Ashvattha Therapeutics Shows Real-World Focus With subQ, Bilateral Dosing For Ophthalmology Drug

A conversation with Susan Schneider, MD, acting CMO, Ashvattha Therapeutics

Clinical trials for ocular diseases often run into the issue of studying an investigational therapy in just one eye. The problem is that the approach doesn’t fully reflect patients’ lived experiences with eye disease.

However, Ashvattha Therapeutics’ Phase 2 study of migaldendranib (MGB) has taken a fresh approach with its subcutaneous (subQ) MGB clinical development program in diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD).

Evaluating both eyes (the designated study eye as well as the fellow eye) and using subcutaneous dosing opened the door for exploring bilateral ocular treatment effects in a single study as well as systemic safety—a big shift for conditions usually treated by local injections into the eye. By keeping lines of communication open with the ophthalmic community, including study investigators and key opinion leaders, the overall study balanced innovation with practical oversight.

Innovative approaches used to optimize outcomes and data interpretation included using an aflibercept run-in phase to identify patients who were true responders before starting MGB. The rescue criteria for use of supplemental intravitreal aflibercept, if deemed needed, were also built with great consideration and expert input, allowing informed decision making about treatment. These moves brought the trial closer to real-world practice, made the data more meaningful, and still protecting study integrity

Ashvattha Therapeutics Acting CMO Susan Schneider, MD, explains.

Clinical Leader: How was the trial designed, and what was the reasoning behind those design choices?

Susan Schneider, MD: This was a Phase 2 chronic dosing, 40-week clinical study of migaldendranib (MGB) administered subcutaneously (subQ). After consultation with many of our key opinion leaders, such as Peter Campochiaro, MD, of the Wilmer Eye Institute, we designed the trial to evaluate two dosing regimens of MGB, 2 mg/kg every two weeks or every four weeks each in patients with diabetic macular edema (DME) or neovascular age-related macular degeneration (nAMD) for a total of four treatment cohorts. We wanted to test the hypothesis of subQ administrated MGB as a novel VEGF receptor tyrosine kinase inhibitor (TKI) hydroxyl dendrimer that targets inflammation without systemic side effects.

In addition, we wanted to evaluate the potential for bilateral effects and that is why we designed the study to evaluate both the study eye and the fellow eye, and, thus demonstrate a reduced treatment burden. Study participants had to have had a history of prior intravitreal (IVT) anti-VEGF treatment. In addition, potential study participants needed to demonstrate a response to a single aflibercept IVT injection with recurrence of intra- or sub-retinal fluid by optical coherence tomography (OCT) during a 12-week run-period. During this run-in period, non-responders (those with no improvement at week 4) and super-responders (those who had no fluid return at 12 weeks) were excluded from entering the MGB treatment trial. Participants who entered the trial could receive supplemental IVT aflibercept based on predefined criteria.

These design elements were chosen to optimally understand the durability of the drug and the dosing regimen for MGB for the next study, moving toward registration. With no active comparator arm, it was important to include participants with a demonstrated response to IVT anti-VEGF, that is, having active disease, and each participant could act as their own control (baseline activity for each participant was identified).

In addition, and importantly, the criteria for receiving supplemental IVT anti-VEGF, while receiving MGB, reflected real-world practice, and we used this approach to differentiate MGB from other programs that are in clinical development.

Is this approach typical, or were there novel components?

This Phase 2 clinical study employed a novel approach to evaluating subQ MGB in DME and nAMD patients. One novel component in this trial was the aflibercept run-in period, which identified responders to anti-VEGF therapy as an inclusion criterion to receive MGB in the study. A patient needed to meet the responder definition before being randomized to receive MGB and to continue in the study. Another novel component was demonstrated in the criteria for receiving supplemental IVT anti-VEGF while on study.

These were predefined and reflected real-world clinical practice, which permits an IVT anti-VEGF injection when return of retinal fluid is identified by OCT. The response to this approach and the feedback received during clinical advisory board meetings held in both the U.S. and Europe have been very positive, and we think bode well for future clinical studies for MGB.

The bilateral treatment evaluation and single-subcutaneous dosing were innovative components of this study. How can clinical teams in other fields identify and balance opportunities for design innovation without compromising interpretability or regulatory acceptability?

A key component of innovation is putting an idea into action. A key objective of innovation is to create value. A key outcome of innovation is improving upon a concept or bringing forth a breakthrough. This is true in clinical development and requires understanding both the patient and the physician perspective in addressing the disease a therapy is targeting. How can we make that better for both while maintaining a positive benefit-risk ratio within that scenario? In retinal vascular disease, particularly in diabetic eye disease, the disease is bilateral. Currently, standard of care treatments are local, meaning direct intravitreal injections into the eye. This means, therefore, one injection per eye with no robust bilateral effect. Clinical trials can only report out one study eye result from this approach. Subcutaneous administration delivers a drug systemically and results in a bilateral treatment effect if it is efficacious. It made sense to the Ashvattha clinical team to evaluate subcutaneous dosing to potentially result in a bilateral treatment effect in this population with generally bilateral disease. Study design needed to address a designated study eye, consistent with standard clinical trial design, but also assess data for each participant's fellow eye to support overall interpretability. In addition, safety is of primary importance, thus ocular as well as systemic safety were of paramount importance and were key contributors to a positive benefit-risk profile, which is key to regulatory acceptability. 

What were the rescue criteria, and how were they determined?

The rescue criteria were as follows and were determined based on clinical input, focusing on patient safety and reflecting real-world experience:

• An increase in central subfield thickness (CST) above MGB treatment period baseline (pre-dose Day 1), OR
• ≥10 ETDRS letter loss in best corrected visual acuity (BCVA), OR
• New or increased macular hemorrhage by fundus photography
• A study participant could also qualify by demonstrating clinical deterioration upon discussion with the study medical monitor.

How did the rescue criteria perform during the trial? What were some examples of patients needing rescue therapy?

A marked reduction in the need for supplemental IVT aflibercept was seen during the MGB 40-week treatment period versus pre-study IVT in both designated study eyes (worse BCVA at baseline) and fellow eyes. This decrease was 78.6% for DME study eyes (approximately a five-fold reduction), 83.4% for nAMD study eyes (approximately a six-fold reduction), and 89.1% for fellow eyes (approximately a nine-fold reduction). Importantly, a bilateral treatment effect was observed in reducing anti-VEGF IVT treatment burden in both indications.

Incorporating flexible rescue criteria allowed for individualized patient management while preserving data integrity. What governance or data monitoring processes were essential to make this balance successful, and how could they translate to heterogeneous disease populations like oncology or neurology?

The rescue, or supplemental, criteria were researched to reflect the current standard of care and general physician acceptance. The Ashvattha clinical team actually used more conservative rescue, or supplemental, criteria with respect to a key structural change (retinal fluid) with a more "real-world" approach to this aspect of the story. Good and consistent communication between investigators and the sponsor's medical monitor is essential in not deviating from protocol criteria and in supporting a clinical trial's success. This would apply to all disease populations under study.

Finally, this trial emphasized consultation with key opinion leaders to refine study design elements early. What frameworks or feedback mechanisms have you found most effective for bridging the gap between early advisory input and operational implementation in complex multi-region studies?

Clinical trials need to be executed flawlessly to keep the clinical development process moving forward. Patient advocacy, clinical advisory board, strategic advisory board, and KOL input all represent key inputs to trial design elements. Thus, protocols for clinical trials can go through a number of iterations before achieving the optimal mix of what brings the patient, the clinician, the clinical site staff, the regulatory agency, safety/pharmacovigilance, and other perspectives into a study design that can be operationalized successfully. This requires dedication to consistent communication and a common understanding of decision-making. 

About The Expert:

An ophthalmologist by training, Susan Schneider, MD, brings her expertise in developing high-performing ophthalmic therapeutic teams and building strong cross-functional programs to further strengthen AGTC’s leadership in advancing their clinical stage assets. Before joining AGTC, Dr. Schneider served various roles in clinical and medical affairs, most recently as SVP, clinical development, ophthalmology at Ji Xing Pharmaceuticals. Previous roles include serving as SVP, clinical development, ophthalmology at Eloxx Pharmaceuticals, CMO at Oxurion (formerly ThromboGenics), and vice president and therapeutic area head of glaucoma and retina at Allergan. She began her corporate career in clinical development at Genentech where she worked extensively on the ranibizumab program, leading to the approval and launch of LUCENTIS. Dr. Schneider completed her residency in ophthalmology at the Medical College of Virginia followed by fellowships in ocular oncology at Thomas Jefferson Wills Eye Hospital and in ophthalmic pathology at The Johns Hopkins Wilmer Eye Institute.