VBS 2023: Medical Debates

Luis Martinez-Velazquez, MD, PhD
Massachusetts Eye and Ear
Boston, MA

The Medical Retina Debates section “I’m Not Locked in Here with You. You’re Locked in Here with Me!” of the 11^th Annual Vit-Buckle Society Meeting generated exciting debate about the evolving landscape of intravitreal therapies and practice ownership. The session was moderated by Drs. Carl D. Regillio, and Priya Vakharia. It highlighted the challenges of incorporating new tools to our intravitreal utility belt such as biosimilar anti-VEGF molecules and complement inhibition, and the advantages and threats of practicing in Private Equity (PE).

Debate #1: Anti-VEGF Biosimilars

The first debate was on biosimilar anti-VEGF agents. On the “Biosimilar drugs are better” side, Dr. Maura Di Nicola from the Bascom Palmer Eye Institute reminded of the important benefits of expanding our toolkit.

• Biosimilar medications are highly similar biologic agents to the reference product.
• Due to the complexity of the manufacturing process of biological agents in living cells, these are strictly FDA regulated.
• New biosimilar agents still need to generate a clinical trial to establish their efficacy and safety profile prior to approval. This trial can be focused to recruit patients from high-risk populations and designed with lessons from the reference agent trials to demonstrate their efficacy. These trials will have lower duration and costs.
• We have a positive experience with biosimilars in ophthalmology in the treatment of non-infectious uveitis with anti-TNF-alpha agents.
• The resulting products should be available at a lower cost to patients due to increasing downwards price pressure. The industry might also benefit from better reimbursement programs.
• In practice, we have learned from bevacizumab that we often need the lower cost option to increase access to treatment for our patients.

 

Dr. Di Nicola reminded us that prior to their FDA-approval, these agents require clinical trial data that highlights their clinical efficacy and safety profile. Nevertheless, many physicians remain skeptical for the following reasons:

• Potential for immunogenicity as evidenced from other biological agents.
• Need to establish efficacy and safety profile for the new biosimilar agent. Differences in the manufacturing process in living cells can lead to differences from the reference product.
• The clinical trials will have a shorter duration and lower enrollment numbers raising concerns about detecting rare adverse events.

On the “Reference Drugs are Better” Dr. Nika Bagheri from California Retina Consultants emphasized that FDA approval does not always equal safety and that real-world data following initial approval is essential to determine the safety for our patients. She reminded us of our recent experience in retina with brolucizumab. This agent was FDA approved in October 2019 with exciting efficacy data in reducing macular edema and allowing for treatment extension. However, it was linked to extreme vision loss secondary to occlusive vasculitis limiting its use due to safety concerns and the availability of other alternatives. She listed other concerns:

• The time and cost invested by pharmaceuticals into the development of biosimilars is lower than for the reference product.
• We have millions of injections supporting the safety and efficacy profile for the reference anti-VEGF agents. The required numbers in trials for biosimilars will pale in comparison.
• Physicians are concerned about safety or immunogenicity given our experience with these drug classes.
• Market forces might push for rapid adoption.

Their debate generated an interesting discussion from the moderators, panelists, and audience, which highlighted our experience with an off-label lower cost option in Avastin (bevacizumab). Why would payers remove this option? Biosimilar agents, if approved, might be more expensive than off-label bevacizumab. Regardless, this might create market pressure that could lead to difficulty sourcing bevacizumab for ophthalmic use in private practices. This might not be the case in academic centers which might be able to continue providing bevacizumab from their own compounding pharmacies.

How do we discuss transitioning to a biosimilar ranibizumab with our patients given the lower availability of safety data? The clinical trials should help demonstrate equivalent safety and efficacy. Furthermore, it will be good to have more options. As we are aware, not all patients respond well to bevacizumab and other anti-VEGF agents can produce better responses in patients. (i.e. aflibercept, ranibizumab).

What about an aflibercept biosimilar?

More tools at our disposal would be better. However, we remain more excited about agents that will provide better outcomes to our patients, such as a decreased treatment burden.

Debate #2: Dry AMD Injections

The second debate was on Dry AMD injections. On the “Are Not Sustainable” side, Dr. Lejla Vajzovic from Duke University School of Medicine expressed her excitement about new complement inhibitors for the treatment of dry AMD.

• Pegcetacoplan, an inhibitor of C3/C3b and the downstream complement pathway, is the first FDA approved treatment for geographic atrophy secondary to AMD.
• The agent was approved based on positive evidence for reduction in GA progression on the OAKS and DERBY trials.
• The data highlights that the effect of treatment is larger after 18-24 months of monthly injections with a 30% reduction in the rate of GA progression.
• Other agents are in the pipeline including avacincaptad pegol, which works through C5 inhibition. The Gather 1/2 trials show positive results in reduction of GA at 12-18 months.

Her concerns based on the sustainability of intravitreal injections for this condition are based on the increased burden of treatment to physicians and patients. The field has now approved intravitreal therapies for AMD, RVO, diabetes, and GA. She raised many open questions:

• How will we keep up with the injection volume?
• Which patients would benefit the most from therapy?
• How often should we inject to achieve the treatment benefit?
• How do we demonstrate the treatment benefit to our patients to ensure adherence to prolonged therapy?
• Who will do well? How do we risk stratify patients to recommend treatment?
• Who is at risk of exudation after initiating complement inhibition therapy?
• Who is at risk of inflammation and other side effects?

She raised an important consideration at the end of her discussion. We have learned from treating wet AMD that monthly injections work well, but there are real-world challenges with adhering to this treatment burden. While many patients are enthusiastic to initiate therapy, they soon become discouraged after monthly injections.

On the side for “Dry AMD Injections Are Sustainable,” Dr. David Xu from Wills Eye Hospital echoed Dr. Vajzovic’s excitement for having a treatment option for patients with Dry AMD. He reminded us about the un-met clinical challenge of patients with dry AMD suffering from GA, and the exponential increase in GA incidence with advanced age. While we tend to think about GA in dry AMD, it is also occurring in patients with wet AMD and progressing secondary to loss of vascular maintenance following anti-VEGF injections. His support for complement inhibition therapies included the following arguments:

• We have explored gene and cell-therapies, anti-inflammatory therapies, visual cycle modulators, and neuroprotection, but complement inhibition is currently the most promising avenue to prevent GA progression.
• The data from clinical trials for pegcetacoplan (OAKS and DERBY) and avacincaptad pegol (Gather 1 and Gather 2) highlight similar benefits in decrease of GA progression that is potentiated with the longer duration of therapies.

He raised several important questions from skeptics:

• Does slowing GA progression save vision?
• Could GA size be an improper surrogate marker?
• Could anti-complement treatment slow the loss of anti-FAF and affect our monitoring of progression improperly?
• Can you identify any other pleomorphic biomarkers in patient imaging after complement inhibition treatment?

He suggested that some of these concerns are unlikely, and no additional pleomorphic biomarkers have been identified during the trials.

Finally, he discussed that saving tissue and slowing down progression of GA has an impact on preserving RPE cells. He reviewed data estimating the number of RPE cells that are preserved with complement inhibition and how this number also increases in order of magnitude with the duration of therapy.

The discussion for this section emphasized the challenges of engaging patients for prolonged treatment. Many patients are eager to get started, but after several injections, the treatment burden sets in. As clinical trial and real-world data is analyzed, we should pay attention for better biomarkers or metrics of benefit to share with our patients.

Debate #3: Private Equity

The third debate centered on whether private equity is good for young retina practitioners.

For the side of “For Young Retina Specialists Private Equity is Great” Dr. Philip Storey from Austin Retina Associates drew from his experience in his practice, a member of Retina Consultants of America.

He summarized several benefits for patients and young practitioners from private equity:

• He invited us to consider the benefit of establishing a community of 2000 retina physicians.
• Collective bargaining leads to decreased overhead and increased margins on medications.
• The increased lobbying power with government for supporting the retina profession and reimbursements.
• Value of having managers for the business end of the practice. MDs are then able to focus on how to provide great care.
• Income from a private equity sale is taxed at a lower capital gains rate.
• He suggests that when compared to non-private equity private practice, salaries can be better in the initial years.
• The larger practices are involved in research.
• He emphasized that these benefits do not have to equate loss of autonomy for your practice patterns. He shares his experience with RCA and retaining his autonomy to plan vacations and for making local decisions in the practice for hiring support staff.

Dr. Esther Kim from Orange County Retina followed with her rebuttal and argued that “Private Equity is Terrible for Young Retina Specialists.” She reminds us that the goals of private equity are not aligned with that of a young retina specialist. For one, the timelines are at odds. Senior partners sell the practice for large sums of money but young associates do not share in this transaction. Furthermore, private equity pools capital from investors with a goal of generating 25-30% of profit with a turnaround time of 2-5 years to sell the practice again. Instead, young physicians are trying to establish a long-term practice and earn a stake. Her arguments reminded us of others experience with PE.

• You must be a partner. If you are associate when the practice is sold, you will not benefit from the buyout.
• The buyouts result in taking upfront cash in exchange for a 30-40% reduction in pay compared to pre-sale compensation, which is likely to lead to a net loss for junior partners.
• You are unlikely to ever meet your new bosses (the investors in the PE group).
• Loss of autonomy as a former practice owner. This may lead to others dictating when, how, and where to work. Seeing more patients, doing more procedures, and less support (staff and supplies).
• After the buyout, you often sign years-long contracts and non-compete clauses that make it hard to leave.
• Goals of the PE group are to increase profits. For the physician, this can represent foregoing other goals of improving patient care, physician and community well-being.
• PE practices switch ownership frequently. Your practice is no longer your forever home. She humorously suggested that PE had turned our profession into a house that we flip or a rental car. She reminded us about how we drive rental cars.

There are other additional concerns regarding PE including the lack of transparency. Most physicians working for PE must sign non-disclosure agreements and cannot provide an honest opinion about the practice. The non-disclosure extends to financial interests.

She reminded private practice owners that there are other options to PE even in the face of declining reimbursements.

• Sell to your younger partners
• Sell to other practices
• Sell to a hospital system
• Lobby with the Academy for improved reimbursements
• Negotiate better reimbursements with insurance companies
• Hire an MBA or consultant to improve efficiency in your practice

After the presentation, the audience was invigorated to join the discussion. Many young retina specialists echoed their concerns about lack of transparency in PE and frustration about the decreasing number of private practices where they can join with prospects of becoming a partner owner. Many suggested that PE relies on young retina associates joining their practices. You should consider the two sides of the coin including your own interests and family interests when looking for your next position.