & Item 2.02 cash disclosure (Jan 11, 2021)
Press release with financials (Mar 4, 2021)
SY‑2101 acquisition release (Dec 5, 2020)

Syros Pharmaceuticals, Inc. (SYRS)·Q4 2020 Earnings Summary