GRACE Screening Milestone Masks Placebo Design Risk and No Efficacy Readout

Granata Bio Completes Screening for Phase III GRACE Trial in IVF

Granata Bio has completed participant screening for its Phase III GRACE trial of Granata Bio human menopausal gonadotropin (GB-hMG) in women undergoing in vitro fertilisation (IVF). The randomized, multi-centre, placebo-controlled, double-blind trial screened over 750 women across US fertility clinics, aiming to enroll approximately 625 participants aged 18-42 years. The study assesses GB-hMG's safety and efficacy in supporting cumulative live births, with the first live birth anticipated by year-end. Data from GRACE is expected to support a potential Biologics License Application (BLA).

• Granata Bio has successfully concluded participant screening for its pivotal Phase III GRACE trial, a significant milestone in the development of GB-hMG for IVF. The trial, designed as a randomized, multi-centre, placebo-controlled, double-blind study, screened over 750 women across various fertility clinics in the US. This extensive screening process sets the stage for the planned enrollment of approximately 625 participants, aged 18 to 42 years, across two distinct cohorts, demonstrating the broad reach and rigorous design of the study.
• The GRACE study's primary objective is to assess the safety and efficacy of GB-hMG in supporting cumulative live births following a single stimulation cycle. This comprehensive approach involves following participants throughout their entire treatment journey, from ovarian stimulation through all available embryo transfers, to evaluate the ultimate outcome of achieving a live birth. Granata Bio anticipates the first live birth from the study by the end of this year, with the overall data intended to support a Biologics License Application (BLA).
• Granata Bio, founded in 2018, is dedicated to advancing reproductive health by developing fertility therapies that broaden treatment options, expand access, and improve affordability. The successful conclusion of screening for the GRACE trial underscores the company's commitment to addressing unmet needs in IVF. The CEO, Evan Sussman, acknowledged the exceptional work of 15 participating fertility clinics and their teams in identifying, screening, and enrolling cohorts, highlighting the collaborative effort behind this significant clinical advancement.

Why New Options for In Vitro Fertilization Are Needed

Recent literature underscores that in vitro fertilisation success remains limited for poor responders, women of advanced age, and those with endometriosis, PCOS, or cancer, alongside broader gaps in fertility awareness and endometrial receptivity. Research over the past 3 years has targeted these high-risk and underserved populations with tailored stimulation, adjunct, and preservation strategies.

• Poor ovarian response and diminished ovarian reserve: Approximately 15% of women undergoing assisted reproductive treatment fall in the category of poor ovarian reserve defined as the retrieval of three or fewer oocytes following conventional ovarian stimulation with a daily gonadotrophin dose of 150-450 international units, according to the Bologna criteria. Studies report overall clinical pregnancy and LBR of 16.4% and 12.6% respectively, with cumulative LBR per patient of 13.1%, and both age and number of oocytes retrieved as independent factors influencing cumulative LBR. Adjunct approaches under investigation include acupuncture, multinutrient supplementation with Omega 3, coenzyme Q10, folic acid, selenium, vitamin E, catechins, and intraovarian platelet-rich plasma for diminished ovarian reserve, premature ovarian insufficiency, and pre-menopause, with reported increases in serum anti-Müllerian hormone levels and reductions in follicle-stimulating hormone levels but inconsistent effects on antral follicle counts or oocyte yield.

• Advanced maternal age 40 years and above: Among 1,088 women with mean age 41.56 ± 1.82 years, embryo formation occurred in 69.67% and ET in 62.22%, with CPR of 17.92%, MR of 40%, and live birth rate of 10.75%. Cumulative live birth rate per woman declined steeply with increasing age - 14.35% at 40 years, 9.63% at 42 years, and 0% beyond 47 years, with negligible live birth rates beyond 45 years despite multiple cycles. A significantly lower chance of successful outcome was noted in women 43-45 years old versus younger age groups, irrespective of number of oocytes collected.

• Polycystic ovary syndrome and prevention of ovarian hyperstimulation syndrome: Women with polycystic ovary syndrome are at a substantially increased risk of developing OHSS compared to those without, with OHSS described as a serious iatrogenic complication associated with significant morbidity and a small risk of mortality. Mitigation strategies reviewed include co-treatment with metformin in gonadotropin releasing hormone agonist cycles, use of GnRH antagonist or PPOS protocols, appropriate gonadotropin dosing, use of a GnRH agonist trigger for oocyte maturation in antagonist or PPOS protocols, cryopreservation of all embryos with deferred frozen embryo transfer, and treatment with dopamine-agonists after oocyte collection.

• Endometriosis and endometrioma: Endometriosis affects women of reproductive age and is a common contributor to subfertility, with ovarian endometrioma cystectomy consistently lowering anti-Müllerian hormone and described as the principal iatrogenic threat to ovarian reserve. Surgery before in vitro fertilisation does not reliably improve live birth and routine cystectomy before treatment is therefore not supported, prompting feasibility work on randomised comparison of surgery versus no surgery to endometrioma prior to IVF with live birth as the most important outcome. Investigational fertility-focused interventions include a 12-week anti-inflammatory diet before controlled ovarian stimulation and reserve-sparing approaches such as ethanol sclerotherapy of endometrioma.

• Thin endometrium and recurrent implantation failure: Intrauterine platelet-rich plasma has been proposed as an adjunctive intervention for patients with thin endometrium or recurrent implantation failure before embryo transfer. In 620 ET cycles comprising 310 cycles exposed to intrauterine PRP before ET and 310 matched control cycles, live birth occurred in 82/310 PRP cycles (26.5%) and 53/310 control cycles (17.1%) (risk ratio [RR], 1.55; 95% CI, 1.14-2.10; P = 0.005), with post-procedure endometrial thickness, ET-day endometrial thickness, and triple-line pattern more favorable in the PRP group. Comparisons of platelet-rich plasma and Plasma Rich in Growth Factors focus on endometrial thickness response when EMT is below 7 mm, implantation success, and pregnancy rates.

• Oncofertility and fertility preservation in gynaecological cancer: With delayed childbearing, need for fertility-sparing treatment and demand for fertility preservation have increased. In 144 women (median age 31 years) attending an OncoFertility Clinic, 69 (47.9%) had uterine conditions, 65 (45.1%) had ovarian conditions, six (4.2%) had cervical conditions and four (2.8%) had synchronous uterine and ovarian conditions, with fertility-sparing surgery performed in 90.6% of ovarian cancer cases and fertility preservation offered to twenty women. In thirteen patients receiving fertility-preserving therapy for early-stage endometrial carcinoma and endometrial intraepithelial neoplasia, overall treatment response rate was 76.9%, including 69.2% complete and 7.7% partial responses.

• Fertility awareness and elective egg freezing in young women: Among 138 undergraduate female students, almost half (48.89%) incorrectly believing age-related fertility decline occurs after age 40, awareness of elective egg freezing was low, but nearly half (48.89%) expressed interest in it, primarily to retain the option for a biological child. While most (62.96%) considered childbearing necessary, they would not have a child without a partner, a significant portion was open to donating their eggs (41.48%), and cost of elective egg freezing was a significant deterrent.

• Immune-mediated implantation failure: Antiphospholipid antibodies compromise trophoblast function, enhance thrombosis risk and account for in vitro fertilisation failure, recurrent pregnancy loss and pregnancy complications, with aPL correlating with reduced rates of implantation and live birth. Traditional therapies such as low-dose aspirin and low-molecular-weight heparin are routine, whereas novel therapies such as intravenous immunoglobulin, rituximab and eculizumab hold promise for resistant disease. Peri-transfer glucocorticoid therapy in oocyte-donation IVF is also under review, with randomised studies in autologous cycles consistently demonstrating no advantage in live birth rates.

Unpacking the Phase III GRACE Trial Design

Key IVF trials span randomized and observational designs evaluating stimulation protocols, laboratory techniques, and adjunctive interventions. Primary endpoints center on ongoing pregnancy, live birth and OHSS incidence, with embryological and neonatal outcomes as secondary measures.

Cumulative Live Birth: A Key Endpoint for IVF Success

Cumulative live birth rate has emerged as a central endpoint for in vitro fertilisation success, reported per oocyte retrieval, per patient, and over sequential cycles. The mean live birth rate per ICSI cycle was 32.8 %, with a cumulative live birth rate of 45 % after four ICSI cycles. The cumulative clinical pregnancy rate was 35.6% and the cumulative live birth rate was 34.6% per patient following fertility preservation with cryopreservation of oocytes or embryos, with a 10-year utilization rate of 25.5%. The CLBR per oocyte retrieval of the PGT-A group was 25.52% (37/145), while that of the non-PGT-A group was 28.50% (46/161), and use of PGT-A was associated with cumulative live birth with risk ratio [RR]: 0.96; 95% CI: 0.93-0.99 in individuals aged <35 years, RR: 1.04; 95% CI: 1.00-1.08 in ages 35-37 years, and RR: 1.14; 95% CI: 1.07-1.20 in ages 38-40 years.

Embryological and genetic endpoints are reported alongside live birth, including blastocyst formation rate per MII, blastulation rate, euploidy rate, clinical pregnancy rate per transfer, and miscarriage rate. Vitrification significantly reduced blastulation rate per MII-allocated oocyte (24.6 ± 34.1% VW versus 44.2 ± 33.9% F; P < 0.0001), while euploidy rates per biopsied blastocyst were comparable (38.8% VW versus 38.0% F; P = 0.91). Clinical pregnancy (40.9% VW versus 61.2% F, P = 0.11), miscarriage (11.1% VW versus 10.0% F, P = 0.92) and live birth rates (36.4% VW versus 55.1% F, P = 0.14) per single euploid embryo transfer did not differ. Blastocyst formation rate was 59.2%, with a higher euploidy rate with PB-based PGT-A (55.4%) compared to blastocyst-stage PGT-A (43.1%), and euploid blastocyst rates were identical between patients with and without IBD (47.5% vs. 47.5%, P=0.99).

Time to live birth and perinatal outcomes are increasingly reported as complementary endpoints. Median time to live birth was 19.5 months from the first TESE and 10 months from the first ICSI attempt, and median time to live birth was 3 years from the first consultation, irrespective of TESE or sperm donation. Compared with births in the fresh group, births in the frozen transfer group were less likely to be preterm (8.9% vs 13.7%, adjusted risk ratio (aRR) 0.66 0.58-0.76), low birth weight (5.3% vs 8.5%, aRR 0.66, 0.55-0.78), and small for gestational age (4.2% vs 7.9%, aRR 0.62, 0.51-0.75), but more likely to be caesarean section (57.5% vs 50.4%, aRR 1.14, 95% CI 1.09-1.19), high birth weight (10.1% vs 7.0%, aRR 1.43, 1.21-1.68), and large-for-gestational-age (20.0% vs 13.6%, aRR 1.37, 1.23-1.53). Live birth rate per oocyte retrieval ranged between 24% and 26% among seasons, with live birth rate per ET ranging between 29% and 31% among seasons.

Granata Bio's hMG Trial: A Potential Shift in IVF Outcomes

Granata Bio's announcement of completing participant screening for its Phase III GRACE trial of human menopausal gonadotropin (GB-hMG) in in vitro fertilisation (IVF) marks a pivotal moment in reproductive medicine. This large-scale, randomized, double-blind study, enrolling approximately 625 women, aims to rigorously assess GB-hMG's safety and efficacy, particularly focusing on cumulative live births. This endpoint is increasingly recognized as a comprehensive and accurate measure of IVF treatment success, reflecting the overall effectiveness of a single stimulation cycle.

The significance of this trial is underscored by the ongoing debate and evolving evidence surrounding gonadotropin choices for ovarian stimulation. While recombinant FSH (rFSH) has been widely used, recent systematic reviews suggest that human menopausal gonadotropin (hMG) or highly purified hMG (HP-hMG) may offer advantages, including potentially higher live birth and clinical pregnancy rates, and a lower incidence of ovarian hyperstimulation syndrome (OHSS) compared to rFSH. If GB-hMG demonstrates a favorable profile in these critical areas, it could significantly reshape treatment paradigms, offering a compelling alternative for patients and clinicians.

However, the path to market leadership is not without its challenges. The competitive landscape is complex, with some studies indicating little or no significant difference in live birth rates between various gonadotropin types, or even higher oocyte yields with specific rFSH:r-hLH combinations. Granata Bio will need to clearly differentiate GB-hMG based on robust clinical outcomes. Furthermore, while hMG generally has a good safety record, the trial's rigorous evaluation will be crucial, as any unexpected safety signals or higher-than-anticipated OHSS rates could temper enthusiasm. Ultimately, the balance of efficacy, safety, cost-effectiveness, and patient convenience will determine GB-hMG's long-term impact in the dynamic and highly sensitive field of fertility treatment.