Due to the nature of this product being a monoclonal antibody and thus must be manufactured and stored under stringent quality standards, order fulfillment requires additional processing time. Please allow 2–3 weeks for production, plus shipping time, to ensure we deliver a product that meets our quality and purity specifications.

                                         NOT FOR HUMAN CONSUMPTION

Domagrozumab PF-06252616) is a humanized IgG1 monoclonal antibody that neutralizes myostatin (GDF-8)—a TGF-β–superfamily ligand that acts as a dominant negative regulator of skeletal muscle growth. The therapeutic premise was that sustained myostatin blockade would increase lean muscle mass, and ideally improve strength and function in diseases such as Duchenne muscular dystrophy (DMD) and certain limb-girdle muscular dystrophies.

Regulatory status: investigational; not FDA/EMA-approved. Pfizer terminated key DMD clinical studies after Phase 2 efficacy failure.

2) Target biology: myostatin

Myostatin signals via activin type II receptors (ActRIIA/ActRIIB) to activate SMAD2/3 pathways that suppress muscle hypertrophy. Blocking myostatin is a high-confidence way to increase muscle size in many models, but across human neuromuscular disease programs a consistent translational lesson has been:

Lean mass gains do not reliably convert into functional improvements, especially when muscle is compromised by fibrosis, fatty infiltration, denervation, or ongoing degeneration.

3) Proposed benefits under investigation (evidence-weighted)

4) Molecular mechanism of action

4.1 Pharmacodynamics (ligand neutralization)

• Domagrozumab binds circulating myostatin, preventing receptor engagement and reducing SMAD2/3 signaling downstream (conceptual for all anti-myostatin mAbs).

4.2 Target engagement and PD signals

In first-in-human work, domagrozumab showed typical IgG1 PK and evidence of target engagement, with a myostatin-modulation signal that plateaued around the 20 mg/kg IV dose (in that study’s PD readouts).

5) Pharmacokinetics and administration 

In healthy-subject studies, domagrozumab demonstrated typical IgG1 pharmacokinetics:

• slow absorption after SC dosing,

• slow clearance,

• low volume of distribution,

• long half-life (mAb-typical).

In the DMD Phase 2 program, dosing was by IV infusions at multiple ascending dose levels (5, 20, 40 mg/kg) with measured serum concentrations increasing with dose.

6) Clinical evidence 

6.1 Duchenne muscular dystrophy: Phase 2 randomized trial + open-label extension

A Phase 2 randomized, double-blind trial in ambulatory boys with DMD evaluated domagrozumab vs placebo with a primary functional endpoint:

• Primary endpoint: change in 4-stair climb (4SC) time at week 49

• Result: primary endpoint not met; efficacy measures did not show a significant treatment effect

• Body composition / imaging: non-significant increases in muscle volume vs placebo

• Safety: generally safe and well tolerated; most AEs mild and not treatment related

Pfizer subsequently announced termination of the DMD Phase 2 and its open-label extension.

6.2 Limb-girdle muscular dystrophy (LGMD R9/2I; FKRP-related): Phase Ib/IIa

An open-label multiple ascending-dose study in FKRP-related LGMD R9/2I concluded that domagrozumab was safe, but there was no clear evidence of clinically meaningful benefit.

7) Safety and tolerability 

7.1 Common/overall

In DMD Phase 2, most participants experienced at least one AE, typically mild and often not considered treatment-related.

7.2 Serious adverse events and immunogenicity (from public CSR synopses)

Pfizer’s public clinical study report synopsis for the Phase 2 DMD study describes treatment-related SAEs including (examples listed): femoral neck fracture, anxiety, and troponin increased, with one discontinuation due to SAE anxiety (40 mg/kg).

(CSR synopses are helpful for safety granularity, but they are not substitutes for a full regulatory label because the product was not approved.)

8) Development outcome and regulatory landscape

Domagrozumab remained investigational and Pfizer discontinued DMD development after failure to meet the Phase 2 primary endpoint, terminating both the main study and open-label extension.

9) Scientific synthesis

Domagrozumab fits a recurring pattern seen in myostatin inhibition:

1. Target engagement and some mass/volume signals can occur, but

2. Functional endpoints are hard to move in progressive dystrophies where structural pathology limits translation.

This does not invalidate myostatin biology; it indicates that disease context, endpoint choice, and combination strategies (rehab/training, antifibrotics, gene therapies) may be essential for functional impact.

10) Future directions 

If an anti-myostatin approach were pursued now, the “must haves” would be:

• Function-first trial design (power, stair climb, sit-to-stand, VO₂peak, ADLs) plus standardized rehab/training

• Muscle quality metrics (MRI volume + intramuscular fat + strength per CSA), not DXA alone

• Earlier or different indications where muscle is salvageable (frailty, GLP-1–associated lean loss, post-hospital deconditioning) rather than advanced dystrophy alone

• Clear PK/PD target engagement thresholds tied to functional outcomes