Hepatorenal Form of Glycogen Storage Disease

Stéphane Bancel has relented to Wall Street’s desire for cost-cutting and reining in Moderna’s pipeline. To kick off its annual R&D day in New York, Moderna said Thursday that it will slash its annual spending on research and development by $1.1 billion by 2027. The biotech will also stop developing five early-stage programs, place other drugs on the backburner and focus on a handful of late-stage mRNA medicines. Simultaneously, Moderna overhauled its long-term financial projections, and it now forecasts the company’s break-even point in 2028 instead of 2026. The shake-up will not include major layoffs, Bancel told Endpoints News , and he envisions the company staying around its 6,000-employee headcount for the next three to five years. “It’s a moment of evolution, in the sense the platform is working, which is the most important thing,” Bancel said. “We just want to be responsible and financially disciplined.” The new measures are the latest in Moderna’s attempt to diversify beyond the Covid-19 vaccine that supercharged its growth over the past few years and is one of only two approved products. Like Pfizer and BioNTech, Moderna has struggled to predict the Covid shot market through the transition from pandemic to endemic. Moderna’s stock price $MRNA has fallen over 80% over the past three years, erasing about $150 billion in market value from its all-time, pandemic-tinged highs. Several Wall Street analysts have recently argued significant cost cuts could help turn around the biotech’s fortunes. The changes are the result of a summer tradition at Moderna. Each year, leadership and the board review different scenario-based five-year plans for the company, Bancel said. This year’s plan provides cost-cutting concessions desired by some investors, but not large enough to achieve a previously stated forecast of breaking even by 2026. The company is now targeting 2028 to break even on an operational basis, excluding stock-based compensation, depreciation and amortization expenses. Bancel said the summer review considered more drastic cuts that could achieve break-even by 2026, but they determined these weren’t the right steps in creating value. “The scenario of cutting for the sake of cutting to drive profitability we think was destroying enormous amounts of shareholder value and also being the wrong outcome for patients,” he said. He highlighted the company’s norovirus vaccine candidate as an example. Moderna said Thursday it will “imminently” launch a pivotal Phase 3 study for the shot. Bancel said comparable studies cost between $600 million and $700 million, and he would expect to proceed to regulatory filing in roughly two years. On the day of launch, he estimated that the vaccine would be worth $5 billion to $10 billion, calling that a “pretty nice return.” “That’s what investors want us to do more than being profitable next week but not creating the return,” he said. The cuts will slash Moderna’s R&D spending by about 20% from 2025 to 2028, from a total of $20 billion to $16 billion. The biotech also said its expected R&D spending this year is now $4.8 billion, up from $4.5 billion. The focus will be 10 product launches by the end of 2027, including vaccines for Covid, flu, RSV, norovirus, and cytomegalovirus, or CMV. Moderna said Thursday its RSV vaccine succeeded in a Phase 3 study in high-risk younger adults, and it plans to apply to expand its approval into that population this year. The company expects to use a priority review voucher to shorten the review timeline. So far, Moderna has struggled to gain commercial traction with its RSV vaccine, called mResvia, in an intensely and newly competitive market with rival shots sold by GSK and Pfizer. “We should have done a better job planning and forecasting,” Bancel said on the disappointing RSV launch. “We were a bit naïve that because a product is coming in the middle of season, [we thought] customers were going to wait for us.” Other prioritized programs include two rare-disease therapies and a Merck-partnered cancer vaccine program. That cancer vaccine, mRNA-4157, has become a key investor focus following positive mid-stage results in melanoma . Moderna said Thursday that initial FDA feedback “has not been supportive of accelerated approval based on the current data.” A Phase 3 melanoma study is now “substantially enrolled,” although Moderna did not provide timing on a potential readout. Moderna is pumping the brakes on developing vaccine candidates against the Epstein-Barr virus and the varicella-zoster virus. Both shots had been advancing toward Phase 3 studies . “We’re not saying we will never develop them,” Bancel said, noting the company could resume development if sales accelerate or it strikes a deal with a pharma company. But their near-term future remains uncertain. Moderna is also stopping five early-stage programs: In addition, Moderna’s ambitions in rare disease will be dialed back. Bancel said programs against conditions like glycogen storage disease type 1a, ornithine transcarbamylase deficiency, and phenylketonuria have a future at his company, but not as part of this next wave of anticipated approvals. “They are being put on the back burner,” he said, adding they will keep providing the drugs to people in ongoing studies but aren’t enrolling additional patients or expanding those trials. “We’re not increasing investment as we could on those programs because of the clinical signal we are seeing, [but] because we just have to pace ourselves.”

Methylmalonic acidemia, or MMA, is a genetic liver condition that in most cases is caused by a deficiency in an enzyme called MUT. Moderna’s methylmalonic acidemia candidate, mRNA-3705, will be developed under the FDA’s START pilot program for rare disease, the company announced June 6. It joins therapies from Denali Therapeutics, Neurogene, Grace Sciences and Larimar Therapeutics in the initiative, which aims to do for rare disease drugs what Operation Warp Speed did for the COVID-19 vaccines. Methylmalonic acidemia, or MMA, is a genetic liver condition that in most cases is caused by a deficiency in an enzyme called MUT, which processes fatty acids. Without it, the acids build up and damage organs. The disease is usually diagnosed within the first few months of life, and there are currently no treatments. MRNA-3705 is an mRNA-based drug that encodes MUT, thereby restoring acid metabolism. It has orphan-drug, fast-track and rare pediatric disease designations from the FDA and is currently being tested in a 63-subject, phase 1/2 clinical trial.  Under START, mRNA-2705 will get extra attention from FDA officials, who will guide Moderna through product development issues like designing studies, choosing control groups and selecting the right patient population. The effort is being carried out by the agency’s Center for Biologics Evaluation and Research and the Center for Drug Evaluation and Research, which is selecting six participants total for the first iteration of the program, according to a September 2023 announcement from the FDA.  “This selection highlights the promise of Moderna’s innovative mRNA platform beyond vaccines and the potential this novel medicine may have in addressing the serious and unmet medical needs of MMA,” Kyle Holen, M.D., senior vice president and head of development in the therapeutics and oncology unit at Moderna, said in a press release. “Selection for this program will…[result] in acceleration of our development program as we prepare for pivotal study initiation for mRNA-3705 in 2024.” Moderna's other rare disease programs include drugs for propionic acidemia, glycogen storage disorder type 1a, ornithine transcarbamylase deficiency, phenylketonuria, Crigler-Najjar syndrome type 1 and cystic fibrosis. Also picked for the START program is Calico Life Sciences' eIF2B activator fosigotifator, which is under development for Vanishing White Matter disease. The condition is an ultra-rare disease of the brain's white matter caused by variations in an essential enzyme in the cells called eIF2B. This causes a reduction in enzymatic activity that can lead to chronic activation of the integrated stress response.  This causes the white matter to degenerate, causing symptoms such as impaired muscle movement, cognitive decline and seizures. Patients have a shortened life span.  Fosigotifator is being developed in a partnership between Calico and AbbVie through an agreement signed in 2014. 

Treatment with DTX401 resulted in a statistically significant reduction in daily cornstarch intake at Week 48 (p Company will host investor call today at 5:00 p.m. ET May 30, 2024 -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) today announced positive topline results from the Phase 3 GlucoGene study (NCT05139316) evaluating DTX401, an investigational gene therapy for the treatment of patients aged eight years and older with glycogen storage disease type Ia (GSDIa). The study achieved its primary endpoint, demonstrating that treatment with DTX401 resulted in a statistically significant and clinically meaningful reduction in daily cornstarch intake compared with placebo at Week 48. The mean percent reduction was 41.3% in the DTX401 group (n=20) compared with 10.3% in the placebo group (n=24) at Week 48 (p “This is an incredible milestone for the DTX401 program. These clinically important and statistically significant results are consistent with our Phase 1/2 findings, and the continued improvement in these treated patients reflects the acquired ability to break down glycogen as a source of endogenous glucose from their treated livers,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “We want to thank the patients, families and treating community for their ongoing participation in this study and their support of progress for the broader GSDIa community.” The study also successfully met key secondary endpoints of reduction in the number of cornstarch doses per day and maintenance of glucose control at Week 48. Treatment with DTX401 resulted in a mean reduction of 1.1 cornstarch doses per day in the DTX401 treatment group compared with a mean reduction of 0.2 in the placebo group (p=0.0011). Patients in the DTX401 group also showed significant improvement in both frequency and quantity of nighttime cornstarch dosing compared with the placebo group. This blinded study established non-inferiority (p The Patient Global Impression of Change (PGIC) at Week 48 showed a median score of 2.0 (moderately improved) for the DTX401 treatment group and 1.0 (minimally improved) for the placebo group (p=0.132). Moderately or higher improved PGIC scores correlated with a ≥30% reduction in total daily cornstarch intake indicating that this is a clinically meaningful threshold for patients. “With these Phase 3 results, the significant reduction in cornstarch intake with continued management of glucose control has the potential to offer meaningful benefit to patients while improving their quality of life on a daily basis,” stated Rebecca Riba-Wolman, M.D., director of the Glycogen Storage Disease Program & Disorders of Hypoglycemia at Connecticut Children’s Medical Center/University of Connecticut Medical School and study investigator. “GSDIa is a disease that never takes a break, where you must constantly think about your own, or your child's, safety and risk of severe low blood sugar and acidosis throughout the day and especially at night. A treatment that can improve these daily concerns for people with GSDIa without significant risks is essential.” The study demonstrated an acceptable and expected safety profile for DTX401 consistent with Phase 1/2 study results. Anticipated vector-induced hepatic effects were all non-serious and manageable with a prophylactic corticosteroid regimen. No AAV8 class effects of dorsal root ganglion toxicity or thrombotic microangiopathy were observed in the study through Week 48. Full 48 Week data from the Phase 3 study will be presented at a scientific conference later this year. These results will be discussed with regulatory authorities to support a marketing application in 2025. Ultragenyx recently presented long-term DTX401 Phase 1/2 data demonstrating durable response, with sustained, clinically meaningful reductions in cornstarch lasting up to 5 years in patients treated with open-label DTX401 as of the data cut-off. All 12 patients in the study have been followed for an average of 4 years and continue to demonstrate improved glucose control, with a mean total daily reduction of cornstarch intake of 72% (p<0.0001) from baseline to their last available timepoint. The 48-week randomized, double-blind, placebo-controlled study treated 46 patients aged eight years and older with DTX401 (1.0 x 10^13 GC/kg dose measured by ddPCR) or placebo. There were 44 patients in the modified intention-to-treat (mITT) population with efficacy data within the Week 48 analysis period following treatment with DTX401 (n=20) or placebo (n=24). At Week 48, eligible patients crossed over and received the alternate treatment. After crossover, patients will be followed for an additional 96 weeks. After study completion, patients will be offered enrollment into a Disease Monitoring Program (DMP) where they will be followed for at least 10 years post-DTX401 infusion. GSDIa is a serious inherited glycogen storage disease. It is caused by a defective gene coding for the enzyme G6Pase-α, resulting in the inability to regulate blood sugar (glucose). Hypoglycemia in patients with GSDIa can be life-threatening, while the accumulation of the complex sugar glycogen in certain organs and tissues can impair the ability of these tissues to function normally. If chronically untreated, patients can develop severe lactic acidosis, progress to renal failure, and potentially die in infancy or childhood. There are no approved pharmacologic therapies. An estimated 6,000 patients worldwide are affected by GSDIa. DTX401 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase-α under control of the native promoter to allow the treated liver cells to respond to normal hormonal signals intended to manage glucose, including insulin, glucagon and cortisol. DTX401 is administered as a single intravenous infusion and has been shown in preclinical studies to improve G6Pase-α activity and reduce hepatic glycogen levels, a well-described biomarker of disease progression. DTX401 has been granted orphan drug designation, regenerative medicine advanced therapy (RMAT) designation and Fast Track designation from the U.S. FDA, as well as PRIority MEdicines (PRIME) and orphan drug designation from the European Medicines Agency. Ultragenyx is a biopharmaceutical company committed to bringing novel products to patients for the treatment of serious rare and ultrarare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease. The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency. The content above comes from the network. if any infringement, please contact us to modify.