RE104 aims to become the first psychedelic to treat postpartum depression

Credit: Unsplash / Tiago Bandeira

Postpartum depression (PPD) impacts up to 20% of individuals after delivery globally, generally impacting patients with symptoms of depressed mood, changes in sleep and eating patterns, an inability to concentrate and even suicidal ideation. In most cases, PPD can harm the pivotal stage of bonding between a mother and their infant, the mother’s ability to breastfeed, and the psychological development of the infant. In more severe cases of postpartum psychosis, the patient is at a heightened risk of suicidal and infanticidal actions.¹

Despite its high prevalence and potentially severe outcomes, the treatment armamentarium for PPD lacks depth and diversity. The American College of Obstetrics & Gynecology (ACOG) recommends standard selective serotonin reuptake inhibitors (SSRIs) serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants for patients with PPD, despite the common antidepressant drug classes not being indicated for PPD.²

What’s more, many women are resistant to initiating SSRI or SNRI treatment for their PPD due to the inability to breastfeed while on the medication, Sheryl Kingsberg, PhD, chief of the division of behavioral medicine, department of OB/GYN, University Hospitals Cleveland Medical Center, recently told Contemporary OB/GYN.

In recent years, the US Food and Drug Administration (FDA) approved a pair of options from the GABA-A receptor positive allosteric modulator drug class: brexanolone (Zulresso) in 2019, and zuranolone (Zurzuvae) in 2023.^3,4 Though the options are touted for fast-acting efficacy in patients with PPD, their administration can be unfeasible or difficult to maintain for new mothers; brexanolone is administered through a continuous 60-hour infusion provided at a clinical site, and zuranolone is a nightly oral drug regimen administered over 14 days.

Put plainly, gaps in in PPD pharmacotherapy options are still wide, Kingsberg told Contemporary OB/GYN.

“And I should mention…cognitive behavioral therapy (CBT) is actually a very valid and evidence-based treatment for postpartum depression,” Kingsberg said. “I do it for a living, and I do it every day, and there are many women who will absolutely benefit from cognitive behavioral therapy. But for many women, CBT is not going to be enough. And for them, we would like to have pharmacologic options.”

Looking to address that unmet need is an enrolling clinical trial designed to assess a psychedelic drug for the treatment of patients with PPD.

RE104 and RECONNECT

Reunion Neuroscience recently announced the launch of the phase 2 RECONNECT study, a multicenter, randomized, double-blind, parallel-group clinical trial assessing the efficacy and safety of subcutaneous 30 mg RE104 versus an active dose control (1.5 mg) in adult female patients with moderate to severe PPD. As of late July, the first patient had already been dosed, with plans to conclude the trial by June 2025.⁵

The proprietary RE104 is a prodrug of 4-OH-DiPT, a synthetic drug with psychedelic properties designed to provide a shorter duration of experience than psilocybins (approximately 3 – 4 hours per dose), while providing a similar intensity and consistent safety profile—as evidenced in Reunion’s phase 1 trial of the drug.

In the phase 2 RECONNECT trial, investigators including Kingsberg are seeking a primary endpoint of change in total 10-item Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 7 in treated patients versus the control arm. The team is also seeking key secondary efficacy endpoints of change in total MADRS score from baseline to days 1, 14, and 28, as well as rate of patients with ≥50% reduction in depressive symptoms per MADRS, and rate of patients to achieve remission (MADRS scores of ≤10). Safety and tolerability outcomes will additionally be assessed through the trial.

“There is a clear need for fast-acting, single-dose treatments with durable efficacy for PPD patients,” Greg Mayes, president and chief executive officer of Reunion, said in a statement. “Reunion is committed to serving not only the unmet need in PPD, but also the broader community affected by mental health disorders through its development programs.”

Going forward

The psychiatric benefit of RE104 is being explored beyond indications to treat PPD. The synthetic psychedelic is additionally being assessed for the treatment of adjustment disorder in patients with cancer, according to Reunion—another space lacking diverse, targeted treatment options.

Kingsberg expressed excitement and hope that the RECONNECT trial will complete enrollment quickly, providing efficacy and safety that which would warrant a larger, late-stage trial. Beyond outcomes in improved MADRS for treated patients, she is invested in seeing a single-dose PPD treatment option potentially improve the dearth of therapies available to the at-need patient population. Kingsberg also believes RE104 may play a complementary role in improved outcomes of behavioral interventions for PPD; after the treatment, it may be possible that patients respond better to behavioral changes like getting more sleep, improving diet, and undergoing cognitive behavioral therapy (CBT).

“We have evidence that this is a biochemical problem,” she said. “It is a medical condition and deserves treatment: cognitive behavior therapy, pharmacotherapy, and now hopefully a psychedelic option.”

What’s more, the development of RE104 to evidence a multitude of ways to pharmacologically treat PPD may help to reduce stigma around the disease—and therefore increase patient screening and conversations around signs and symptoms between new mothers and caregivers.

“To give a wakeup call and to say this is real and can be treated, and now we are looking at even more options, I hope will encourage women to seek help and for clinicians to ask,” Kingsberg said. “I see lots of referrals from pediatricians, by the way, because many women don't actually see their obstetrician until maybe their 6-week visit if they get there. And so, oftentimes the referral comes from the pediatrician who sees the mom with her baby. So, I ask everybody who's out there who sees new moms: please ask.”

Patients with PPD, as well as clinicians who may have eligible and interested patients, can enroll in the RECONNECT trial here.

References

1. ^{Carlson K, Mughal S, Azhar Y, et al. Postpartum Depression. [Updated 2024 Aug 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK519070/}
2. ^{Treatment and Management of Mental Health Conditions During Pregnancy and Postpartum: ACOG Clinical Practice Guideline No. 5:. Obstetrics & Gynecology 141(6):p 1262-1288, June 2023. | DOI: 10.1097/AOG.0000000000005202}
3. ^{Kunzmann K. FDA Approves Zuranolone for Postpartum Depression. HCPLive. Published August 4, 2023. Accessed October 3, 2024. https://www.hcplive.com/view/fda-approves-zuranolone-postpartum-depression}
4. ^{Kunzmann K. FDA Approves Brexanolone for Postpartum Depression. HCPLive. Published March 19, 2019. Accessed October 3, 2024. https://www.hcplive.com/view/fda-approves-brexanolone-for-postpartum-depression}
5. ^{Reunion Neuroscience Inc. announces first patient dosed in phase 2 clinical trial of RE104 for the treatment of postpartum depression. Reunion Neuroscience. Published July 23, 2024. Accessed October 3, 2024. https://reunionneuro.com/2024/07/23/reunion-neuroscience-inc-announces-first-patient-dosed-in-phase-2-clinical-trial-of-re104-for-the-treatment-of-postpartum-depression/}