#NACFC2022 – ‘Big Need’ for Inflammation-limiting LAU-7B, Laurent Says
Company executives talk of hopes for future trials, how LAU-7B works in CF
Later this month, Laurent Pharmaceuticals will meet with the U.S. Food and Drug Administration (FDA) to discuss next steps for LAU-7b, the company’s experimental inflammation-controlling therapy for cystic fibrosis (CF) that showed promise in a recent Phase 2 study.
“There was no precedent in cystic fibrosis for a drug controlling inflammation that went to approval,” and there is “a big need for that,” Radu Pislariu, MD, president and CEO of Laurent, said in an interview with Cystic Fibrosis News Today.
“That means the [FDA] never went through this process. We are writing the book,” Pislariu added. “They will use our example in establishing what would be a good endpoint for this type of technology going forward for other companies that will come after.”
The next step in development, Pislariu said, could be a Phase 2b trial followed by a Phase 3 study that aims to confirm whether LAU-7b can slow the loss of lung function in CF patients with relatively mild lung disease, as was indicated in Phase 2 APPLAUD study findings.
Pending regulatory authorizations, the next trial will probably start in late 2023, and it would likely include sites in the U.S., Canada, Australia, and Europe, he added.
A novel mechanism of action that’s complementary to CFTR modulators
CF is caused by mutations that impair the functionality of the CFTR protein, which normally sits at the cell’s surface and coordinates the movement of water and salts in and out of the cell. As a consequence of this protein’s dysfunction, patients’ mucus is abnormally thick and sticky, which can interfere with the function of lungs and other organs, as well as set the stage for infections.
CFTR modulators, a recent class of medications that can improve the functionality of the protein in people with amenable mutations, are rapidly becoming standard care for CF. According to Pislariu, LAU-7b is expected to act synergistically with these medications, because it works via a separate, complementary mechanism: targeting chronic inflammation and the cell membrane.
“This mechanism of action that we have does not interfere [with modulators] … it actually benefits the mechanism of action that those CFTR modulators have,” Pislariu said.
Within the lungs, CF is characterized by persistent inflammation that damages tissue, resulting in fibrosis (scarring) and ultimately impairing the lungs’ ability to take in oxygen. Inflammation also can reduce the functionality of the CFTR protein, even in people on modulator therapy.
“When the cell gets stressed by infections or inflammation, those fixed, corrected CFTR receptors sometimes just tend to go into the cell. They are not expressed anymore,” Pislariu said, noting that the CFTR protein can only work properly if it’s at the cell’s surface.
By simultaneously easing inflammation and modulating the activity of the lipids (fat molecules) in the cell membrane, LAU-7b is expected to help stabilize the protein’s function.
“We are saying you fix the receptor, you correct the receptor, you put it on the surface. Our job is to keep it there in good health,” Pislariu said.
Resolving inflammation, but not anti-inflammatory: the ‘eureka moment’
Larry Lands, MD, PhD, chief medical advisor for Laurent, stressed that although LAU-7b is expected to ease chronic inflammation, it’s not an anti-inflammatory. In other words, the therapy won’t stop inflammation from starting, but it may help to resolve inflammation. This is a key distinction since, although inflammation can cause lung damage in CF, it’s also crucial for protecting the body against bacteria and other infectious invaders.
“We know we need a certain amount of inflammation to fight infection, and if you actually don’t have any, you’re going to have horrible infections,” Lands said. “Our concept is not that we’re gonna stop inflammation from starting, but that in CF the system doesn’t know how to shut off.
“It’s like you want the fire department to come, but you don’t want them to cause so much damage with the water and the axe and everything,” he added. “Our idea is: Bring the fire department, have them do their job, but make sure there’s not collateral damage.”
Supporting this mechanism, Lands noted that treatment with LAU-7b reduced inflammation but did not increase the burden of bacterial infections in preclinical mouse experiments. In fact, bacterial burden fell in some LAU-7b-treated mice, implying that rebalancing the inflammatory response could actually help the immune system to more effectively clear lung infections.
“That was the experiment that [made me decide] to go into the field. … That was, for me, the eureka moment,” Pislariu said.
“There is no better killing machine than your body. So you just fix the body, fix that imbalance that’s stopping the body [from clearing] the infection,” he said.
Phase 2 results: Better-than-expected slowing in lung function decline
The Phase 2 APPLAUD trial (NCT03265288) enrolled 166 adults with CF who were randomly assigned to either LAU-7b or a placebo for six treatment cycles, totaling six months. Its main goal was to assess the treatment’s effect on percent predicted forced expiratory volume in 1 second (ppFEV1), a standard measure of lung health based on how much air someone can forcibly exhale.
Results showed that, over the course of the trial, LAU-7b’s use significantly slowed the decline in ppFEV1, by more than one percentage point on average. That might not sound like a big difference — but it’s sizable in the context that, regardless of modulator treatment, CF patients often experience a decline of around two percentage points each year, according to Pislariu.
“So, reducing this by one point is like a 50% reduction. Yes, it is a little, but [over] time this is important,” he said, adding that meeting the trial’s primary endpoint (a significant change in ppFEV1 favoring LAU-7b) was “more than we expected for, to be honest.”
Notably, while LAU-7b slowed lung function decline in APPLAUD, starting on the therapy did not lead to a substantial increase in ppFEV1 for patients — unlike CFTR modulators, which generally lead to an improvement in lung function. This was expected given the differences in how these treatments work.
“Trikafta [a triple combination modulator] is increasing the lung function by eliminating the mucus. You don’t have the [mucus] plugs, you start immediately feeling better,” Pislariu said. “Our drug does not address the mucus. We are addressing the chronic inflammation that destroys the lungs over time.”
Supporting possible synergy between the medicines, a trend toward slower lung function decline was observed among patients who were on modulator therapy during the APPLAUD study.
“Of course it’s perfect to feel very, very good immediately — but you also have to think, how do I preserve this wellness over time?” Pislariu said.
Younger patients with better lung function expected focus of future trials
In subgroup analyses, LAU-7b’s effect on lung function decline was generally more pronounced among patients who started the trial with higher ppFEV1 scores. This was expected since the therapy is intended to prevent damage from accumulating, and those with better lung function initially have more to lose over time.
“We have to realize that when you have a person with significant lung disease, you’re seeing where they are today and not how they … accumulated damage and scarring,” Lands said. “Nothing’s going to reverse that.”
So a treatment effect with “milder disease, where there’s much more plasticity and flexibility because there’s not this installed damage, to us is quite encouraging and fits with what we’re seeing in terms of helping modulators having a significant effect,” he added.
Pislariu thinks LAU-7b is likely to benefit patients with all severities of lung disease, noting evidence of decreases in inflammatory markers across subgroups. But since clinical trials take substantial time, money, and resources to conduct, subsequent testing will likely focus, at least initially, on younger patients with milder disease.
“We have to balance what is feasible and what is clinically relevant,” he said. “We’re thinking that the most feasible trial would be to go into a younger population, those who have a better FEV1 at start just to prove the concept.”
The intent is to conclusively establish efficacy in a highly responsive group of patients to support initial regulatory approvals, then conduct additional testing in groups where the effect is likely to be more subtle.
“You have to choose a population that is clearly controlled so you can confirm the effect. You get the drug approved and then you move in the other populations,” Pislariu said, noting that approved CFTR modulators followed similar developmental routes.
Side effects ‘reversible, transient, and well-known’
LAU-7b is an oral formulation of fenretinide, a compound previously developed as a potential cancer treatment. It also is designed, Pislariu said, to be easier to take than earlier oral fenretinide formulations.
“For the first time we developed a commercial formulation for this drug … that is a powder base that we can put into capsules or make tablets,” he said.
Fenretinide is a derivative of vitamin A, which is needed for proper functioning of the eyes. Because fenretinide and vitamin A have a similar chemical structure, the molecular machinery that transports vitamin A to the eyes can accidentally pick up the medication instead, ultimately lowering how much of the vitamin gets to the eyes.
The reduction can interfere with the ability to see in the dark. This is “a predictable, expected, reversible, transient [temporary] and well-known side effect of fenretinide,” Pislariu said. “That’s the key, key home message,” he added. “It will not harm you. It’s mostly a self-reported inconvenience at the beginning, which with treatment in time will go away.”
Because this was a well-established side effect, patients in the APPLAUD study underwent regular ophthalmologic (eye) evaluations. They also were explicitly asked about any eye-related side effects, and they were referred for additional testing if they reported visual issues on more than one occasion.
The study also included one week off of treatment in each four-week cycle, to allow vitamin A levels to build up and help mitigate this side effect.
Of 24 reports that triggered an extra eye exam, objective abnormalities were found on three, according to Lands. In all cases, the changes were mild and went away in time. There was one case of patient-reported impaired dark adaptation that was judged serious by the study investigator.
Notably, lower vitamin A levels were most evident after the first treatment cycle.
“It was really in that first cycle … the body adapts, the liver starts producing [vitamin A], and then the changes in each [subsequent] cycle was much smaller,” said Lands, who co-holds the patents for fenretinide as a CF treatment.
The rate of pulmonary exacerbations was very low throughout the APPLAUD trial, both in patients on LAU-7b and those on placebo, according to Lands. He thought this attributable in large part to the availability of Trikafta and to lockdowns related to COVID-19, which reduced rates of infections and exacerbations throughout the CF community.
One patient had a serious exacerbation immediately after starting on LAU-7b, which was judged to be related to the medication by a study investigator.
As for the overall safety profile of fenretinide, Pislariu noted that prior studies showed positive results at much higher doses.
“If you look at lab tests, everything else … it’s all very, very, very good from the safety point of view,” he said. “It’s safer than Advil.”
Note: The Cystic Fibrosis News Today team is providing in-depth coverage of the 2022 North American Cystic Fibrosis Conference (NACFC) Nov. 3-5. Go here to see the latest stories from the conference.
About the Author
