FDA Listening Session

On November 6, 2019, Alliance to Cure Cavernous Malformation, including 5 patient members, offered testimony at a US Food and Drug Administration Patient Listening Session dedicated to cavernous malformation. Following is a meeting summary.

Cerebral Cavernous Malformation/Cavernous Angioma/Cavernoma: Patient-Led Listening Session

Date: November 6, 2019

Location: Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD

Objective of Session

This session provided the opportunity to share with FDA officials:

1) Challenges of clinical trial recruitment resulting from enrollment criteria focused on the minute proportion of patients eligible for clinical trials based on symptomatic hemorrhage.
2) Experiences of patients who did not have brain hemorrhage from their lesions but experienced significant functional neurological deficits.
3) Suggestions for using patient symptom stability as a primary endpoint.

Summary of topics discussed

1. Challenges of clinical trial recruitment

a. Representing Alliance to Cure Cavernous Malformation, Connie Lee, President and CEO, as well as mother of an affected young woman, shared the stories of two patients who were severely disabled by sequelae of their lesions and the story of one young patient who passed away in order to illustrate the need for non-surgical treatments.
b. Connie Lee presented literature-based statistics on the prevalence and incidence of cerebral cavernous malformations and on the initial presentation based on symptoms.
c. Using these figures, it appears that there are only ~370 patients across the United States in any given year who could be eligible for a clinical trial based on recent symptomatic hemorrhage (CASH trial). This is only 1% of active cases in the United States.
d. The window of time for patients to decide to participate in a CASH trial is very small given that it often takes 6-9 months before a decision about surgery is made. Once they have expressed interest in participating, patients must make arrangements for time off work, travel, and childcare, adding more barriers.
e. After excluding patients who have their lesion surgically resected, who have had radiation, who have co-morbidities, or women who plan to become pregnant, the pool of potential participants is fewer than 100 at any one time.
f. The only current clinical trial, a Phase I/II experimental proof of concept trial, has enrolled only 26 patients in 10 months. This is 0.1% of active cases in the United States. The pool of CASH patients is not sufficient to fill a full Phase II trial or more than one trial at any phase

2. Patient Experience

a. While reducing the risk of re-hemorrhage is a critical need, the patient experience includes a much broader range of symptoms – functional neurological deficits or FND – that are not the result of detectable hemorrhage. These are often episodically exacerbated.
b. Five Alliance to Cure Cavernous Malformation members shared their stories of functional neurological deficit and the impact on their lives.

i. The first patient, a woman in her 30s, shared how her basal ganglia lesion did not hemorrhage but caused an acute episode of significant arm numbness/dyscoordination and visual impairment which has since become chronic. This caused her to end her career as a bedside nurse and has impacted her ability to find a partner and have a family.
ii. The second speaker was the parent of a 19-year-old with a medulla lesion that hemorrhaged a year ago. The lesion had an acute exacerbation with symptoms similar to hemorrhage this past summer that resulted in hospitalization, a round of steroids, and a return home from college for several weeks of recovery.
iii. The third speaker, a 50-year-old executive with an MD and PhD, shared how his brainstem lesion, diagnosed at age 15 but quiescent for 35 years, caused significant symptoms that could not be detected on traditional MRI, even at university imaging facilities. A very small hemorrhage was detected at the University of Chicago – had he not had the means to be seen in Chicago, he would not have been eligible for trials. He continues to have significant symptoms from this exacerbation including double vision/nystagmus and right-sided numbness and tingling which has resulted in losing the ability to type.
iv. The fourth speaker, a young woman in her 20s with a career as a human resources manager and exercise physiologist, shared her history with a brainstem lesion in the context of familial CCM. She had a significant brainstem lesion hemorrhage in 2017 with migraine-like symptoms and left-sided weakness. One year later, she experienced a temporal lobe hemorrhage that was followed by surgical resection. Most recently, in March, she suffered the onset of symptoms that were identical to her original brainstem hemorrhage. Imaging did not indicate a hemorrhage, but she continues to have left-sided muscle spasms and tingling, blurred vision, tinnitus, and chronic headache.
v. The fifth patient, an Emmy-award winning journalist, shared her experiences with exacerbations over the last 4 years that were severe enough to warrant 10 imaging studies during this time with no hemorrhage detected. These exacerbations, along with her history of familial CCM that included a resection, have made it impossible to consider having children and have severely impacted her professional life.

3. Acute Symptom Exacerbation (FND)

a. Connie Lee presented on issues surrounding acute symptoms exacerbation. Acute exacerbation of symptoms that are not reflected as a hemorrhage visible on MRI are a real and important phenomenon to our patients.
b. The mechanism causing these exacerbations is not known, but the mechanism behind hemorrhage is also not known. Acute exacerbations may be hemorrhages too small to be detected on currently available MRI or maybe the result of an inflammatory process. Inflammation seems to play a role in other CCM symptoms.
c. Acute exacerbations can be measured using patient-reported outcomes measures as well as through patient examination.

4. Concerns/Suggestions/Discussion

a. Connie Lee reported that sponsors have chosen to walk away from CCM as an indication for their drugs in development because they could see no path to filling trials. FDA responded that they are available to discuss potential paths with any sponsor.
b. Connie Lee suggested that patient experience is more important to patients than MRI results, but patient experience must be measured in a consistent way both across patients and across the length of a trial. FDA responded that they are open to using a variety of outcome measures.
c. FDA expressed appreciation to the patients for sharing their stories and helping FDA to understand the patient experience of CCM.

Partner Organization

Alliance to Cure Cavernous Malformation

FDA Divisions Represented


Patients Represented

~528,000 people in the United States have at least one CCM lesion.
~30,000 patients in the US are currently diagnosed and still have a lesion.

6000 active patients in the United States presented for diagnosis with functional neurological deficits unrelated to hemorrhage. It is not known how many experience FND exacerbations after diagnosis.

5400 active cases in the US are believed to have brainstem lesions. These appear to be more likely both to hemorrhage and to be the cause of FND.


Discussions in FDA Rare Disease Listening Sessions are informal. All opinions, recommendations, and proposals are unofficial and nonbinding on FDA and all other participants. This report reflects Alliance to Cure Cavernous Malformation’s account of the perspectives of patients and caregivers who participated in the Rare Disease Listening Session with the FDA. To the extent possible, the terms used in this summary to describe specific manifestations of cerebral cavernous malformations, health effects and impacts, and treatment experiences, reflect those of the participants. This report is not meant to be representative of the views and experiences of the entire cerebral cavernous malformation patient population or any specific group of individuals or entities. There may be experiences that are not mentioned in this report.