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AstraZeneca's Koselugo not a 'meaningful barrier' to SpringWorks' rare disease offering, executives say
16 Nov 2023
Clinical ResultOrphan DrugFast TrackPhase 2
Treatment options for the disease include some off-label medications to support symptoms, but AstraZeneca’s Alexion unit provides the only FDA-approved medication for the underlying condition with Koselugo.
Patients with neurofibromatosis type 1 have an option for treatment: AstraZeneca’s Koselugo. BAstraZenecadifficult 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 reneurofibromatosis type 1inib achieved a 52% response raAstraZenecatric patients with NF1 who have plexiform neurofibromas in the SpringWorks Therapeuticscording 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 disordermirdametinibutations to the NF1 gene, which encodes for a key suppresNF1 of the MAplexiform neurofibromasfibromin. 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 rispain 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 tNF1cally diagnosed in the first two decades of life.MAPKe of the tumors neurofibromind surgically, but not always, leaving a need for therapeutic options.tumorcognitive impairmentNF1plexiform neurofibromastumorspain
NF1atments for the disease include some off-label medications to address symptoms, but AstraZeneca’s Alexion unit provides tumorsly 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 preventAstraZenecafrom 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 withNF1 important.
Koselugoinib is an oral small-molecule MEK inhibitor that is designed to inhibit MEK1 and MEK2 in the MAPK pathway. This key sigSpringWorksork regulates cell growth and survival and plays a role in oncoloNF1and rare diseases such as NF1 when it's genetically altered.
Mirdametinibl Officer Jim Cassidy, M.D.MEKh.D., said mirdametinib demonstrated a MEK1-in-cMEK2 responsMAPK the pediatric population and a first-in-class response among adults. The median duration of treatment in the pediatric group wNF122 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 fomirdametinibe 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.mirdametinib
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 raSpringWorks more discontinuations in the adult arm of the trial, mirdametinib patients stop treatment, compared to five in the pediatric group. SpringWorks implemented a protocorashendment with supportive care MEKer the initial cases of rash were seen, which later cut down on the number of discontinuations in the adult group.
“I srashespoint 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 rashapy 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 rerash 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 diarrheaThacneervomitingan orheadacheg 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.rashesacne
Koselugo notched $208 million in sales for AstraZeneca for 2022. Analysts were keen to hear how SpringWFDAs might break into that market with mirdametinib.
Chief Operating Officer Badreddin Edris, PhAstraZenecaere are 100,000 NF1 patients in the U.S. right now, and 40,000 have NF1-PN.mirdametinib
“This is a lifelong disease. Many patients require active treatment atNF1me point during their treatment journey,” Edris sNF1-PNatients 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.”
Edris also noted that the biotech was able to rapidly enroll the ReNeu trial despimirdametinibbeing Koselugoarket, which supports the claim that there is an unaddreAlexiontient population.
“The fact that [Koselugo] is on market, we do not believe is going to be a meaningfulKoselugo 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.”
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