Patients with neurofibromatosis type 1 have an option for treatment: AstraZeneca’s Koselugo. But it’s “a difficult drug to take,” according to SpringWorks Therapeutics CMO Jim Cassidy, M.D. That’s where his biotech is hoping to make its move, and a batch of mid-stage data seems to support the case.
SpringWorks reported that its mirdametinib achieved a 52% response rate in pediatric patients with NF1 who have plexiform neurofibromas in the phase 2b ReNeu trial, according to a Thursday press release. Adults in the study achieved a 41% response rate. The therapy also led to “deep and durable responses” on key secondary endpoints, including pain and quality of life.
NF1 is a rare genetic disorder caused by mutations to the NF1 gene, which encodes for a key suppressor of the MAPK pathway called neurofibromin. The disease is characterized by abnormal skin pigmentation, skeletal deformities and tumor growth, as well as neurological complications or cognitive impairment. Patients with NF1 also have a high risk of developing plexiform neurofibromas, or PN—tumors that grow along the peripheral nerve sheath and can cause disfigurement, pain and functional impairment. The disease can even be fatal in rare cases.
NF1 typically grows more rapidly during childhood and is typically diagnosed in the first two decades of life. Some of the tumors can be removed surgically, but not always, leaving a need for therapeutic options.
Treatments for the disease include some off-label medications to address symptoms, but AstraZeneca’s Alexion unit provides the only FDA-approved medication for the underlying condition with Koselugo. But, according to SpringWorks, there are major gaps left in care for NF1 patients: That therapy led to a 66% complete or partial response rate in a phase 2 trial, according to an investigator assessment. For a more apples-to-apples comparison, SpringWorks pointed to a Blinded Independent Central Review, which was what the biotech used in the ReNeu trial, where Koseluga scored a 44% response.
Koselugo has a sub-optimal response profile and challenging tolerability, which prevents patients from staying on it long term, SpringWorks CEO Saqib Islam said on a Thursday conference call (PDF). Since NF1 Is a long-term disease, an option that patients can stay with is important.
Mirdametinib is an oral small-molecule MEK inhibitor that is designed to inhibit MEK1 and MEK2 in the MAPK pathway. This key signaling network regulates cell growth and survival and plays a role in oncology and rare diseases such as NF1 when it's genetically altered.
Chief Medical Officer Jim Cassidy, M.D., Ph.D., said mirdametinib demonstrated a best-in-class response in the pediatric population and a first-in-class response among adults. The median duration of treatment in the pediatric group was 22 months, with median time to first response at 7.9 months. But more than 40% of patients had a response by four months. Twenty-eight patients in the pediatric group remain on treatment at the time of data cutoff and 85% of patients opted to continue.
“The number of patients rolling into the long-term follow-up phase is indicative of the enduring clinical benefit that these patients experienced, as well as the tolerability profile, and highlights their desire to remain on mirdametinib,” Cassidy said.
Despite the executive optimism, SpringWorks did not see a bounce in its share price. The company was trading down 10% Thursday morning at $19.83, compared to a previous close of $22.07.
While SpringWorks executives took a shot at Koselugo’s safety profile, mirdametinib wasn’t without its adverse events either. The main treatment-emergent adverse events reported were rash, a known side effect of the MEK inhibitor class, Cassidy noted.
But rashes led to more discontinuations in the adult arm of the trial, which had 13 patients stop treatment, compared to five in the pediatric group. SpringWorks implemented a protocol amendment with supportive care after the initial cases of rash were seen, which later cut down on the number of discontinuations in the adult group.
“I should point out that in isolation, we think the adult tolerability is quite good … What we did learn anecdotally in the context of this study is that with less parental discretion on decision-making, adults were more likely to discontinue therapy for less severe side effects,” Cassidy said. “We saw this in the beginning of the trial, where we initially did not have preventive measures in place to manage rash and a number of adult patients stopped treatment for rather low-grade events.”
Other adverse events were fairly consistent across the two patient populations. Cassidy called the pediatric safety profile “really exceptional.” Other reported events were diarrhea, acne, vomiting and headache. There were 22 grade 3 or higher adverse events in the pediatric cohort, including four cases of increased blood creatine phosphokinase, which can indicate muscle tissue damage. SpringWorks did not report any cases of that adverse event in the adult group. There were 21 grade 3 or higher events, however, including six rashes and five cases of acne.
With the topline mid-phase data in hand, SpringWorks now plans to file a new drug application with the FDA in the first half of 2024, after a first-quarter meeting with the agency. The therapy has an orphan drug designation in the U.S. and Europe, as well as fast-track designation in the U.S. Further data will be published from the ReNeu trial at a future medical meeting and in a peer-reviewed journal.
Koselugo notched $208 million in sales for AstraZeneca for 2022. Analysts were keen to hear how SpringWorks might break into that market with mirdametinib.
Chief Operating Officer Badreddin Edris, Ph.D, said there are 100,000 NF1 patients in the U.S. right now, and 40,000 have NF1-PN.
“This is a lifelong disease. Many patients require active treatment at some point during their treatment journey,” Edris said. Patients with NF1-PN typically are not candidates for surgical removal of their tumors, so they require systemic therapy. “What this does is it places a premium on effective systemic options that have tolerability profiles that are suitable for long-term use, especially because patients are known to progress when they stop treatment.”
SpringWorks believes that the benefit-risk profile presented today will help lift mirdametinib over Koselugo. While it’s unclear exactly how many people are taking Alexion’s medicine today, Edris said that other off-label therapies are still taking up a share of the market.
Edris also noted that the biotech was able to rapidly enroll the ReNeu trial despite Koselugo being on the market, which supports the claim that there is an unaddressed patient population.
“The fact that [Koselugo] is on market, we do not believe is going to be a meaningful barrier to entry for mirdametinib, especially with the strength of the data that we shared today,” Edris said. “Koselugo’s very encouraging revenue run rates set a nice backdrop for us for to come in and have an agent that could really improve the treatment paradigm.”