Sodium Dichloroacetate

Taylor Tieden for BioSpace The FDA in September issued two rejections for spinal muscular atrophy therapies—both linked to manufacturing problems—and granted approvals in Barth syndrome and for a subcutaneous version of Merck’s Keytruda that could be key to the blockbuster’s future earnings. September was a busy month for the FDA, which issued a key approval for Merck’s Keytruda, one that should help the pharma shore up its sales as the blockbuster’s loss of exclusivity approaches. The regulator also approved Eli Lilly’s oral SERD Inluriyo for patients with certain types of breast cancer. Meanwhile, the rare disease space saw key approvals in Barth syndrome and acromegaly but suffered two rejections linked to manufacturing problems. Read below for more. Stealth’s Long Barth Syndrome Journey Ends in Approval After more than a decade of research and regulatory discussions, Stealth BioTherapeutics on Sept. 19 finally secured FDA approval of its Barth syndrome therapy elamipretide, now to be marketed under the brand name Forzinity. Barth syndrome is an ultra-rare, mitochondrial disease affecting around 150 patients in the U.S. The disease is characterized by cardiac problems, including heart failure, muscle weakness, fatigue, recurrent infections and delayed growth. Many patients don’t survive past the age of 5 years. Forzinity targets an important molecule in the mitochondria, in turn boosting its activity and generating cellular energy to maintain healthy organ function. But Forzinity’s path to approval was anything but smooth. In May, the FDA rejected the drug after it failed in a mid-stage study to demonstrate significant improvements in fatigue and motor skills versus placebo. Alongside the rejection, however, the FDA proposed that Stealth use the accelerated pathway to seek approval for the drug. The biotech refiled last month , using an intermediate endpoint as the main basis for accelerated approval. Forzinity’s approval covers patients weighing at least 30 kg, while leaving out children under the age of 5, who are often the most severely afflicted by Barth syndrome. Stealth’s Phase II TAZPOWER trial, on which the approval was based, only tested the drug in patients 12 years and older. Merck Wins Nod for Subcutaneous Keytruda as LOE Approaches The FDA on Sept. 19 approved a subcutaneous version of Merck’s blockbuster immunotherapy Keytruda, handing the pharma a win that could help it reinforce sales when the drug loses exclusivity in 2028. The under-the-skin injection, which will carry the brand name Keytruda Qlex, is approved for “most” of the solid tumor indications as the intravenous version, Merck announced at the time of the approval. All told, Keytruda Qlex is approved for 38 cancers. The company expects to have the subcutaneous injection available in late September. Merck has not revealed the price point for Keytruda Qlex, though a spokesperson told Endpoints News on Sept. 19 that it will be priced “at parity” to the intravenous version. According to Merck’s website , a three-week course of Keytruda costs almost $11,800. In 2023 and 2024 , Keytruda was the world’s top-selling pharmaceutical product, with earnings of $25 billion and $29.5 billion , respectively. But analysts have warned of a sales dip in the near future, particularly as key patent protections expire in 2028, making the mega-blockbuster therapy susceptible to challenge from biosimilars. Keytruda Qlex is a significant part of Merck’s efforts to soften the fall from this patent cliff. In approving the subcutaneous version, the FDA reviewed data comparing both formulations. A pivotal study found a 45% overall response rate in non-small cell lung cancer patients treated with Keytruda Qlex versus 42% in those given the original Keytruda. Progression-free and overall survival rates were likewise similar between the two formulations. Takeda Pushes Vonvendi Into Common Bleeding Disorder On Sept. 5, the FDA signed off on the use of Takeda’s Vonvendi for the routine prophylaxis of adults with von Willebrand Disease (VWD), helping reduce the frequency of bleeding episodes in those with type 1 and type 2 disease. The approval also allows the use of Vonvendi for the on-demand perioperative management of bleeding in pediatric patients with VWD. According to Takeda, Vonvendi is the only recombinant von Willebrand Factor replacement therapy indicated for both adults and children with VWD. Afflicting more than 3 million people in the U.S., VWD is a bleeding disorder characterized by life-threatening episodes, prolonged nosebleeds and easy bruising, among other symptoms, which can greatly compromise patients’ quality of life. The disease is linked to low levels of VWF, a key protein involved in clotting. Vonvendi addresses this deficiency by replacing missing or dysfunctional VWF. Data from three late-stage studies “showed success in treatment control of bleeding episodes” in patients of all ages, according to the FDA’s announcement of the approval . As for safety, Vonvendi’s most common adverse events included nausea, vomiting, dizziness and generalized itchiness, according to the regulator. Before this label expansion, Vonvendi was only indicated as a perioperative on-demand therapy for bleeding episodes in adult patients, and as a preventive option only in adults with type 3 VWD, the most serious form of the disease. FDA Clears J&J’s Drug-Device Combo for Bladder Cancer Johnson & Johnson notched a regulatory victory for its drug-device combo Inlexzo for certain types of bladder cancer on Sept. 9. The FDA approved the use of Inlexzo for patients with non-muscle invasive bladder cancer with carcinoma in situ who are unresponsive to Bacillus Calmette-Guérin treatment. Inlexzo can be used regardless of the presence of papillary tumors. According to J&J, Inlexzo is the first and so far only intravesical drug-releasing system that delivers an anti-cancer therapy locally into the bladder. The approval was backed by results from the Phase IIb SunRISe-1 study, in which Inlexzo elicited an 82.4% complete response rate , according to an April readout. At one year, 52.9% of treatment responders were able to maintain undetectable levels of cancer, demonstrating what the pharma at the time called “sustained disease control.” The median duration of response was 25.8 months. In its news release announcing the approval, J&J emphasized that Inlexzo is for patients who want to preserve their bladders. The drug-device product comes with a urinary catheter and stylet to facilitate its insertion into the bladder. The procedure can be performed by a healthcare professional in the outpatient setting without the need for general anesthesia. There is no need for patients to be monitored in the doctor’s office after insertion. Cortasis’ Gets Go-Ahead for Nasal Spray Loop Diuretic The FDA on Sept. 16 signed off on Corstasis Therapeutics’ Enbumyst, the first intranasal loop diuretic indicated for edema in patients with congestive heart failure, as well as hepatic and renal disease. The company expects to make the nasal spray available in the fourth quarter. Enbumyst’s new drug application, which the FDA accepted in January , was backed by data from a clinical trial that compared the absorption of bumetanide—the spray’s active ingredient—when given intranasally versus orally and intravenously. Results, presented last November at the American Heart Association’s 2024 Scientific Sessions, showed the nasal spray formulation could reach comparable blood level concentrations as its oral and intravenous comparators. Variability in absorption was 27% for both the intranasal and intravenous formulations, versus 40% when given orally. This suggests that bumetanide is more stably administered via a nasal spray or an infusion. According to Corstasis’ press announcement of the approval, the fluid overload is responsible for more than 1 million hospitalizations per year. Oral loop diuretics are effective but can be limited by poor absorption in the gut and delayed onset, while intravenous diuretics require the patient to be in a hospital or infusion center. Enbumyst, meanwhile, is self-administered in the outpatient setting. Saol’s Ultra-Rare Disease Drug Runs into Regulatory Roadblock The FDA on Sept. 8 rejected Saol Therapeutics’ application for SL1009, which the company was proposing for the treatment of pyruvate dehydrogenase complex deficiency (PDCD), an ultra-rare mitochondrial disease in children. Saol did not reveal the regulator’s reasons for the rejection, only stating that the complete response letter detailed “specific observations” that the privately held biotech “will need to address to clarify the path forward.” The company hinted, however, that it may not have the ability to resolve the issues. “To address the deficiencies as the FDA requested, it would take several years and require significant financial resources,” Saol wrote in its announcement . Currently, the biotech is working with the FDA to find a way forward for SL1009 “that does not require an additional trial.” The rejection came as a “ deep disappointment ” to the United Mitochondrial Disease Foundation, a nonprofit pushing for diagnosis, treatment and cure of mitochondrial diseases. “While we fully support rigorous scientific standards, regulatory flexibility is essential for rare disease populations” like PDCD, the group wrote in an open letter. PDCD is characterized by the toxic buildup of lactic acid in the body, resulting in what Saol calls “overwhelming health challenges.” These include nausea, vomiting, severe breathing problems, neurological impairments and an abnormal heartbeat. Most patients with PDCD do not survive beyond early childhood. There are no approved treatments for the disease. Spinal Muscular Atrophy Space Hit With Two Rejections Scholar Rock’s Apitegromab Sept. 23 was a difficult day for the spinal muscular atrophy community. First, the FDA rejected Scholar Rock’s apitegromab, an investigational myostatin blocker, due to issues at a third-party manufacturer. In particular, the regulator flagged “observations” during a routine inspection at Catalent Indiana LLC, a fill-finish site that was acquired by Novo Nordisk in December last year . “The observations are not specific to apitegromab,” Scholar Rock said in a news release on Tuesday, adding that the FDA “did not cite any other approvability concerns,” including problems with efficacy or safety. Scholar Rock is working closely with Catalent Indiana regarding the FDA’s observations, building up to a resubmission “as soon as possible,” CEO David Hallal said in the company’s announcement. The biotech has not yet provided specific timing for its resubmission. The rejection did not come as a surprise to BMO Capital Markets. In a note to investors, BMO analysts said the FDA’s decision was “in line with our expectations,” nevertheless noting that the uncertain timing of Scholar Rock’s refiling “could create more downside” to the company’s shares. Still, the lack of issues with apitegromab’s data package is a “mild positive” for Scholar Rock, BMO added, writing that this could “mitigate further concerns” surrounding the rejection. To support its application for apitegromab, Scholar Rock filed data from the Phase III SAPPHIRE study, which in October 2024 demonstrated a significant improvement in motor function. Benefits were apparent as early as eight weeks and further improved through 52 weeks of follow-up, the company said at the time. Biogen’s High-Dose Spinraza The same day, the FDA denied approval for a higher-dose formulation of Biogen’s antisense oligonucleotide Spinraza for spinal muscular atrophy. Biogen’s rejection was likewise linked to manufacturing concerns. In its news release on Sept. 23, the company noted that the regulator asked for updated technical information in the chemistry manufacturing and controls portion of the application. The FDA did not identify problems with Biogen’s clinical data package for high-dose Spinraza (nusinersen). The company is working to address the agency’s requests and plans to re application “promptly,” according to the press announcement. “Given the limited scope of updates required and lack of efficacy concerns raised, we see no true concerns to high-dose nusinersen’s ultimate approval,” analysts at BMO Capital Markets told investors in a Sept. 23 note, adding that the FDA’s issues pose a “quickly resolvable setback” for Biogen. Spinraza ’s active ingredient is the antisense oligonucleotide nusinersen, which works by promoting the production of the SMN protein, which is typically deficient in patients with spinal muscular atrophy. The drug was approved in 2016 for this condition, though its current regimen involves a 12-mg dose with an induction schedule involving four loading doses. Biogen’s proposed higher-dose formulation uses two 50-mg intrathecal injections for initiation, followed by 28-mg maintenance doses. Data from the Phase II/III DEVOTE study showed that the investigational formulation of Spinraza elicited significantly higher improvements in motor skills as compared with a sham control. Higher-dose Spinraza also outperformed the standard-dose formulation, though the effect fell short of significance.

iStock, leolintang After receiving a complete response letter for its pyruvate dehydrogenase complex deficiency candidate, Saol Therapeutics anticipates it will need “several years” and “significant financial resources” to address the FDA’s concerns. The FDA has rejected Saol Therapeutics’ application for SL1009, which it was proposing for the treatment of pyruvate dehydrogenase complex deficiency, an ultra-rare mitochondrial disease in children. Saol did not reveal the regulator’s reasons for the rejection, only announcing that the Complete Response Letter detailed “specific observations” that the privately held biotech “will need to address to clarify the path forward.” The FDA’s findings and recommendations for resolution could prove too burdensome for Saol. “To address the deficiencies as the FDA requested, it would take several years and require significant financial resources,” the company wrote on Monday. Currently, Saol is working with the FDA to find a way forward for SL1009 “that does not require an additional trial,” as per its announcement . Affecting less than 1,000 patients in the U.S. and occurring in about 90 births per year, pyruvate dehydrogenase complex deficiency (PDCD) is characterized by the toxic buildup of lactic acid in the body, resulting in what Saol calls “overwhelming health challenges.” These include nausea, vomiting, severe breathing problems, neurological impairments and an abnormal heartbeat. Most patients with PDCD do not live beyond early childhood. There are no approved treatments for the disease. Saol’s SL1009 is an oral formulation of sodium dichloroacetate that had previously won the FDA’s orphan drug, rare pediatric disease and priority review designations for PDCD. The drug is designed to be used with a proprietary genetic test. In a statement on Friday, days before Saol’s formal announcement of the CRL, the United Mitochondrial Disease, a nonprofit pushing for diagnosis, treatment and cure of mitochondrial diseases, released an open letter to express its “ deep disappointment ” with the FDA’s rejection. The decision, according to the group, could delay access to life-saving therapies, in turn leading to “irreversible damage – or even death.” “While we fully support rigorous scientific standards, regulatory flexibility is essential for rare disease populations like PDCD,” the open letter read. Other patient advocacy groups, including MitoAction, Cure Mito Foundation, Hope for PDCD and the Elizabeth Watt PDCD Research Fund, also signed the letter. Monday’s PDCD rejection comes after a standout month for the rare disease space, which in August secured four regulatory firsts . Jazz Pharmaceuticals’ Modeyso , for instance, became the industry’s first drug for diffuse midline glioma with an H3 K27M mutation. Then, Insmed’s Brinsupri secured the FDA’s first approval for non-cystic fibrosis bronchiectasis—and also became the first therapy that blocks the DPP1 enzyme. Last month, Precigen’s Papzimeos likewise became the “ first-of-its-kind ” non-replicating immunotherapy for recurrent respiratory papillomatosis. Finally, Ionis’ Dawnzera secured the industry’s first RNA-targeting prophylactic nod for hereditary angioedema.