One afternoon in May, Bob Mauriello was going through his phone and deleting old voicemails that had accumulated. But he made sure to save every single message from his wife, Lisa Stockman Mauriello, no matter how short or trivial. “Just so I can hear her voice again,” he says.
Hoarseness was one of the first signs that something was wrong with Stockman Mauriello, a former health care public relations (PR) professional and mother of three from Summit, NJ. “It started in August or September 2020, and it's progressively gotten worse,” says her husband. “Now, if you eliminate all ambient noise and you're a couple inches away from her, you can hear just a little bit when she speaks, but there's no tone to it.”
The hoarseness was soon accompanied by another troubling symptom: Stockman Mauriello could no longer lift her left arm to dry her long, dark hair. It took several months to solve the mystery of her symptoms, but on January 6, 2021, Stockman Mauriello, who is now 52, was diagnosed with bulbar onset amyotrophic lateral sclerosis (ALS), a form of the disease in which symptoms first appear in the face and neck. The family also learned that she had a rare mutation in an ALS-associated gene known as SOD1, which means her disease progresses very rapidly. “Her symptoms are progressing so quickly that we're not sure how much longer she will be with us,” says Mauriello.
His wife's diagnosis came a week too late for her to enroll in a trial of an investigational medication for ALS called tofersen, which targets inherited mutations in the SOD1 gene—the trial had closed enrollment at the end of 2020. Tofersen is the first targeted therapy against a gene known to cause ALS, and higher doses of it correlated with a slowing of loss of function in early phases of the trial.
So Stockman Mauriello's family, with the help of her neurologist, Neil A. Shneider, MD, PhD, appealed to the drug's manufacturer, Biogen, to give her tofersen outside of the trial, under a program supervised by the US Food and Drug Administration (FDA) and known as expanded access. Sometimes called “compassionate use,” expanded access is a potential pathway for a patient with a serious or life-threatening disease or condition who has no other treatment options to receive an experimental medication that has yet to be approved by the FDA.
Dr. Shneider, who is director of the Eleanor and Lou Gehrig ALS Center at Columbia University Irving Medical Center in New York City, cautioned the family that tofersen is still experimental. Even in the best-case scenario, he told them, it would not cure Stockman Mauriello's ALS and may not even halt its progression. But the family hoped it might at least slow the rapid pace of the disease's relentless advance.
Trial results published in the New England Journal of Medicine in July 2020 suggested that the drug might slow disease progression: Study participants taking a placebo deteriorated more on measurements of lung and muscle function than those taking tofersen. Although the trial was not designed to detect significant changes in people's symptoms, patients with a mutation associated with fast-progressing disease (such as the one Stockman Mauriello has) experienced a slight improvement on an ALS functional rating scale when given tofersen, compared with a marked deterioration for fast progressors on the placebo. In phases 1 and 2 of the trial, tofersen appeared to lower levels of SOD1 protein in the central nervous system, and few side effects were reported from the drug.
Patients with ALS and other neurologic diseases, including treatment-resistant epilepsy, tuberous sclerosis complex, glioblastoma, and Duchenne muscular dystrophy, have received investigational drugs and biologic treatments under expanded access. The initiative began in 1976 when the FDA introduced the “Group C Cancer Investigational New Drug Program,” and it was expanded during the HIV/AIDS crisis in the 1980s. A physician seeking compassionate use for a patient must submit an IND (investigational new drug) application and get approval from an institutional review board, a group of experts charged with protecting the rights and welfare of volunteers participating in biomedical research. (The IND application is also used by pharmaceutical companies in order to administer a drug to humans in a clinical study.)
In 2019, the FDA received a total of 1,720 applications for expanded access; only 11 of them were denied. And approvals came quickly: typically, on the same day as submission for emergencies and within only four days for non-emergencies, according to Compassionate Use and Preapproval Access (CUPA).
“A lot of new disease-modifying therapies are becoming available for patients with neurologic diseases, and we want patients to have access to these treatments as quickly as possible,” says Nicholas E. Johnson, MD, FAAN, associate professor of neurology and human and molecular genetics at Virginia Commonwealth University, who has conducted a number of therapeutic trials in muscular dystrophy and other inherited nerve and muscle disorders. “Many drugs being tested in clinical trials are for people who are relatively healthy or early in the course of their disease, which leaves many patients unable to participate,” Dr. Johnson says. “For example, with spinal muscular atrophy, there have been three clinical trial programs in which patients who were unable to walk or older than 18 didn't meet the criteria to enroll. In cases like that, where no other treatments exist or other options have been exhausted, patients may want to seek expanded access to a drug.”
Starting on the Path
Some patients learn of expanded access because they are being treated at a major medical center by doctors who know of possible experimental treatments. That's what happened to Mark Griffin, a former trial attorney from Durham, NC, who was diagnosed with stage 4 glioblastoma multiforme, a highly aggressive brain tumor, in 2009. When the cancer returned after surgery, Griffin began undergoing intensive chemotherapy at the Preston Robert Tisch Brain Tumor Center at Duke Cancer Institute. After the chemo left him debilitated and seeking other options, his neuro-oncologist, Katherine Peters, MD, PhD, FAAN, associate professor of neurology at Duke, helped him enroll in an expanded access program for the investigational immunotherapy drug rindopepimut, manufactured by Celldex.
As of June 2021, Griffin had been receiving monthly injections of rindopepimut for more than eight years. Regular MRIs show no sign of his brain tumor progressing, and he has experienced no further symptoms like the seizures and vision problems that led to his diagnosis. “Other people who started taking it at the same time didn't do as well,” he acknowledges. And results from clinical trials have been largely disappointing. “But I've been fine for eight years and eight months now.”
Patients not being treated at a major facility or by a physician involved with expanded access may need to research possible treatments on their own, says Jonathan Santoro, MD, assistant professor of neurology and director of the Neuroimmunology and Demyelinating Disorders Program at the University of Southern California's Keck School of Medicine. “Most neurologists are not actively investigating early-stage compounds to use for their patients.”
Advocacy groups may know of potential new therapies, suggests Alison Bateman-House, MPH, PhD, assistant professor of population health at New York University's Grossman School of Medicine and a member of NYU's Working Group on CUPA. “The more you can help your doctor identify products, the easier it is for the doctor,” she says. “It's not right that we should put that on patients and families, but we don't have a better system at this time.”
Once patients have identified a drug that might help, they need to work with a neurologist who is willing and able to pursue the process. “Not all clinicians can organize an expanded access application,” says Dr. Shneider. “Not every clinician has relationships with companies that would make these things possible.”
Considering the Risks
Patients should carefully assess the pros and cons of proceeding with experimental treatment. “You will be taking a drug that is not proven for your disease. In many cases, the drugs have not had wide clinical exposure, so we don't understand all the potential side effects and other complications,” says Dr. Shneider. “You have to weigh those risks against the possible benefits in the context of your disease. Someone like Lisa Stockman Mauriello, with one of the most aggressive forms of ALS and only six months to live if untreated, may have a much higher tolerance for risk than someone whose disease is debilitating over a period of 20 years.”
There are financial considerations as well. Insurance companies are not required to pay for drugs provided through expanded access, and they usually don't. In addition, the drug manufacturer may request authorization from the FDA to charge the patient for the direct and indirect costs of making the medication available. (They're not allowed to make any profit in expanded access.)
“Other expenses may be involved,” says Dr. Johnson. “If you have to get an IV infusion or a spinal injection, the drug may be provided for free but the hospital may still charge for the procedure and the equipment.” In Griffin's case, Celldex has provided his drug at no charge, but he covers the cost of receiving the injections and other related expenses through a combination of Medicare, Medicaid, and out-of-pocket payments.
Drug companies do not always agree to provide compassionate use treatment. Stockman Mauriello was repeatedly denied expanded access to tofersen despite multiple appeals—and the savvy that comes from a career in pharmaceutical PR. In April, largely as a result of the Mauriello family's campaign, Biogen agreed to begin providing expanded access to tofersen in mid-July, after study participants in the placebo arm are switched to tofersen but before the trial is complete and results are reported.
In the meantime, Stockman Mauriello's disease progressed severely. In March, she was able to slow dance with each of her three sons for videos filmed to play at their eventual weddings. By May, she could walk only with her husband or an aide at her side, holding on to her waist. “I don't want to be far from her in case she chokes,” says Mauriello. “Because it's hard for Lisa to talk or get my attention, she ordered these school-style bells and we attached them to her right foot, which is the one she can move the best. If I'm more than a couple of feet away from her, she can shake her foot; I hear the bells and I know to come. It's like having a 120-pound baby who can't cry, move, or feed herself and you have the constant fear that if you do something wrong, the baby's going to die.”
ALS advocate Mike Henson, who left his career as a stage manager with Hard Rock Entertainment after his own diagnosis in 2018, compares Stockman Mauriello's protracted wait for approval from Biogen to calling 911 because your house is on fire and being told the fire department will arrive in two months. “Early treatment is key,” he says. “People are getting worse every day. Are these experimental treatments home runs? No. But ALS is such a heterogeneous disease that it will take expanded access to help us understand how new drugs work.”
Manufacturers say no for a variety of reasons. They may not have a large enough supply of the drug for everyone who requests it or for people outside of the clinical trial. Or a drug maker might be concerned that if a patient has a bad outcome, it will influence how the FDA reviews the results of the clinical trial—a worry that seems unwarranted, according to Dr. Bateman-House. “I've reviewed the last 10 years of data for thousands of drugs provided through expanded access,” she says, “and in only two cases were investigational drugs put on a temporary hold by the FDA due to serious adverse events associated with expanded access. Both cases were resolved quickly, and both drugs were ultimately approved.”
For Stockman Mauriello, Biogen raised another objection. “They feel they can't ethically give the drug to Lisa when there are people getting the placebo as part of the clinical trial,” says her husband. “I agree there's some merit to that, but our counterargument is that the people in this trial had a two-thirds chance of getting the real drug. We're willing to do something unprecedented: Have them randomize Lisa outside the trial and give her a two-thirds chance of getting the real drug through expanded access. They said no to that as well.”
Mauriello notes that prior to her diagnosis, both he and his wife participated in the Pfizer trial of its COVID-19 vaccine. “She got the placebo, and I got the real thing,” he says. “She wouldn't have wanted them to deny the vaccine to people until they made sure everyone who had the placebo got it. I find it hard to believe that, weeks before the clinical trial is supposed to end, any of the 60 people in this trial who are getting the placebo would say that they shouldn't give the drug to a woman who is losing function so quickly.”
Editor’s Note: Lisa Stockman Mauriello died from complications of amyotrophic lateral sclerosis on August 4, 2021. We send our condolences to her husband, Bob Mauriello, and their three sons.
Right to Try: Another Possible Avenue
Like expanded access, the federal Right to Try Act—which was signed into law in May 2018—is aimed at providing investigational treatments to terminally ill patients outside of clinical trials. The differences between the two programs are that with Right to Try, a patient's physician does not have to submit an investigational new drug (IND) application to the US Food and Drug Administration (FDA) and the process does not require approval from an institutional review board (IRB). But the doctor still must apply to the manufacturer for the drug.
“Under Right to Try, if a physician is willing to prescribe the medication and monitor its use, and the medication has already successfully completed a phase 1 (safety) trial, then the manufacturer can provide it,” explains Jonathan Santoro, MD, assistant professor of neurology and director of the Neuroimmunology and Demyelinating Disorders Program at the University of Southern California Keck School of Medicine in Los Angeles.
At least one patient with amyotrophic lateral sclerosis (ALS) has received the investigational drug NurOwn (made by BrainStorm Cell Therapeutics) through Right to Try, and seven patients have received Gliovac, an immunotherapy vaccine manufactured by Epitopoietic Research Corp. that's being studied for glioblastoma, according to news reports. But pharmaceutical companies still aren't required to provide these drugs, so the law changes nothing for Lisa Stockman Mauriello, who has a fast-progressing case of bulbar onset ALS. “It's more like Right to Ask instead of Right to Try,” says her husband, Bob Mauriello.
And while Right to Try eliminates the need for FDA approval, that was not the primary problem with the expanded access program, says Alison Bateman-House, MPH, PhD, assistant professor of population health at New York University's Grossman School of Medicine and a member of NYU's Working Group on Compassionate Use and Preapproval Access. “The vast majority of the time, when patients are unable to get a drug through expanded access, it's because the manufacturers won't give it to them,” she says. “And if you take the FDA out of the equation, companies would be even less likely to provide access, because the goal is for the company to bring their drugs to market through FDA approval.”
Expanded access will probably remain the preferred program for access to investigational drugs, especially for patients with rare diseases, says Pat Furlong, founding president and CEO of Parent Project Muscular Dystrophy, who notes that pharmaceutical firms want the additional safeguards of FDA and IRB supervision. “We have many companies in active studies of new agents in muscular dystrophy, with different mechanisms of action, and they're all looking at Right to Try and saying it's not an appropriate pathway for them,” she says. “They don't think they have either sufficient safety data or material to do this, and when they do, they would rather go through a pathway where the FDA is involved in evaluating the safety of the patient's request before moving forward.”
Improving the Expanded Access Process
Some health care providers are trying to make it easier for doctors to apply for expanded access on behalf of their patients. “At the Healey Center for ALS at Massachusetts General Hospital, we've enrolled more than 100 participants in a series of expanded access programs for eight investigational drugs over the past three years,” says Sabrina Paganoni, MD, PhD, co-director of Mass General's Neurological Clinical Research Institute. “Now we are about to launch a multisite expanded access companion to the Healey ALS platform trial, which is testing several investigational products simultaneously. Each drug will have a small expanded access companion program. And based on this, we plan to develop a set of templates, resources, and educational materials to empower physicians to pursue applications for their patients.”
