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When Neil Shneider, MD, PhD, got results back that Lisa Stockman Mauriello's amyotrophic lateral sclerosis (ALS) was driven by a SOD1 mutation, enrollment in had just closed.

The phase III trial is testing Biogen's investigational antisense oligonucleotide (ASO) aimed at knocking down levels of the mutant protein thought to play a major role in contributing to ALS in the 2% of patients with SOD1 mutations.

Shneider, an investigator on the VALOR trial at Columbia University who has long worked on therapies targeted to specific mutations in ALS, figured he'd be able to go the route of "expanded access" (also called "compassionate use") instead. He requested access from Biogen for the 51-year-old mother of three on Feb. 4.

Twenty days later, Biogen responded -- and their answer was no. That has remained the answer after several conversations, Shneider said.

"This therapeutic is specifically designed for people with this mutation, which is why I'm interested in this for Lisa," he noted.

"We don't know whether this trial is going to read out positive," he added. "All we know is that we have encouraging phase II data, which suggests that ... people like Lisa who have a fast progressing form of SOD1 seem to respond better to tofersen than others."

Media outlets have increasingly picked up on , and the family is hoping the pressure may change Biogen's opinion. They're also hoping that their case has an impact on access for patients who don't fit clinical trial inclusion criteria or whose diagnosis comes just as a trial enrollment window closes.

Placebo Patients, Jeopardizing Access

Stockman Mauriello is no stranger to the pharmaceutical industry. She has spent 30 years in healthcare communications, most recently as a president of public relations for the contract research organization Syneos Health.

Diagnosed in January with bulbar ALS driven by an aggressive SOD1 mutation -- A5V, which had also been called A4V, depending on whether the initial methionine (a "start codon") in the amino acid sequence is counted -- her disease has progressed rapidly. She recently lost her ability to speak and can only type with one hand, but that is fading fast, her husband, Bob Mauriello, told 名媛直播.

The family understands that the therapy is not yet proven and may not work in this case, but they see it as their best hope of slowing disease progression and enabling Stockman Mauriello to witness a handful of family milestones over the next few months: her oldest son's graduation from college, her youngest son's graduation from 8th grade, and her middle son starting college in September.

Shneider says a post-hoc analysis from the phase I/II study, , suggested that patients with faster-progressing SOD1 mutations, like A5V, may benefit more from tofersen than those without faster-progressing mutations.

Despite repeated requests and a highly visible grassroots campaign -- including , support from , and a Change.org petition with -- Biogen has not backed down, posting an , its executive vice president of research & development.

The company maintains that its chief concern is the dilemma of providing expanded access while a third of patients enrolled in the phase III trial remain on placebo.

"We cannot overlook these patients when considering questions of broader access, and cannot keep them on placebo while at the same time offering tofersen to those outside of our study," Sandrock wrote in the letter. "Offering tofersen outside of the study would risk failing to complete the study and risk failing to obtain access for all SOD1-ALS patients."

In an emailed statement to 名媛直播, Biogen said that "providing individual access to tofersen at this time could jeopardize access to tofersen for hundreds of SOD1-ALS patients by impeding our ability to complete the study and seek subsequent regulatory approvals."

"Obtaining approval for a new drug from regulatory authorities around the world is the fastest way to help the largest number of people with a specific disease," the statement said.

The company is "working as fast as we can and preparing to open an Early Access Program after patients in the study are no longer randomized to placebo and if the study data show that tofersen is safe and effective."

But Shneider said that's likely to be too late for Stockman Mauriello, since the trial won't read out until the fall at the earliest.

A Sign of Things to Come

Shneider and Bob Mauriello think it's unlikely that patients would opt out of the trial at this point over the one in three chance they're on placebo.

"Why drop out if you don't know if you're getting the real thing?" Mauriello said. "Even if you thought you were on placebo, you're several months in at this point. Unless you're imminently dying, wouldn't you finish? Especially since people in the trial are guaranteed access to the drug for the next 5 years."

On fairness, Mauriello notes that patients in the trial have a two in three chance of getting the drug, while his wife currently has no chance at all. She would be willing to be randomized so that she could have the same odds of getting the drug as people in the trial, but it doesn't look like the company would go along with that option at this point, he said.

Mauriello also says the argument that an adverse event in an expanded access program could derail approval is weak, as the FDA has encouraged such programs and there are no examples in which such an event prevented a drug's approval.

Gregg Gonsalves, PhD, of Yale School of Public Health in New Haven, Connecticut, also feels these reasons don't hold water. As an AIDS activist with ACT UP in the 1990s, Gonsalves championed parallel track studies -- a larger type of expanded access program for patients who didn't meet inclusion criteria for clinical trials. Paired with those trials, the program provides a better picture of how a drug will work in the real world, Gonsalves said.

"Less common side effects would show up in those programs," he said. "It generally showed that the drugs were really tolerable, with rare side effects, that they were safer in larger groups of people."

Shneider's upcoming trial of a different investigational ASO for ALS targeting the FUS mutation is indeed set up with a type of parallel track. Patients who don't fit the inclusion criteria for the trial will be enrolled in a , Shneider said. (The last time ALS "compassionate use" hit the national media was for an ALS FUS patient, Jaci Hermstad, who was also Shneider's patient. Hermstad at age 26.)

"There are plenty of instances where we've seen companies say, 'we can't give you expanded access because we need to get it approved as fast as possible, wink, wink,'" Gonsalves said. "Exondys 51 was the worst-case scenario in recent history. It's wildly expensive and young kids with Duchenne muscular dystrophy deserve better."

"Many disease groups don't have an ACT UP," Gonsalves said. "They may have a big national organization funded by pharma that's not going to tell Biogen, 'hey you can afford to give 1,000 patients expanded access today while we keep this trial going.'"

Daniel McIntyre, a former senior vice president of corporate affairs at Biogen, who says he has known Stockman Mauriello for 30 years, wrote in an a biotech investor newsletter, that cases like this one are only going to become more common, "as public policy fails to keep pace with science, communication, and expectations."

"Every company should be paying close attention: It is a horrible state of affairs for one company and one family, but it is likely a harbinger of what is to come for many biotech companies and families," McIntyre wrote. "The fact that we have so many excellent treatments in the industry pipeline, especially for rare genetic diseases with no currently available treatments, makes situations like this inevitable."

Biogen, he said, "has the chance to take a pioneering role yet again, this time shaping a future for compassionate use that affirms its core values, and aligning them to the values of current society."

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