ProEd Regulatory’s 4 Key Project Management Principles for Successful AdCom Preparation

Preparing for an FDA advisory committee meeting (AdCom) is a daunting task that can take anywhere from 3 to 9 months of intense preparation. At ProEd Regulatory, we partner with our clients to ensure that they’re well prepared to present their data and answer questions from the committee with confidence and poise. Our clients have an important scientific story to tell, and they need to be prepared to present it effectively and defend it so that regulators, their advisors, and the public will support approval. In this blog post, we’ll explore 4 fundamental project management principles that we use when helping our clients prepare for an AdCom.

Establish a Clear Goal & Objectives

When working with our clients, we always begin each project with a kickoff strategy meeting where we set clear goals, go over the timeline, identify potential issues, and start to determine how they want to tell their story to the advisory committee and to the world. We do this in a collaborative setting where we carefully review the client’s data, develop key messages, and conduct a SWOT analysis. Our kickoff meetings are usually 2 days in length, and we, as project managers, put together an agenda for each day that serves as a guide to keep us all on track. The kickoff meeting provides the team with clear roles and responsibilities as well as goals and objectives for what needs to be done throughout the course of the project, along with key dates to keep in mind.

Effective Communication 

Effective communication with your internal team and client team is critical for success. The team, which is composed of researchers, clinicians, regulatory affairs experts, and others, must work harmoniously to achieve project milestones. Organizing this cross-functional team and maintaining effective communication channels are essential project management practices. Regular updates, transparent discussions, and well-defined roles help prevent misunderstandings and keep projects on track. In the regulatory world, where rapid responses are often necessary, seamless communication ensures that critical decisions are made with accurate information and in a timely manner.

Organizing this cross-functional team and maintaining effective communication channels are essential project management practices. Regular updates, transparent discussions, and well-defined roles help prevent misunderstandings and keep projects on track.

Progress Tracking

At each strategic milestone throughout the project, we challenge your team and facilitate discussions to build consensus and leverage critical feedback that advances your strategy and prepares the team for success. We set goals for each major milestone, and we track your progress toward meeting those goals and deadlines. We do this during weekly meetings and provide status updates. For example, key milestones during these projects are the mock meetings that are designed to mimic the FDA AdCom. The sponsor/client team gives their core presentation, which tells their story as to why this drug should be approved by the FDA. Then the mock panel, composed of clinical experts in their field, asks the client team questions regarding their data. Through the mock meetings, we can identify gaps in the story and refine our strategy. Tracking the team’s progress through these mock meetings and measuring performance at every stage are crucial to staying aligned with project objectives. Our proven processes are built on 25 years of experience and are purposefully designed to drive consensus and keep you on a trajectory of continuous progress.

Tracking the team’s progress through these mock meetings and measuring performance at every stage are crucial to staying aligned with project objectives. Our proven processes are built on 25 years of experience and are purposefully designed to drive consensus and keep you on a trajectory of continuous progress.

Problem Solving With Preparedness

Challenges are inevitable in any project, but in preparation for an AdCom, where the path to success is often complex and nuanced, being a proactive problem solver is a must. Shifting timelines, FDA feedback, and limited availability of key members of the team are just a few examples of challenges that can arise. By exercising flexibility and having well-considered plans in place, our project managers navigate these obstacles with agility and minimize their impact. Anticipating potential roadblocks and having contingency plans in place can mitigate disruptions and ensure that projects stay on course. These are just a few ways in which we problem-solve with preparedness.

ProEd’s Proven Approach to Project Management

By adhering to these 4 project management principles, we help our clients prepare for one of the most challenging and stressful regulatory interactions they will face, and in the process, we can enhance their ability to deliver innovative treatments to patients in need. Clear objectives, effective communication, diligent progress tracking, and strategic problem-solving form the foundation upon which successful projects are built. By embracing these principles, we help transform data into approvals.

Samantha Procell
Samantha Procell
Senior Account Manager

Samantha has more than 5 years of client service experience and is an excellent communicator. She works closely with both internal and client teams to ensure success in all facets of projects, from slide management to operations, timeline management, agenda development, meeting planning, and logistics. She also is a liaison with ProEd’s social media communications. Samantha has a BS in Public Relations with a minor in Advertising from Texas Tech University.

Connect with Samantha on LinkedIn.


EMDAC meeting for Intarcia’s Diabetes Drug-Device Combo ends in rejection, but is there a silver lining?  

On Thursday, September 21, 2023, the FDA held a meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) to discuss Intarcia’s new drug application (NDA) for ITCA-650, an implantable device intended to provide continuous dosing of a GLP-1 agonist (exenatide) to treat type 2 diabetes. In a highly unusual move, Intarcia opted to request a public FDA advisory committee meeting (AdCom) in lieu of a formal evidentiary hearing following 2 Complete Response Letters (CRLs) and several formal dispute resolution requests dating back to 2017. Given this history, the prospects of swaying the panel and the FDA in favor of approval was certainly a long shot. In the end, the panel voted 19-0 that the benefits of ITCA-650 did not outweigh the risks.

It appears Intarcia was motivated not only by the prospects of a positive vote but also by the chance to present their argument for approval in a public forum. In that respect, their strategy and perseverance may have paid off. The meeting highlighted a creative use of the FDA AdCom process to communicate directly with patients and the medical community. Let’s look at how Intarcia got there.  

The long path to a highly unusual EMDAC meeting: 2 CRLs, 3 rejected formal dispute resolution requests, and 1 citizen petition requesting a public AdCom

NDA #209053 for ITCA-650 (exenatide in DUROS device) was submitted on November 16, 2016. Exenatide is a GLP-1 receptor agonist, which is currently FDA-approved in formulations for subcutaneous injection twice daily or weekly. ITCA-650 is delivered by an osmotic mini-pump that is implanted under the skin and only needs to be refilled every 6 months.

The first CRL for ITCA-650 was issued by the FDA in September 2017, citing “clinical deficiencies, and device and product quality-related issues.” Shortly after the CRL, 2 ongoing trials for ITCA-650 were put on hold by the FDA due to serious safety issues, and the trials were later terminated by the company. Despite these setbacks, Intarcia resubmitted the NDA in September 2019, only to receive another CRL just 6 months later in March of 2020

Over the rest of 2020, Intarcia filed 3 formal dispute resolution requests (FDRRs). The first 2 FDRRs were promptly denied by the Office of New Drugs (OND), reiterating unresolved safety issues, including an imbalance in severe acute kidney injury (AKI) and deaths due to major adverse cardiovascular events (MACE), as well as issues with the implanted device appropriately regulating dose. The third and final FDRR was submitted in November of 2020—this time, Intarcia requested a public FDA AdCom. The third FDRR was also rejected.

On September 2, 2021— the FDA published a notice in the Federal Register of their intention to deny the NDA for ITCA-650, and offering the opportunity for Intarcia to request a hearing. The notice outlined the agency’s reasons for the 2 prior CRLs, the 3 FDRRs, and the unresolved safety and product issues that, in their view, had never been adequately addressed. The notice detailed the conditions under which a hearing would be entertained.

It is fair to say that at this point in the process, most companies would have resigned themselves to conducting additional clinical trials or discontinuing development of the drug. Intarcia, however, did not not give up. Perhaps anticipating that their pending request for a formal hearing would ultimately be denied, Intarcia opted to request a public FDA AdCom meeting in lieu of a closed-door, formal evidentiary hearing. This request was made on February 20, 2023, via a citizen petition submitted by Intarcia, arguing that they were entitled to a public AdCom under 21 CRF part 14.

On March 24, 2023, FDA Chief Scientist, Namandje Bumpus, issued a letter granting Intarcia’s request for a public AdCom. The EMDAC meeting would be conducted under “the typical process for convening an advisory committee under 21 CFR part 14.”

So, after nearly 6 years, Intarcia would get their public meeting, but only on CDER’s terms.

EMDAC discussion centers on safety concerns, benefit-risk

The discussion centered around serious safety concerns identified by the FDA reviewers, including a higher risk of AKI, an imbalance of deaths due to MACE, and uncertainties about the drug delivery device appropriately regulating dose.

The sponsor argued that the incidence of AKI was low overall and should be understood as a class effect of GLP-1 agonists. The approved injectable formulations of exenatide (eg, Byetta and Bydureon) include warnings that the drug should not be used in individuals who have kidney disease because of increased risk of kidney injury.

The FDA also noted that the risk of death associated with MACE was unfavorable with a hazard ratio of 1.12 (95% CI: 0.83, 1.51). This was especially concerning given that other GLP-1 agonists had shown favorable results in reducing the risk of adverse cardiovascular outcomes (Figure 1).

Figure 1: Screenshot from September 21, 2023 EMDAC meeting

Finally, the FDA presented data showing that there was large variability in the devices delivery of the drug that could potentially lead to large amounts of drug being suddenly released into the patient. They noted that the data provided by the applicant could not rule out the possibility that adverse events were associated with inconsistencies in drug delivery. Because of these concerns, the panelists sided with the FDA, recommending that an additional safety study would be needed prior to approval to determine if the increased incidence of AKI or MACE was being caused by the implanted delivery system.

A negative vote, but a silver lining?

While a 19-0 vote against approval was surely a disappointment for the sponsor, the meeting was not entirely negative. Several panelists highlighted the superior efficacy demonstrated by the drug in controlling HbA1C levels and helping patients lose weight. During the open public hearing segment of the meeting, patient and physician testimonials were passionate and overwhelmingly positive, highlighting the benefits of ITCA-650 in improving compliance and quality of life for patients. After implantation, ITCA-650 only needs to be refilled every 6 months, eliminating the need for multiple weekly or daily injections. Several panelists were moved by these testimonials and agreed that an implantable device for diabetes treatment has potential as an important innovation.

The panelists also provided feedback regarding the types of clinical data that would be necessary to demonstrate a positive benefit/risk. For example, panelists suggested that a clinical study comparing ITCA-650 to an active control arm (such as Byetta) could help elucidate if there is a “true” increased risk of AEs with the continuous delivery mechanism compared with injectable formulations. This advice could inform future clinical trials and increase the chances of success in eventually gaining approval for ITCA-650, or similar implantable drug-devices.

Notably, Intarcia’s clinical pipeline was acquired by i2o Therapeutics in August 2023. In addition to ITCA-650, i2o is continuing development of 5 additional pre-clinical stage drug candidates for type 2 diabetes, nonalcoholic steatohepatitis, and obesity—several of which are delivered via similar implantable osmotic mini-pump technology.

While it is unlikely that the FDA will approve ITCA-650 without substantial additional clinical data, Intarcia’s decision to persevere and demand a public meeting may have a faint silver lining.

Ultimately, there are potential benefits and advantages of enduring an uncomfortable AdCom that may extend beyond simply achieving a positive vote.

Angela W. Corona, PhD
Senior Scientific Director, Scientific Services
Angela is responsible for helping sponsors navigate complex regulatory communications, with a focus on FDA advisory committee meetings. She develops clinical and regulatory strategy along with high-quality scientific and medical content across a wide range of therapeutic and drug development areas. Angela received her PhD in Neuroscience from The Ohio State University and completed her postdoctoral training at Case Western Reserve University. Connect with Angela on LinkedIn.

The Not-So-Far-Out Therapeutic Promise of Psychedelics


Throughout history, humans have had a complex relationship with psychedelics. For millennia, ancient indigenous cultures used them for spiritual and healing purposes. For example, in 2007, archaeologists in Spain discovered mushrooms found at a burial site dated more than 7,000 years old. The mushrooms found at the site were identified as psilocybin, a type of psychedelic mushroom. Fast forward to today, and psychedelics are still in use for spiritual and mystical experiences but are also being studied more scientifically as pharmacotherapy for various psychological conditions, including anxiety, depression, posttraumatic stress disorder (PTSD), dependency/addiction, eating disorders, and end-of-life distress. In fact, the FDA even released a draft guidance to industry for designing clinical trials for psychedelic drugs.

What Are Psychedelics?

Psychedelics are derived from plants and fungi, but some are also synthesized in the lab. Psilocybin, the most studied psychedelic comes from fungi, which are unique organisms that are neither plants nor animals. They share some characteristics with plants, such as the ability to photosynthesize, but they also share some characteristics with animals, such as the ability to digest food. Computational phylogenetics have revealed that fungi split from animals about 1.538 billion years ago, whereas plants split from animals about 1.547 billion years ago. This means fungi split from animals 9 million years after plants did, meaning that fungi are actually more closely related to animals/humans than to plants.

LSD, lysergic acid diethylamide; MDMA, 3,4-Methylenedioxymethamphetamine.

Psychedelics modulate brain activity and have been associated with therapeutic effects such as increased neuroplasticity and modulation of reward pathways, not dissimilar to the mechanism of action underlying conventional antidepressants. Psychedelics work by binding to the serotonin 2A receptor on neurons throughout the brain, which causes

  • The neurons to fire more rapidly
  • More effective neuronal communication between different brain regions
  • Disrupted sensory processing leading to changes in sight, hearing, taste, smell, and touch

These changes in the brain lead to alterations in perception, thought, and mood that are characteristic of a psychedelic experience.

The discovery and synthesis of lysergic acid diethylamide (LSD) in 1938 by Albert Hofmann brought about a surge of research into the use of psychedelics in the 1950s and 60s. But this research was largely halted in the 1970s due to unsubstantiated concerns about their safety and potential for abuse. However, in recent years there has been a resurgence of interest concerning the therapeutic potential of psychedelics.

How Are Psychedelics Being Studied?

As of today, psychedelics remain a Schedule 1 drug in the United States, meaning that per the federal government, psychedelics have no medical value and hold high potential for abuse. Despite this designation, the study of psychedelics is acceptable under highly regulated and controlled circumstances. Anyone conducting research with these drugs must obtain approval from the US Food and Drug Administration (FDA) and request a Schedule 1 license from the Drug Enforcement Administration (DEA).

Several recent studies have shown the effectiveness of psychedelics:

LSD, lysergic acid diethylamide; MDMA, 3,4-Methylenedioxymethamphetamine; PTSD, posttraumatic stress disorder.

It is important to note that this field is still in its infancy, with the benefits of psychedelics yet to be proven in large, randomized trials. With psilocybin, the best-characterized psychedelic, several early-phase studies have been conducted. The most notable of these is a phase 1 study (NCT04052568) designed and conducted by Johns Hopkins University, investigating psilocybin in patients with anorexia nervosa.6

There are several explanations for why this field is moving so slowly, including but not limited to

  • Legal and regulatory hurdles
  • Difficulty blinding psychedelic trials because of the obvious effects of the drug
  • Patient expectations of efficacy are often too high and not realistic
  • Social perceptions as well as economic issues make enrollment challenging
  • Requirement of special authorization to study a Schedule 1 drug
  • Limited funding at academic institutions for the large trials needed to produce robust data

FDA Draft Guidance Concerning Psychedelic Clinical Trials

In an effort to highlight fundamental considerations for researchers investigating the therapeutic use of psychedelic drugs, the FDA recently released their first FDA draft guidance to industry for designing clinical trials for psychedelics.7 Key takeaways from the guidance include

  • The FDA recognizes that psychedelic drugs have therapeutic potential for the treatment of a range of medical conditions
  • The FDA is willing to work with sponsors to develop psychedelic drugs for clinical use
  • The FDA has identified challenges that need to be addressed in the development of psychedelic drugs and provides sponsors with recommendations for addressing these challenges

It is important to point out the contradiction between the federal status of psychedelics as Schedule 1 drugs and the simultaneous FDA acknowledgement that these agents do in fact hold therapeutic potential. This will need to be remedied through federal law, opening the door to more pharmaceutical industry investment in clinical trials.


Our current knowledge of psychedelics owes much to our ancient ancestors’ wisdom in exploring these substances. Today, despite being classified as Schedule 1 drugs at the federal level, psychedelics are being studied more seriously for their potential to treat psychological conditions. The recent release of the FDA’s draft guidance for designing clinical trials on psychedelics demonstrates a growing recognition of their therapeutic potential. As we move forward, rigorous research will be essential to fully understand the advantages and risks of psychedelics, potentially leading to groundbreaking medical treatments in the future.


  1. Griffiths RR, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.
    J Psychopharmacol. 2016;30(12):1181-1197.
  2. Noller GE, et al. Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. Am J Drug Alcohol Abuse. 2018;44(1):37-46.
  3. Davis AK, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-489.
  4. Mitchell JM, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021;27(6):1025-1033.
  5. Holze F, et al. Lysergic acid diethylamide-assisted therapy in patients with anxiety with and without a life-threatening illness: a randomized, double-blind, placebo-controlled phase II study.
    Biol Psychiatry. 2023;93(3):215-223.
  6. Effects of psilocybin in anorexia nervosa. identifier: NCT04052568. Updated: May 6, 2023. Accessed: July 21, 2023.
  7. US Food and Drug Administration, Center for Drug Evaluation and Research. Psychedelic Drugs: Considerations for Clinical Investigations. Guidance for Industry. US Food and Drug Administration; June 2023. Accessed July 28, 2023.

Aaron Csicseri, PharmD
Aaron Csicseri, PharmD
Senior Scientific Director

Dr. Csicseri joined the ProEd team in November 2017 as a scientific director, responsible for scientific leadership, content development, strategic input, and effective moderation of team meetings. Aaron has extensive experience guiding Sponsor teams through the AdCom preparation process. He received his PharmD at the University of Buffalo, where he studied the clinical curriculum. Aaron has 10+ years of experience as a medical director/clinical strategist in the accredited medical education field (CME), as well as in the non-accredited PromoEd sphere. Over the past 6 years, he has been supporting Sponsors in their preparations for FDA and EMA regulatory meetings in a wide variety of therapeutic areas. Aaron is based in Grand Island, NY, just outside Buffalo.

Connect with Aaron on LinkedIn.


Quick Snips: CRISPR

CRISPR is a powerful gene-editing tool that enables targeted therapeutic gene editing, with clinical applications for improving treatment of inherited and/or rare genetic diseases, viral infections, and arresting the progression of cancer. CRISPR gene-editing technology has the potential to revolutionize the treatment of rare genetic disorders, with the first product poised for FDA approval in December 2023.

In early 2023, Vertex and CRISPR Therapeutics submitted the first CRISPR-based therapy in the US, UK, and Europe for the treatment for sickle cell disease (SCD) and beta thalassemia using a CRISPR-based ex vivotherapy called exagamglogene autotemcel (exa-cel). Priority review was granted to the SCD whereas standard review was granted for transfusion-dependent beta thalassemia. If all goes well, this will be a landmark approval, markedly changing the regulatory environment and expanding the possibilities for precision-based medicine.

CRISPR: Revolutionizing Science

Emmanuelle Charpentier and Jennifer A. Doudna discovered the CRISPR method of genome editing, described as “genetic scissors: a tool for rewriting the code of life,” and were awarded the Nobel Prize in Chemistry in 2020. CRISPR has been described as a “revolution in progress” and it has been used in a multitude of basic science and clinical applications, ranging from agricultural (modification of crops) to animal models to therapies for rare diseases. More than 200 people have now been treated with CRISPR-based therapies in clinical trials.

Expanding the Applications of CRISPR

Traditionally, CRISPR had been used to genetically modify cells ex vivo followed by re-infusion of the cells into the patient. Recently, the first in vivo study, which directly edited genes in the body, occurred in 6 patients with transthyretin amyloidosis, was successful, and the company now has clearance to start clinical trials in hereditary angioedema using a new delivery method for in vivo treatment (lipid nanoparticles). Trials have begun in several therapeutic areas such as diabetes, HIV/AIDS, cancer, cardiovascular disorders, and genetic blindness. In the future, CRISPR-based methods may even have the potential to reduce the spread of antimicrobial resistance or to serve as a rapid diagnostic for early diagnosis of COVID-19 or pancreatic cancer. Additional applications include serving as a screening tool for identification of new drug targets and biomarkers with the potential to identify mechanisms of underlying disease.

As CRISPR Technology Continues to Evolve, Concerns Remain

Basic science research is accelerating, and process innovations are making CRISPR-based gene editing more efficient and reducing off-target effects. However, any gene-editing technology has the potential to cause adverse downstream effects, and ethical and safety concerns are still being hotly debated. In the scientific community, that debate centers around treating heritable diseases with gene-editing therapies, especially since the 2018 announcement that He Jiankui had used CRISPR-based technology to create genetically modified embryos. Clinical trials have not been without their stumbling blocks, as evidenced by the October 2022 death of a volunteer who had entered a study for Duchenne muscular dystrophy. Recently, it has been reported that his death was linked to the virus used to deliver the therapy, not CRISPR itself (note: this study has not yet been peer reviewed).

The Bottom Line

CRISPR-based therapies can treat diseases by fixing the root cause: the underlying genetics. This, in addition to their potential as a drug screening tool and use in various diagnostics, has wide (and mostly positive) implications for public health. Stay tuned for updates as we get closer to a potential approval.

Jackie Orabone, PhD, helps clients prepare for FDA Advisory Committee meetings by combining her scientific expertise and research knowledge in immunology with medical communications agency experience. Connect with Jackie on LinkedIn.


The Rise of ChatGPT in the Pharma Industry

Artificial Intelligence (AI) is rapidly transforming how we work, and the pharmaceutical industry is no exception. In particular, the emergence of Generative Pre-trained Transformer (GPT) models has the potential to revolutionize several aspects of the biotech business, including drug discovery and clinical trials. According to a recent survey, 39% of healthcare professionals see AI (including ChatGPT), as the most disruptive emerging technology in 2023. Let’s explore a few ways this incredible new tech might create efficiencies for industry.

AI/ChatGPT Models in Drug Discovery

  • Analyze vast amounts of data (research papers, clinical trials, etc.)
  • Identify previously unknown patterns and insights that could inform drug discovery
  • Reveal new drug targets
  • Predict (eventually) the efficacy and safety of potential drugs prior to clinical trials, lowering safety risks for future trial subjects

Drug Discovery Use Case: DSP-1181 is the first example of a drug originally identified by AI to enter clinical trials. In rapid time, Sumitomo Dainippon Pharma developed and secured approval for obsessive-compulsive disorder (OCD) in Japan in 2020. The process of designing, synthesizing, and testing the molecule took just 12 months—compared to an average of 4.5 years for traditional drug discovery methods.

AI/GPT Models in Clinical Trials

  • Accelerate patient recruitment/enrollment
  • Generate predictive “synthetic data” that can be used in place of trial subjects, lowering patient risks as well as decreasing recruitment requirements
  • Manage large amounts of trial data more efficiently, freeing up trialists to focus on non-administrative tasks
  • Increase patient trial engagement via GPT-powered chatbots that provide frequent personalized communication both in terms of giving patient advice and in receiving input on trial design from the patient…ultimately improving trial quality
  • Automate reporting of trial information, such ADR case reports, required for ongoing pharmacovigilance

Clinical Trials Use Case: The phase 3 ATTR-ACT study was a collaboration between Pfizer and Saama Technologies in which Saama provided their AI-powered clinical analytics platform to accelerate patient recruitment. This partnership resulted in significantly reduced recruitment time and cost. The trial enrolled more than 1,000 patients with transthyretin amyloid cardiomyopathy in just 6 months—compared to an average of 1 to 2 years for traditional patient recruitment efforts in this disease.

AI/ChatGPT clearly have the potential to create expansive evidence-based efficiencies for pharmaceutical and biotechnology companies. Despite the potential benefits described above, it’s important to note that AI/ChatGPT are only as effective as the data they are trained on, which, in reality, can be biased and have limitations. This is why it will always be important for treating clinicians to be involved in the training and implementation of AI/ChatGPT and to provide their interpretation of the data produced by such technologies.

Currently, AI/ChatGPT do not always provide accurate summaries of data, which can lead to misinterpretations and what are sometimes referred to as confident response errors (see AI hallucinations). However, as the technology develops, it’s likely these issues will be resolved, making this unexpected and disruptive technology an essential tool for the pharma industry to use in a variety of areas…many of which haven’t even been dreamed of yet.

Aaron Csicseri, PharmD
Aaron Csicseri, PharmD
Senior Scientific Director

Dr. Csicseri joined the ProEd team in November 2017 as a scientific director, responsible for scientific leadership, content development, strategic input, and effective moderation of team meetings. Aaron has extensive experience guiding Sponsor teams through the AdCom preparation process. He received his PharmD at the University of Buffalo, where he studied the clinical curriculum. Aaron has 10+ years of experience as a medical director/clinical strategist in the accredited medical education field (CME), as well as in the non-accredited PromoEd sphere. Over the past 5 years, he has been supporting Sponsors in their preparations for FDA and EMA regulatory meetings in a wide variety of therapeutic areas. Aaron is based in Grand Island, NY, just outside Buffalo.

Connect with Aaron on LinkedIn.


FDA Decision for Sarepta’s Gene Therapy for DMD Sets New Regulatory Precedent

Historic Regulatory Decision for First FDA-Approved Gene Therapy for DMD

On June 22, 2023, in a-much anticipated decision, the United States Food and Drug Administration (FDA) granted accelerated approval for Elevidys (also known as SRP-9001), Sarepta’s one-time gene therapy for ambulatory children with Duchenne’s muscular dystrophy (DMD). However, the accelerated approval was limited to the subset of boys between 4 and 5 years of age who had the debilitating disease but were still able to walk. Sarepta had originally sought accelerated approval in ambulatory children aged 4 to 7 years of age, but the FDA pushed back, citing no evidence of benefit in the older patient subgroup (ages 6 to 7). Exploratory subgroup analyses are generally considered to be prone to statistical bias and/or misinterpretation; however, the FDA has used such analyses to limit indications to patients who are most likely to benefit (see our recent blog post to learn more).

While this approval is a symbol of hope for patients and families dealing with this devastating condition, the accelerated approval means that clinical benefit for SRP-9001 has not yet been established. As a condition of approval, Sarepta will be required to generate confirmatory data showing clinical benefit, including an improvement in motor function, compared with placebo. This confirmatory data will likely be forthcoming soon from the Phase 3 EMBARK trial. The FDA has promised to rapidly review these data as soon as they are available and, if necessary, adjust the indication further or recommend withdrawal of accelerated approval if clinical benefit is not confirmed.

Regardless of the ultimate outcome, this historic decision paves the way for future accelerated approvals of a rapidly growing class of gene therapies for rare diseases.

FDA sought expert advice on accelerated approval from their Cellular Tissue and Gene Therapies Advisory Committee (CTGTAC)

The FDA decision follows a May 12, 2023, meeting of the FDA’s CTGTAC where the topic of accelerated approval based on a surrogate biomarker, namely expression of micro-dystrophin (the transgene product of SRP-9001), was hotly debated. The FDA asked the committee to vote on whether the data generated from Part 2 of Study 102 were sufficient to support accelerated approval while “taking into account the existing uncertainties.”

The vote landed slightly in favor of accelerated approval, with 8 yes votes, 6 no votes, and no abstentions. However, the discussion revealed a dramatically split committee with considerable nuance associated with individual votes.

FDA commissioner, Robert Califf, has indicated that advisory committees should prioritize discussion and feedback over the strict, “thumbs-up, thumbs-down” results of the voting questions, which often receive the most media coverage. While the FDA usually makes decisions in line with the committee’s vote, it is not required to do so.

Notably, several panelists who voted “yes” revealed that they might have voted “no” on the basis of insufficient data to meet regulatory requirements but were swayed by the extremely high unmet need and the emotional testimonies of parents whose children appeared to have benefitted from SRP-9001 in videos shown during the open public hearing. Those statements, and the overwhelming unmet need likely factored heavily into the FDA’s ultimate decision to grant accelerated approval, despite major reservations on the part of FDA reviewers..

Surrogate endpoints and substantial evidence of efficacy called into question

In briefing documents released prior to the CTGTAC meeting, the FDA raised several concerns regarding Sarepta’s proposed surrogate endpoint, noting that expression of the micro-dystrophin transgene product (a purely synthetic protein not naturally expressed in skeletal muscle) does not necessarily translate into an improvement in muscle function. In other words, it is not known if expression of the transgene is “reasonably likely to result in clinical benefit” (an essential requirement for accelerated approval). This question likely cannot be answered without further placebo-controlled clinical study data. 

Importantly, the only randomized, double-blind, placebo-controlled clinical study (Part 1 of Study 102) failed to demonstrate a statistically significant treatment effect on muscle function versus placebo, as measured by the North Star Ambulatory Assessment (NSAA) Total Score. While an apparent effect could be discerned in the small subgroup of children aged 4 to 5 years, the study was not powered to detect a change in this group.

Slide 31 from the FDA’s CTGTAC meeting presentation (show below) illustrates these data. In the 4- to 5-year-old subgroup there was a 2.5 point difference in the change from baseline on the NSAA in patients treated with SRP-9001 versus placebo at Week 48 (P = .0172), indicating a possible clinical improvement. The 6- to 7-year-old subgroup treated with SRP-9001 had a decline in their NSAA score of -0.7 compared with placebo, indicating no apparent difference between the treatment groups. Sarepta’s scientists pointed out that an imbalance in the NSAA score at baseline may have affected the results in the 6- to 7-year-old subgroup, further confounding interpretation of the results.

The FDA concluded that

“the clinical studies conducted to date do not provide unambiguous evidence that SRP-9001 is likely beneficial for ambulatory patients with DMD. It is challenging to conclude with reasonable certainty from the data provided by the Applicant either that SRP-9001 is likely effective for younger patients, or that it is likely ineffective for older patients or those with somewhat poorer functional status. Additionally, FDA has safety concerns related to the possibility of administering an ineffective gene therapy.”

During the discussion, the CTGTAC panelists agreed that expression of the micro-dystrophin transgene speaks to the biological plausibility of SRP-9001; however, there was disagreement as to whether this expression could serve as a surrogate endpoint. Dr. Rajiv Ratan indicated, “I was not convinced, either by the nonclinical or the clinical data, that an effect on the primary functional endpoints really provided plausibility that expression of micro-dystrophin would predict clinical outcome,” and later voted “no.”

Dr. Caleb Alexander, a temporary panelist at the CTGTAC meeting and veteran of the Peripheral and Central Nervous System (PCNS) advisory committee, noted that nothing changes the fact that there was no significant effect on the primary endpoint, making it difficult to attribute any predictive power to expression of the transgene. He stated that

“…the threshold of substantial evidence has to be met whether or not a product is being approved under the standard pathway or accelerated pathways…the totality of evidence that we’ve reviewed today simply doesn’t rise to the threshold of substantial evidence that’s required for accelerated approval.”

It should be noted that the FDA has previously granted accelerated approval to 4 other therapies for DMD, three of which were developed by Sarepta – eteplirsen (Sarepta, exon 51 skipping), viltolarsen (NS pharma, exon 53), golodirsen (Sarepta, exon 53), and casimersen (Sarepta, exon 45).. These 4 therapies are all antisense oligonucleotides targeting specific mutational subtypes of DMD and use exon-skipping technology to remove a specific mutated region of the dystrophin protein to render it more functional. To date, however, none of those therapies have successfully confirmed clinical benefit, raising concerns about the feasibility of confirmatory trials in DMD.

The surrogate endpoint used in those prior approvals was expression of the “edited” dystrophin protein. The shortened versions of endogenous dystrophin produced by exon-skipping technology mimic the shortened forms of dystrophin protein found in patients who have Becker Muscular Dystrophy (a much milder form of DMD). In contrast, the expression of the SRP-9001 transgene lacks the type of empirical evidence that has been previously used to support a determination that a surrogate endpoint is reasonably likely to predict clinical benefit in DMD.

Difficulties in confirming clinical benefit following accelerated approval in DMD

Sarepta will be required to generate confirmatory data from the Phase 3 EMBARK trial to ensure that the expression of the micro-dystrophin transgene translates into significant improvement on clinical outcomes, including slowing of progression on the NSAA.

During the CTGTAC meeting, the committee emphasized the importance of the confirmatory trials to confirm clinical benefit, regardless of whether they voted yes or no, with Dr. Raymond Roos indicating that his yes vote “included the results of the [EMBARK] study that’s going to end in September 2023.”

The committee members who voted in favor of accelerated approval frequently cited the dire unmet need for treatments as their reason for voting “yes,” rather than the strength of the data package. With the added confidence that confirmatory results will be available soon, they argued that it is important not to delay treatment any longer. The dissenting committee members came to the opposite conclusion. They expressed concern that, given the uncertainty around the surrogate endpoint and the fact that a definitive answer would be available so soon, approval should only follow evidence of clinical benefit on muscle function.

Two additional considerations include the impact of accelerated approval on completing EMBARK while maintaining study integrity and what will happen if the confirmatory trial fails to generate conclusive data. Historically, withdrawal of accelerated approval after a confirmatory trial has failed has been a lengthy and complicated process resulting in potentially ineffective drugs remaining on the market for far longer than intended. We have previously written about the difficulties with confirmatory trials after accelerated approval on this blog.

Mitigating much of the concern around the confirmatory trial is the fact that the results are expected soon. The last patient, last clinical visit for EMBARK is expected to be completed by September 2023, which is very soon by accelerated approval standards. In addition, in September all patients who were on placebo are scheduled to switch over to SRP-9001. However, this does not mean that the accelerated approval will have no effect on completion of EMBARK. Patients currently in the placebo group of the EMBARK trial may demand to receive SRP-9001, rather than waiting an additional 3 to 4 months. If enough patients drop out of the study, it could reduce the ability to generate conclusive data.

In any case, the results of the confirmatory EMBARK study are highly anticipated and will determine the next steps for Elevidys. Positive results could lead to a potential conversion to full approval, along with a potential expansion of the label to include older children (6 to 7 years of age). Negative or inconclusive results, however, may result in the withdrawal of the accelerated approval.

New regulatory precedent may affect future approvals

There are currently more than 1,745 gene therapies in development, including several gene therapies for DMD (Pfizer’s gene therapy may be next in line). Indeed, gene therapy approvals seem to be gaining steam in the first half of 2023. The newest approval is Biomarin’s gene therapy for hemophilia A, Roctavian, which gained full FDA-approval on June 29. This new wave of gene therapies is promising but brings questions regarding multimillion-dollar price tags, safety of the gene delivery vectors, and longevity of transgene expression. Ultimately, many unknowns remain.

With so little precedence for gene therapy approvals, the accelerated approval of Elevidys is likely to have a major effect on future approvals for gene therapies in rare diseases. The approval establishes a regulatory precedent indicating that simply demonstrating that the transgene is expressed in the target tissue may be sufficient to use as a “reasonably likely surrogate endpoint” for accelerated approval. This indicates a willingness on the part of FDA leadership to expand the definition of what will be accepted as surrogate endpoints for gene therapies, especially when dealing with diseases of high unmet need.

Angela W. Corona, PhD
Senior Scientific Director, Scientific Services
Angela is responsible for helping sponsors navigate complex regulatory communications, such as FDA advisory committee meetings. She develops clinical and regulatory strategy along with high-quality scientific and medical content across a wide range of therapeutic and drug development areas. Angela received her PhD in Neuroscience from The Ohio State University and completed her postdoctoral training at Case Western Reserve University. Connect with Angela on LinkedIn.

Kathryn M. Madalena, PhD
Scientific Associate, Scientific Services
Kathryn provides scientific support for content development and FDA advisory committee meeting preparation across a broad range of therapeutic areas. A neuroscientist by training, with specializations in neuroendocrinology and neuroimmunology, she received her PhD in Neuroscience at The Ohio State University. Connect with Kathryn on LinkedIn.

New Weapons Emerge in the Fight Against Respiratory Syncytial Virus (RSV)

Imagine your newborn baby has been hospitalized with a serious respiratory infection and is struggling to breathe. That’s a reality for thousands of US newborns and their parents every year during the respiratory syncytial virus (RSV) season. This common endemic virus doesn’t cause clinically significant disease in most children and adults, but it can cause serious respiratory disease in some newborns—particularly those born prematurely or with underlying conditions—and for older adults with weakened immune systems.

Unfortunately, until this year there were no vaccines available to prevent RSV infection. GlaxoSmithKline (GSK) and Pfizer both made history earlier this year with the approval of an RSV vaccine for older adults. On May 3, the US Food and Drug Administration (FDA) approved GSK’s Arexvy (the world’s first RSV vaccine for older adults), and on May 31, FDA approved Pfizer’s ABRYSVO™ RSV vaccine. In both cases, these vaccines were shown to significantly prevent lower respiratory tract infection caused by RSV in individuals 60 years of age or older. But what about infants and young children at risk for serious disease?

Every year in the United States nearly 600,000 infants and young children—mostly healthy, full‑term infants in their first year of life—will develop a lower respiratory tract infection from RSV, and up to 80,000 will be hospitalized.1,2 Some of these infants will require intensive care with oxygen and intravenous (IV) fluids, and a few of the most vulnerable infants—those born prematurely with underdeveloped lungs or with congenital heart disease—may die.

Synagis® (palivizumab)

Until now, the only option to prevent RSV infection was an anti-RSV antibody developed by MedImmune in the 1990s known as Synagis®. Synagis® (palivizumab) was approved in 1998, but only for use in high-risk infants like those described above. Synagis can be given during the 5-month RSV season, and it neutralizes the virus, thus reducing the risk of infection and serious respiratory disease. However, it requires 5 monthly intramuscular injections, and there was nothing available to prevent RSV infections in healthy, full-term infants.

But that all changed this week with the FDA approval of BEYFORTUS™ (nirsevimab) on July 17, which is indicated for the prevention of RSV lower respiratory tract disease in neonates and infants born during or entering their first RSV season, and in children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season. Nirsevimab is a potent RSV‑neutralizing antibody that can be given to an infant before or during the RSV season, and it has been engineered to have an extended half-life.

There will soon be two new weapons available in the US to protect infants and young children from RSV infection. The first is nirsevimab, which has been shown to provide ~75% protection from any medically attended RSV-associated lower respiratory tract infection for at least 5 months. Thus, a single shot can protect the infant for the entire RSV season. On June 8th, the Antimicrobial Drugs Advisory Committee unanimously endorsed approval of nirsevimab for all neonates and infants born during or entering their first RSV season. Importantly, there are no serious safety concerns with nirsevimab. A small number of infants who received the antibody had a minor rash or injection site reaction, as would be expected with a childhood vaccination, but there was no evidence of any serious risks associated with nirsevimab.

There will soon be two new weapons available in the US to protect infants and young children from RSV infection.

The second is a vaccine that can be given to the mother with the goal of boosting maternal antibodies against the virus, which are passed to the fetus through the placenta. Pfizer’s maternal vaccine ABRYSVO™ (the same formulation as the adult vaccine described above) was reviewed by the FDA Vaccines and Related Products Advisory Committee on May 18th and received a favorable recommendation. The maternal vaccine can be administered during the 2nd or 3rd trimester and provides the baby with about 80% protection from severe RSV lower respiratory tract infection for 3 to 4 months after birth. The advisory committee expressed some concern about the potential for the vaccine to increase the number of premature births but ultimately agreed that the benefits outweigh the risks. FDA will make a decision about the Pfizer vaccine in the near future.

Nirsevimab has the added benefit that it can provide protection regardless of when the baby is born. Nirsevimab can be given to the infant in the hospital, immediately after birth, or by a pediatrician just before the RSV season begins. That’s important because the RSV season in the United States typically occurs from October to March in most locations. So, if a mother who received the maternal vaccine gives birth in the Spring, her baby will no longer be protected when the next RSV season begins in October because of the waning of maternal antibodies present in the baby after 3 to 4 months. In such a case, the baby can be given nirsevimab in September or October and be protected for the full RSV season.

Together, these two interventions could dramatically reduce the burden of RSV infection in the United States. It is estimated that if every infant born in the United States received nirsevimab, it could prevent 300,000 RSV-related medical visits, 100,000 emergency room visits, and up to 60,000 hospitalizations every year. That would have a huge impact on busy pediatric emergency rooms and intensive care units that are often overwhelmed during the winter months due to RSV and influenza.

Together, these two interventions could dramatically reduce the burden of RSV infection in the United States.

The Long Road to RSV Prevention

It has been a long road to developing a broadly effective RSV-prevention strategy.3 The virus was first discovered in the 1950s, and the first trials of a formalin‑inactivated vaccine were conducted in the mid-1960s. However, that vaccine caused enhanced disease in some children who were later exposed to RSV and resulted in the death of two infants, which dramatically impeded subsequent vaccine development.

In the mid-1980s, the first studies demonstrating passive immunization with an antibody were completed; this led to the development of RSV-intravenous immunoglobulin (IVIG) and its approval in 1996. Next came the approval of palivizumab in 1998, an antibody that targets the RSV F fusion protein.

In 2013, the conformational mapping of the prefusion F protein by Jason McLellan and Barney Graham at the National Institutes of Health revolutionized the field.4 They identified important epitopes on the prefusion F protein, including Site 0, which is highly conserved and when targeted by antibodies can neutralize the virus so that it cannot infect cells. This ground-breaking research ultimately led to development of nirsevimab in 2014.

Timeline of the development of RSV prevention strategy for all infants.

The FDA approval of both vaccines and neutralizing antibodies against RSV in 2023 is another shining example of the power of biomedical research to address infectious diseases that pose a threat to human health. Although it took much longer to achieve this goal than anyone could have anticipated when the virus was first identified in 1958, science ultimately prevailed, thanks to the thousands of parents who were willing to enroll in clinical trials.

The FDA approval of both vaccines and neutralizing antibodies against RSV in 2023 is another shining example of the power of biomedical research to address infectious diseases that pose a threat to human health.


  1. Rainisch G, Adhikari B, Meltzer MI, Langley G. Estimating the impact of multiple immunization products on medically attended respiratory syncytial virus (RSV) infections in infants. Vaccine. 2020;38(2):251-257.
  2. McLaughlin JM, Khan F, Schmitt H-J, et al. Respiratory syncytial virus-associated hospitalization rates among US infants: a systematic review and meta-analysis. J Infect Dis. 2022;225(6):1100-1111.
  3. Villafana T, Falloon J, Griffin MP, et al. Passive and active immunization against respiratory syncytial virus for the young and old. Expert Rev Vaccines. 2017;16(7):1-13.
  4. McLellan JS, Chen M, Joyce MG, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science. 2013;342:592-598.

Jeffrey S. Riegel, PhD
SVP, Scientific Communications, ProEd Regulatory
Jeff combines his scientific expertise in molecular biology and immunology with more than 25 years of global healthcare agency experience in guiding medical and regulatory communication strategies for biopharma companies. Jeff leads the scientific team at ProEd Regulatory, which helps clients prepare for FDA Advisory Committee meetings and other health authority interactions. Connect with Jeff on LinkedIn.

Communicating the Complexities of Subgroup Analyses at an AdCom

Within clinical trials, exploratory or post-hoc subgroup analyses are widely recognized as only “hypothesis generating” due to their high potential for bias and/or misleading interpretation. This is the main reason why Sponsors cannot make efficacy claims or seek regulatory approval based on evidence of efficacy in a certain subgroup unless that benefit is consistent with the broader trial population and unless the trial is positive overall for the intention-to-treat (ITT) population. This begs the question, “Is it acceptable to use an exploratory subgroup analysis to restrict an indicated population when the data suggest less benefit in a particular subgroup?”

That is exactly what FDA asked the Oncologic Drugs Advisory Committee (ODAC) to consider in the case of the PROpel data, based on their conclusion that the combination of olaparib plus abiraterone has a favorable benefit/risk only in the subgroup of patients with advanced prostate cancer who test positive for a mutation in the BReast CAncer (BRCA) gene, which regulates homologous recombination repair of DNA. However, one might argue that the exploratory/post-hoc analysis on which FDA based their conclusion remains, by its very nature, fraught with potential for bias and/or misleading interpretation and is thus only hypothesis generating.

“Is it acceptable to use an exploratory subgroup analysis to restrict an indicated population when the data suggest less benefit in a particular subgroup?”

In the era of precision medicine, we expect that treatment choices are driven by biomarkers that can predict clinical benefit. In the case of poly ADP-ribose polymerase (PARP) inhibitors, like olaparib, BRCA mutations or deficiencies in homologous recombination repair (HRR) can predict clinical benefit. But there may be clinical situations where biomarker testing is limited or where patients without BRCA mutations might benefit from treatment with a PARP inhibitor. Indeed, the science suggests that patients with metastatic castration-resistant prostate cancer (mCRPC) may benefit from the combination of a PARP inhibitor with an antiandrogen, like abiraterone, regardless of BRCA mutation status, based on the synergistic activity of these 2 drug classes. In addition, the majority of patients with mCRPC (especially in disadvantaged communities) do not have definitive biomarker testing for BRCA mutations, usually due to cost and/or lack of available tumor tissue. That is the context for the PROpel study investigating the combination of the PARP inhibitor olaparib (Lynparza) plus abiraterone (Zytiga) as first-line treatment of mCRPC.

The PROpel trial was designed to assess the activity of this combination in the broad, unselected, ITT population, and data on BRCA mutation status by ctDNA and tissue tests were collected for the purpose of exploratory subgroup analysis. The trial met its primary endpoint in the ITT population, demonstrating a statistically significant 40% improvement in radiologic progression-free survival (rPFS). Therefore, AstraZeneca was seeking a broad indication that includes BRCA mutant, BRCA wild-type, and BRCA unknown patients. The Sponsor also presented evidence that patients without BRCA mutations or with unknown BRCA status benefited from the combination of olaparib plus abiraterone. However, on April 28, 2023, the ODAC voted 11 to 1 (with 1 abstention) to limit use of the combination to men whose tumors tested positive for a BRCA mutation, which represents only about 10% of patients with mCRPC. This was based on post-hoc subgroup analyses that created the perception of a less favorable benefit/risk in the BRCA wildtype or unknown patients.

On April 28, 2023, the ODAC voted 11 to 1 (with 1 abstention) to limit use of the combination to men whose tumors tested positive for a BRCA mutation

Dr. Chana Weinstock articulated the FDA’s position on this issue at the April 28 ODAC meeting. She said that the Agency discourages using subgroup analysis to try to argue for efficacy in a specific group, particularly in a failed trial (although PROpel was a positive study). However, she highlighted historical precedent for limiting indications based on post-hoc subgroup analysis suggesting that certain subgroups might have compromised safety or a potential overall survival detriment. Finally, she cited the FDA guidance that states that if a trial only shows benefit in a selected subgroup, the indication may be limited to a narrower population, especially if that same signal is observed in other comparable trials. (Figure 1)

Figure 1


Jorge Nieva, section head of solid tumors at the University of Southern California, objected to restricting the indication to only those patients with known BRCA mutations, saying “I worry that the approach used in this application can justify removing any subgroup from any application where that subgroup has an OS curve that crosses one. FDA seems to be looking at these OS curves in a vacuum and is ignoring the corroborating evidence that some non-BRCA patients could benefit significantly.”

“I worry that the approach used in this application can justify removing any subgroup from any application where that subgroup has an OS curve that crosses one.”

It is common for Sponsors to find themselves in this situation at ODAC where the data are somewhat ambiguous and the arguments/counter arguments are highly statistical in nature. This is especially true for subgroup analyses. The key communication goal when addressing an advisory committee is to make your position as easy to understand as possible by breaking down your argument into digestible bites. If your messages are too complex, statistical or philosophical, the committee may not fully appreciate your position. When this occurs at ODAC, the committee typically defers to the FDA’s position.

Aaron Csicseri, PharmD
Aaron Csicseri, PharmD
Senior Scientific Director

Dr. Csicseri joined the ProEd team in November 2017 as a scientific director, responsible for scientific leadership, content development, strategic input, and effective moderation of team meetings. Aaron received his PharmD at the University of Buffalo, where he studied the clinical curriculum. He has 10+ years of experience as a medical director/clinical strategist in the accredited medical education field (CME), as well as in the non-accredited PromoEd sphere. Over the past 5 years, he has been guiding Sponsor teams in their preparations for FDA and EMA regulatory meetings in a wide variety of therapeutic areas. Aaron is based in Grand Island, NY, just outside of Buffalo, New York.

Connect with Aaron on LinkedIn.


Neurology Takes a Page Out of the Oncology Playbook of FDA Accelerated Approvals

The field of neurology is experiencing a significant upswing in innovative therapeutic development, propelled by advances in genetics, neuroimaging techniques, and biomarker research. However, neurological diseases are inherently difficult to treat, and there remains an urgent need to rapidly translate these advances into more effective treatments. It is timely then, that several recent drug approvals in neurology have benefited from FDA’s Accelerated Approval pathway— designed to expedite access to promising drugs to treat serious, life-threatening conditions with a high unmet medical need—a regulatory path most often traveled by oncology drugs.

Four recent accelerated approvals—2 for amyotrophic lateral sclerosis (ALS) and 2 for Alzheimer’s disease—appear to support a shifting regulatory approach to neurological drugs by the FDA, particularly in its willingness to deploy regulatory flexibility.

The ALS Treatment Landscape is Evolving Rapidly

On April 25, 2023, the FDA granted accelerated approval to Biogen’s Qalsody™ (tofersen), indicated to treat a rare, genetic form of ALS mediated by the superoxide dismutase 1 (SOD1) gene, referred to as SOD1-ALS. The approval was based on evidence that tofersen significantly reduced neurofilament light chain (NfL)—a marker of axonal degeneration that is elevated in the blood of many neurologic and neurodegenerative conditions—which correlated with a delay in disease progression and death. Although a failed clinical trial proved a barrier to full approval, the Peripheral and Central Nervous System Drugs Advisory Committee reviewed the data on March 22, 2023, and voted in favor of NfL’s utility as a surrogate endpoint supporting conditional approval. This marks the first instance of a blood biomarker being effectively used as a surrogate endpoint to secure accelerated approval for a neurology drug and underlines the potential benefits of incorporating NfL—and other blood biomarker measurements—into other neurology trial designs.

The FDA’s review of Amylyx’s Relyvrio™ (AMX0035)—a fixed-dose combination of sodium phenylbutyrate plus taurursodiol—was a closely watched regulatory event last year. Marginal efficacy in a phase 2 trial initially prompted the FDA to call for more data; however, they ultimately decided to review the application. Two advisory committee meetings were convened in 2022 and reached opposing outcomes. Panelists on the Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) voted in favor of approving Relyvrio™, just months after voting against the drug. The committee appeared to be swayed by additional analyses of survival benefit, a more acute focus on the unmet need, the FDAs own emphasis on exercising regulatory flexibility, and the sponsors statement that it would withdraw their drug if their phase 3 confirmatory trial fails. Subsequently, the FDA granted accelerated approval of Relyvrio™ for the treatment of ALS in September 2022.

A review in JAMA of oncologic drugs approved between 2000 and 2016 revealed that oncology drugs granted accelerated approval demonstrated a median overall survival (OS) benefit of 2.4 months1. Comparing this to Amylyx’s Relyvrio, which exhibited a 4.8-month median OS benefit, illustrates both a heightened standard of approval for neurologic drugs by the FDA and its advisory committees, and a gulf in the perception of meaningful clinical benefit in the fields of oncology and neurology. Patients and caregivers will argue that the benefit of adding a few months—and vital quality-of-life improvements—to the 3- to-5-year life expectancy of a patient suffering from ALS is just as clinically meaningful as in advanced cancers.

Alzheimer’s Accelerated Approvals Signal Renewed Scrutiny of Surrogate Endpoints

One key factor contributing to the success of accelerated approvals in oncology is the use of surrogate endpoints. These are indirect measures of clinical benefit that can be assessed more quickly than traditional endpoints, like overall survival, and are reasonably likely to predict clinical benefit.

The utility of amyloid-beta protein buildup in the brain (assessed by brain imaging) as a surrogate endpoint believed to be correlated with cognitive decline in Alzheimer’s disease was greenlighted with the approval of Biogen’s Aduhelm™ (adacanumab) in June 2021—the first accelerated approval of an Alzheimer’s drug.

The FDA’s recent willingness to apply regulatory flexibility when reviewing neurology applications, as in the case of Qalsody and Aduhelm—and subsequently approve these drugs under the Accelerated Approval pathway, has resulted in a shift in the regulatory strategy being employed by sponsors. The strategy to utilize the Accelerated Approval pathway in neurology drug development programs may, in part, be driven by (1) the evolution of imaging and biomarkers that can potentially be used as surrogate endpoints, and (2) the openness of FDA to accept those surrogate endpoints.

While the use of the expedited pathway and the decision to use amyloid-beta as a surrogate endpoint reasonably likely to predict clinical benefit was surprising in the case of adacanumab, it has changed the regulatory landscape in neurology by setting precedent. Eisai and Biogen subsequently capitalized on that precedent by picking up another accelerated approval for Leqembi™ (lecanemab) for Alzheimer’s disease, and on June 9th the PCNS voted unanimously for full approval of Leqembi, based on results of the confirmatory trial.

It appears that the regulatory environment surrounding the amyloid-beta class of treatments for Alzheimer’s disease—primed by Aduhelm and Leqembi—continues to bear more fruit. In Eli Lilly’s May 3 press release, we saw the most encouraging results yet for a drug that targets amyloid beta. In a phase 3 trial of more than 1,000 people with early signs of Alzheimer’s disease, donanemab treatment resulted in a slowing of cognitive decline by 35% compared to placebo. It also resulted in 40% less decline in the ability to perform activities of daily living.

Interestingly in that trial, biomarkers were used in a relatively dynamic manner. Firstly, patients were prescreened using a predictive biomarker—plasma p-tau-181—thought to select for patients with both amyloid and tau tangle pathology (the 2 prominent pathologies in Alzheimer’s disease). Subsequently, the data revealed that those who start the trial with fewer tau tangles benefitted the most from donanemab. Incidentally, donanemab slowed (but did not stop) tangle growth, underscoring the benefit of treating earlier in the course of disease.

Secondly, the amyloid beta surrogate biomarker was used to inform clinicians on when to complete patients’ course of treatment with donanemab—by reaching a threshold of amyloid plaque clearance—a strategy that has not been employed in other Alzheimer’s disease trials testing antibodies against amyloid beta.

The National Academies of Sciences, Engineering, and Medicine (NASEM) convened a workshop in January 2023 to examine the FDA’s use of the Accelerated Approval program. There was renewed criticism of the FDAs approval of Aduhelm and a call to increase the transparency around FDA decision-making and its stance on surrogate endpoints. According to Peter Stein, director of the FDA’s Office of New Drugs, “We don’t have a simple formula or algorithm for evaluation of a potential surrogate for accelerated approval.” He went on to emphasize the limitations of using a correlation between the surrogate and established clinical outcomes that demonstrate clinical benefit.

There is clearly a need for a set of transparent standards for the utility of surrogate endpoints, both in therapeutic areas where accelerated approvals have traditionally been applied (oncology and HIV/AIDS) and in neurology. FDA guidance on surrogate endpoints is being developed. Under the Food and Drug Omnibus Reform Act of 2022 (FDORA), the FDA must issue 4 guidance documents related to accelerated approvals within 18 months of FDORA being enacted in December 2022; 2 of which will address surrogate endpoints.

As a wave of innovation continues to crash on the shores of neurological research, the interplay between novel therapeutics, surrogate endpoints, and regulatory flexibility has brought about tremendous progress in the field of neurodegenerative diseases. The FDA’s updated guidance on surrogate endpoints is likely to further accelerate the development of novel treatments based on the best available science.


  1. Ladanie A, Schmitt AM, Speich B, et al. Clinical trial evidence supporting US Food and Drug Administration approval of novel cancer therapies between 2000 and 2016. JAMA Netw Open. 2020;3(11):e2024406. doi: 10.1001/jamanetworkopen.2020.24406.

Muzamil Saleem, PhD
Associate Scientific Director, ProEd Regulatory
Muz is a trained neuroscientist with a diverse skillset, combining a 10-year neurology-focused research career, scientific consulting experience, and a 3-year tenure in healthcare equity research on Wall Street before joining ProEd Regulatory—all supported by a passion for written and visual scientific communication. Connect with Muz on LinkedIn.

Thinking Outside the Beta-Amyloid Box

The dominant amyloid hypothesis of AD has translated into an armada of anti-amyloid biologics in the near-term pipeline—led by Eisai and Biogen’s lecanemab. Last month, lecanemab showed a slowing in the rate of cognitive decline by 27% over 18 months versus placebo. Lecanemab also possesses a relatively improved safety profile among the beta-amyloid mAbs, as a result of lower rates of amyloid-related imaging abnormalities (ARIA) (this was a significant issue with aducanumab). This improved safety profile eliminates the need for a dose titration period. The other notable beta-amyloid mAb drug contenders include Roche’s gantenerumab and Eli Lilly’s donanemab, which may achieve the fastest amyloid plaque clearance among its competitors.

These recent successes, however, come after an approximate 98% failure rate in phase 2 and 3 trials since 2003.1 For a disease that kills more people than breast cancer and prostate cancer combined,2 a modest improvement in cognitive decline is not enough. This has led many labs to pursue other potential targets in AD, with some encouraging early signals of success (Table 1).3

Table 1. Alzheimer’s drug development pipeline: disease-modifying drug candidates with non-amyloid mechanisms of action with corporate sponsor in phase 2 and 3 and select phase 1 drug candidates, grouped by target. Source: Cummings et al (2022).3

SponsorDrug candidateTargetTrial status
Vigil NeuroVGL101TREM2Phase 1
Denali Therapeutics Inc.DNL919TREM2Phase 1
TauRx TherapeuticsTRx0237TauPhase 3; active
AC Immune, JanssenACI-35TauPhase 2; recruiting
UCB BiopharmaBepranemabTauPhase 2; recruiting
EisaiE2814TauPhase 2; recruiting
Ionis PharmaceuticalsIONIS MAPTRx (BIIB080)TauPhase 2; active
JanssenJNJ-63733657TauPhase 2; recruiting
Eli LillyLY3372689TauPhase 2; recruiting
Samus TherapeuticsPU-ADTauPhase 2; active
GenentechSemorinemab (R07105705)TauPhase 2; active
AgeneBio, NIAAGB101Synaptic plasticityPhase 3; active
CortexymeAtuzaginstat (COR388)Synaptic plasticityPhase 3; active
Anavex Life SciencesBlarcamesine (ANAVEX2-73Synaptic plasticityPhase 3; active
Cassava SciencesSimufilam (PTI-125)Synaptic plasticityPhase 3; recruiting
Tetra Discovery PartnersBPN14770Synaptic plasticityPhase 2; active
Neurotrope Bioscience, NIH, NIABryostatin 1Synaptic plasticityPhase 2; recruiting
Cyclerion TherapeuticsCY6463Synaptic plasticityPhase 2; recruiting
Toyama ChemicalEdonerpic (T-817MA)Synaptic plasticityPhase 2; active
Cognition TherapeuticsElayta (CT1812)Synaptic plasticityPhase 2; recruiting
Athira PharmaFosgonimeton
Synaptic plasticityPhase 2; recruiting
Neurokine Therapeutics, et al.MW150Synaptic plasticityPhase 2
EIP PharmaNeflamapimod
Synaptic plasticityPhase 2; recruiting
Biohaven Pharma, ADCSTroriluzole
Synaptic plasticityPhase 2; active
KeifeRxNilotinib BEProteostasis/ proteinopathiesPhase 3
QR Pharma, ADCSPosiphenProteostasis/ proteinopathies
NeurogenesisPhase 2; recruiting
Novo NordiskSemaglutinideMetabolism and bioenergeticsPhase 3; recruiting
CerecinTricaprilinMetabolism and bioenergeticsPhase 3
T3D Therapeutics, et al.T3D-959Metabolism and bioenergeticsPhase 2; recruiting
NewAmsterdam PharmaObicetrapibLipids and lipoprotein receptorsPhase 2
NeurmedixNE3107InflammationPhase 3; recruiting
Alector, AbbVieAL002InflammationPhase 2; recruiting
NovartisCanakinumabInflammationPhase 2; recruiting
GMP BIO, BHT Lifescience AustraliaGB301InflammationPhase 2
IntelGenx Corp.MontelukastInflammationPhase 2; recruiting
Vaccinex, ADDF, Alzheimer’s AssociationPepinemab (VX15)InflammationPhase 2; recruiting
TrueBinding, IncTB006InflammationPhase 2; recruiting
Mindful Diagnostics and TherapeuticsTdap vaccineInflammationPhase 2
Northwell Health, JanssenDaratumumabInflammationPhase 2; recruiting
Shanghai Green ValleyGV-971Gut-brain axisPhase 3; recruiting
Actinogen MedicalXanamemGrowth factors and hormonesPhase 2; active
GemVax & KaelGV1001EpigeneticPhase 2
Neuroscience Trials AustraliaDeferiproneCell deathPhase 2; active

The AD therapeutic landscape appears to be shifting away from symptomatic drugs and focusing more on disease-modifying drugs (DMDs)—a report by the Alzheimer’s Association (AA) showed that 68% of agents in phase 3 trials are DMDs (Figure 2).3 Most of these DMDs target beta-amyloid (29%); however, the remainder represent innovative new directions in targeting the multifactorial, complex pathology of AD.

Figure 2. Mechanisms of action of agents in phase 3.3

The discovery that mutations in “triggering receptor expressed on myeloid cells 2” (TREM2) can increase the risk of AD by up to threefold, suggested the involvement of inflammatory pathology in AD.4-6 TREM2 is a transmembrane protein located on the surface of microglia, the resident immune cells of the brain. Microglia are dynamic, innate immune cells of the brain: functioning to constantly sense extracellular cues (e.g., cellular debris, invading viruses or bacteria) in the central nervous system (CNS). In the absence of extracellular cues, the microglia are in a homeostatic conformation. When cellular debris binds to TREM2, homeostatic microglia are activated and transition to disease-associated microglia (DAM). Microglia in the DAM state also function to clear proteins that aggregate in neurodegenerative diseases—such as amyloid plaques in AD. Because TREM2 loss-of-function mutations are associated with the inability of microglia to transition to the DAM phenotype, they are a rational target in AD. Dysfunctional microglia expressing mutated TREM2 are unable to clear cellular debris, and this leads to a perpetuation of neuroinflammation and subsequent neurodegeneration.

Further research bridging pathologies has revealed that TREM2 biology directly involves beta‑amyloid: TREM2 binds to beta-amyloid, and this binding is compromised in the presence of AD‑associated mutations.7 Moreover, TREM2 has been linked to the long-established genetic risk factor of the late-onset (after age 60) form of AD: the ε4 allele of apolipoprotein E (APOE).8

Targeting TREM2 is particularly attractive because it is restricted to the area of pathology—the brain. Denali Therapeutics’ TREM2-targeted therapy, DNL919, uses a proprietary antibody delivery technology to deliver drug across the protective blood-brain barrier and activate the receptor. DNL919 was this year placed on a clinical hold before it entered human trials due to issues surrounding the preclinical toxicology assessment. Denali is working to provide the FDA with the information needed to restart the clinical trial.

Massachusetts-based Vigil Neuro is developing disease-modifying therapeutics to restore the microglia DAM phenotype by activating TREM2 signaling in order to treat neurodegenerative diseases such as AD. Vigil is targeting the activation of TREM2 with VGL101, a drug currently in a phase 1 healthy volunteer trial that is slated to read out by the end of the year.

The potential role of gut microbiota in AD pathogenesis9 has culminated in the discovery of a plant-based compound, sodium oligomannate (GV-971), by Shanghai Green Valley Pharmaceutical. GV-971 contains an active ingredient derived from brown algae and was recently shown to therapeutically remodel gut microbiota, resulting in the suppression of inflammation and inhibition of AD progression10. China’s drug regulator approved marketing of GV-971 following encouraging results from a 36-week phase 3, multicenter, randomized, double-blind, placebo-controlled parallel-group clinical that revealed significant improvements in cognition.

Deficits in axonal transport—a cellular process that mediates the movement of diverse cargoes along axons—has been shown to be a contributing pathology in the neurodegeneration seen in AD (as well as other neurological diseases).11,12 Buntanetap, a drug being developed by Annovis Bio, inhibits multiple neurotoxic aggregating proteins—including beta-amyloid, tau, α-synuclein and TAR DNA-binding protein 43 (TDP-43)—to restore axonal transport to normal levels. Annovis recently reported positive safety data and a statistically significant improvement in cognition from its phase 2a Alzheimer’s study, and this month received FDA authorization to initiate a phase 2/3 clinical trial of buntanetap in moderate AD.

It appears that the AD field is now refocusing on pathologies outside of aberrant amyloid and tau protein, and looking more closely at diverse biological processes including inflammatory cascades, gut-brain signaling, and axonal transport. It’s likely that ongoing translational research will eventually lead to a better understanding of these diverse pathologies and that overall treatment of AD will ultimately be multifactorial.

Muzamil Saleem, PhD
Associate Scientific Director, ProEd Regulatory
Muz is a trained neuroscientist with a diverse skillset, combining a ten-year neurology-focused research career, scientific consulting experience and a three-year tenure in healthcare equity research on Wall Street before joining ProEd Regulatory—all supported by a passion for written and visual scientific communication. Connect with Muz on LinkedIn.


  1. Kim CK, Lee YR, Ong L, Gold M, Kalali A, Sarkar J. Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures. J Alzheimers Dis. 2022;87(1):83-100.
  2. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement. 2022;18(4):700-789.
  3. Cummings J, Lee G, Nahed P, et al. Alzheimer’s disease drug development pipeline: 2022. Alzheimers Dement (N Y). 2022;8(1):e12295.
  4. Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368(2):117-127.
  5. Ulland TK, Colonna M. TREM2 – a key player in microglial biology and Alzheimer disease. Nat Rev Neurol. 2018;14(11):667-675.
  6. Qin Q, Teng Z, Liu C, Li Q, Yin Y, Tang Y. TREM2, microglia, and Alzheimer’s disease. Mech Ageing Dev. 2021;195:111438.
  7. Zhao Y, Wu X, Li X, et al. TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function. Neuron. 2018;97(5):1023-1031 e1027.
  8. Fitz NF, Wolfe CM, Playso BE, et al. Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice. Mol Neurodegener. 2020;15(1):41.
  9. Varesi A, Pierella E, Romeo M, et al. The Potential Role of Gut Microbiota in Alzheimer’s Disease: From Diagnosis to Treatment. Nutrients. 2022;14(3).
  10. Wang X, Sun G, Feng T, et al. Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019;29(10):787-803.
  11. Millecamps S, Julien JP. Axonal transport deficits and neurodegenerative diseases. Nat Rev Neurosci. 2013;14(3):161-176.
  12. Guo W, Stoklund Dittlau K, Van Den Bosch L. Axonal transport defects and neurodegeneration: Molecular mechanisms and therapeutic implications. Semin Cell Dev Biol. 2020;99:133-150.