In Phase 1b Study, Patients Treated in First-Line Demonstrated a Confirmed Objective Response Rate of 65%
Despite finding initial success in Phase II, FibroGen recently announced that topline results from its second Phase III trial of pamrevlumab in Duchenne muscular dystrophy failed to meet the primary endpoint. While FibroGen stated it is evaluating the total data, there are multiple confounders between the Phase II MISSION trial and Phase III program that warrant a closer look.
Earlier this summer, pamrevlumab missed the primary endpoint in the Phase III LELANTOS-1 trial, failing to improve the Performance of the Upper limb 2.0 score in patients with non-ambulatory Duchenne muscular dystrophy (DMD). The second Phase III trial, LELANTOS-2, enrolled 73 boys with ambulatory DMD.
DMD is the most common form of muscular dystrophy in children. Usually manifesting in young boys, it is an X-linked recessive genetic disorder characterized by muscle wasting and loss of ability to walk, leading to complete wheelchair dependence by around 13 years of age.
Topline results from LELANTOS-2 showed that multiple standardized endpoints were not met. In addition to failing North Star Ambulatory Assessment (NSAA) score assessments, pamrevlumab also missed secondary endpoints such as 4-stair climb velocity, the 10-meter walk/run test, time to stand and time to loss of ambulation. This is a clear issue as these unsatisfactory outcomes suggest the clinical trial methodology may be at fault.
Several confounders may have led to the trial’s failure. First, MISSION was a single-arm, open-label study in which non-ambulatory DMD patients were dosed only with pamrevlumab and a stable regimen of corticosteroids without the use of a placebo arm. Without a comparator trial arm, accurate assessment of other confounders became more difficult because the clinical trial risks were pushed into Phase III.
In addition, without splitting the LELANTOS-2 cohorts into groups based on genetic mutations, FibroGen lacks detailed genomic data to carry out a root cause analysis on whether or not genetics was a factor. While the company has stated in the past that pamrevlumab “can potentially be used in DMD patients regardless of specific mutations,” it remains to be seen whether clinical data bears this out.
Finally, the presence of systemic corticosteroids throughout all of pamrevlumab’s trials makes it difficult to isolate the effect of the drug. In mice, systemic corticosteroids may induce connective tissue growth factor (CTGF) expression in normal tissues and organs but not in highly inflamed areas. In DMD, patients may have varying degrees of inflammation depending on the progression of the disease. Therefore, despite being a current standard of care treatment for DMD, systemic corticosteroids are not effective enough to treat the root cause of the disease, and their overall role in treating DMD is unclear.
FibroGen’s DMD failure could also have larger implications for the company. In June, pamrevlumab also failed a Phase III study in idiopathic pulmonary fibrosis. While the company has other products, such as roxadustat for anemia caused by chronic kidney disease, this drug is only available in Europe and certain countries within Asia—the FDA rejected the drug in 2021, requesting another trial. Thus, as FibroGen currently has no products approved in the U.S., recent repeated trial failures are not reassuring to investors.
Therefore, examining what went wrong in LELANTOS-2 will be a crucial test if the company hopes to regain investor confidence in the coming months.
This week, GSK is expecting a verdict for its myelofibrosis candidate momelotinib and Alnylam will make the case for patisiran in cardiomyopathy of ATTR amyloidosis.
On September 13, the FDA will convene its Cardiovascular and Renal Drugs Advisory Committee to discuss Alnylam’s supplemental New Drug Application (sNDA) for Onpattro (patisiran) in adults with cardiomyopathy of wild-type or hereditary transthyretin-mediated (ATTR) amyloidosis. The FDA’s verdict is due on October 8.
ATTR amyloidosis is a rare and progressive disease that arises when misfolded transthyretin proteins accumulate as amyloid fibrils in various organs throughout the body—including the nerves, gastrointestinal tract and heart—leading to dysfunction. In the heart, these amyloid clumps make the walls stiff and compromise its pumping function.
In its current application, which the FDA accepted in February 2023, Alnylam is proposing patisiran as a treatment for cardiomyopathy arising from transthyretin accumulation in the heart. The sNDA includes data from the Phase III APOLLO-B trial, a randomized, placebo-controlled and double-blinded study that demonstrated improvements in quality of life and functional capacity in patients following treatment with patisiran.
Patisiran was found to be safe in ATTR-cardiomyopathy patients in APOLLO-B, with most side effects being mild or moderate in severity. The overall adverse event profile was consistent with that established in prior clinical studies.
Patisiran—marketed in the U.S. as Onpattro in polyneuropathy of hereditary ATTR amyloidosis—is an injectable double-stranded siRNA therapeutic that works by binding to messenger RNA encoding transthyretin and tagging it for destruction, which results in an overall lower level of the protein in the body.
This mechanism of action won Onpattro the FDA’s approval in August 2018 for hereditary ATTR amyloidosis polyneuropathy, making it the first-ever RNA interference therapeutic to secure the regulator’s authorization.
Following a three-month delay to review new information, the FDA is expected to release its decision on GSK’s NDA for momelotinib as a treatment for myelofibrosis patients with anemia by September 16.
Momelotinib is an investigational medication that has a “novel mechanism of action,” inhibiting three signaling pathways: the JAK1 and JAK2 pathways and the activin receptor type I (ACVR1) cascade, according to a GSK press release announcing the delay. The molecule was most recently developed by California biotech Sierra Oncology, which was acquired by GSK for $1.9 billion in April 2022.
By silencing the JAK1 and JAK2 pathways, momelotinib eases symptoms of splenomegaly and elicits improvements in the patients’ constitution. This is complemented by its activity along the ACVR1 cascade, potentially lowering levels of the hepcidin protein, which is elevated in myelofibrosis and contributes to anemia.
The FDA first accepted GSK’s NDA in August 2022 and set an initial target action date of June 16, 2023. On the day of the deadline, the regulator announced it would need three more months to evaluate new data.
GSK supported momelotinib’s regulatory bid with data from the Phase III MOMENTUM trial, which showed that the candidate met its primary efficacy endpoint, reducing Total Symptom Score after 24 weeks of treatment by at least 50%. Momelotinib likewise aced its secondary efficacy metrics, including transfusion independence and splenic response rate.
The company presented these 48-week data in December 2022 at the 64th American Society of Hematology (ASH) Annual Meeting.
https://www.biospace.com/article/fda-action-alert-roche-halozyme-gsk-and-alnylam-s-adcomm/
