Aromatic Amino Acid Decarboxylase Deficiency

It's not a well-known disease. But transthyretin amyloidosis cardiomyopathy, a rare condition affecting the heart, has become the target of a major drug development effort.One medicine, from Pfizer, is approved and two others, from BridgeBio Pharma and Alnylam Pharmaceuticals, have succeeded in late-stage testing. Deciding which offers the greatest benefit has consumed analysts on Wall Street and top experts in the field. At stake is a market worth billions of dollars.By Thanksgiving, the Food and Drug Administration is expected to decide on approval of BridgeBio's acoramidis, likely kicking off a new phase in the debate. The agency is also set to reach verdicts this quarter on important drugs from AstraZeneca, Vertex Pharmaceuticals, Bristol Myers Squibb and PTC Therapeutics. Here are five FDA decisions to watch:BridgeBios acoramidis for transthyretin amyloidosis cardiomyopathyRarely do biotechnology companies rebound from lackluster Phase 3 trial results. But BridgeBio Pharma did exactly that with acoramidis in transthyretin amyloidosis cardiomyopathy.Like Pfizers Vyndamax the only available treatment and a multibillion-dollar seller acoramidis is supposed to stop a protein implicated in the disease from misfolding. Preclinical data suggested it did so more effectively than Vyndamax, raising expectations it might be superior.But BridgeBio had difficulty proving its case. In 2021, the drug missed the first of two main Phase 3 study goals when people who received a placebo performed better on a walking test than past results suggested. BridgeBio attributed that result, in part, to the better all-around care people with the disease now receive, which in turn means studies may have to run longer to detect a benefit.The company was proven right in 2023, as acoramidis extended lives and kept people out of the hospital in that same trial the type of outcome that led to Vyndamaxs U.S. approval.Acoramidis is now on the verge of joining Vyndamax on the U.S. market, should regulators clear it by a Nov. 29 deadline. If approved, treating physicians could soon be left with difficult decisions to make, as its unclear whether acoramidis is more effective than Vyndamax or a rival therapy from Alnylam Pharmaceuticals the FDA could soon be evaluating. Ben FidlerAstraZeneca and Daiichi Sankyos dato-dxd for lung cancerAstraZeneca and Daiichi Sankyo already have one breakout success in Enhertu, a drug the companies teamed up to develop and that has since changed how certain breast cancers are treated. Their chances at another, with a similar type of drug called datopotamab deruxtecan, could hinge on the outcome of an FDA review due to wrap up by Dec. 20.Like Enhertu, dato-dxd is a targeted medicine known as an antibody-drug conjugate. And as with Enhertu, the partners hope to prove the drug can supplant chemotherapy in multiple cancer settings.But Enhertu has succeeded in a variety of different clinical trials, in some cases producing dramatic benefits. Dato-dxds case to regulators is less straightforward.AstraZeneca and Daiichi originally intended to bring the drug to market for all people whose non-small cell lung cancers express a protein, TROP2, that it targets. But while dato-dxd delayed tumor progression compared to chemotherapy, it didnt meaningfully extend survival. It was later associated with a numerical, but not statistically significant improvement when the companies zeroed in on people with nonsquamous tumors, whom the partners expected to benefit the most.AstraZeneca and Daiichi are now aiming for an approval in nonsquamous non-small cell lung tumors specifically. Theyve also been working to better identify responders to strengthen their case for a drug analysts have projected as a future blockbuster. But the survival findings make us suspicious about a straight approval, and could portend a delayed decision and advisory committee meeting, wrote Stifel analyst Eric Le Berrigaud in a research note last month. Ben FidlerVertexs vanza triple for cystic fibrosisSince 2012, Vertex Pharmaceuticals has won U.S. approvals for four cystic fibrosis medicines, making the lung condition manageable for thousands of people. Along the way, Vertex has turned into one of the industry's most valuable companies and is now worth $120 billion.Vertex could expand its cystic fibrosis franchise further if the FDA decides to approve a combination treatment regimen known as “vanza triple.“ The FDA's deadline is Jan. 2, 2025, but the agency sometimes issues decisions early.Like Vertex's current top-seller Trikafta, the vanza triple uses a compound called tezacaftor as its backbone. But the experimental drug replaces Trikafta's two other components with newer versions the company developed.In testing, the vanza triple was found to be “non-inferior“ to Trikafta on a measure of lung function commonly used in cystic fibrosis studies. It also proved superior to Trikafta on a secondary measure of sweat chloride, which is associated with the function of proteins that are mutated in people with the disease.If approved, the vanza triple would offer patients the convenience of once-daily treatment, rather than the twice-daily dosing of Trikafta. And because it contains two newer compounds, Vertex would owe a lower rate of royalty payments than it does selling Trikafta.Vertex could also enjoy longer patent protection on the vanza triple than for Trikafta, which is covered through 2037 in the U.S. Ned PagliaruloPTC's Upstaza for AADC deficiencyOftentimes, the FDA moves ahead of its regulatory counterparts around the world, approving drugs for the U.S. before they're available elsewhere.That pattern flipped for a gene therapy PTC Therapeutics is developing for a rare genetic nervous system disorder known as AADC deficiency. In May 2022, the European Medicines Agency recommended the therapy, called Upstaza, for authorization, which the European Commission granted later that year.But the regulatory process has taken longer in the U.S., where the FDA has gone back and forth with PTC over data intended to demonstrate the comparability of clinical and commercial drug product. The company could finally have its answer by Nov. 13, when the agency is set to decide on approval.An approval would add Upstaza to a lengthening list of approved gene therapies for inherited diseases. But few have been commercial successes, putting pressure on biotech developers like PTC to prove they can profitably manufacture and sell the complex treatments. So far in Europe, PTC has not generated significant revenue from Upstaza. Ned PagliaruloBristol Myers subcutaneous Opdivo for solid tumorsBristol Myers Squibb has earned tens of billions of dollars from its cancer immunotherapy Opdivo since an initial approval a decade ago. But that revenue could dry up within years, as the expiry of a key U.S. patent in 2028 will pave the way for biosimilar competitors. One way Bristol Myers could protect its profits is by bringing a new version of Opdivo to market. That could happen by Dec. 29, when the FDA is expected to issue a verdict on an Opdivo formulation administered via an under-the-skin injection.Subcutaneous Opdivo is the product of a partnership between Bristol Myers and drug delivery specialist Halozyme. The alliance involves a Halozyme technology capable of making a more convenient version of Opdivo, which is typically given through an intravenous infusion lasting 30 minutes. Other drugmakers, among them Johnson & Johnson and Argenx, have worked with Halozyme for similar reasons. So has Roche, which got Halozymes help in making a subcutaneous version of the immunotherapy Tecentriq the FDA approved last month.Bristol Myers and Merck & Co. are trying to catch up. Merck has a formulation of its drug Keytruda currently in late-stage testing, and initial study results could be coming soon, according to a federal database. Bristol Myers is closer, having already proven its under-the-skin Opdivo is statistically non-inferior to the marketed version. Approval would make the newer version available for all the tumors original Opdivo is cleared to treat.Preserving Opdivos revenue is an essential part of Bristol Myers near-term strategy. The companys top seller, the blood thinner Eliquis, will lose market exclusivity in 2026 and faces pricing pressure from Medicare. Jonathan Gardner '

PTC Therapeutics has suffered multiple rejections of its Duchenne muscular dystrophy drug at the FDA but will try for approval again after receiving "recent feedback" from the agency. Despite Translarna's troubled history at the FDA—and a recent regulatory stumble in Europe—PTC Therapeutics once again hopes to convince U.S. regulators of the value of its Duchenne muscular dystrophy (DMD) therapy. Tuesday, the company revealed that it plans to resubmit Translarna to the FDA for the treatment of nonsense mutation DMD by the middle of the year. The decision is based on "recent feedback" and comes after FDA rejections of the drug in 2016 and 2017. In its first rejection of the drug, the FDA told the company the application wasn't sufficiently complete. In the second rejection, the agency raised flags about a lack of clinical evidence and other shortfalls in PTC's filing. More recently, European regulators in January issued a negative opinion on renewing the DMD drug's authorization nearly a decade after its debut there. That decision came after a negative recommendation in September 2023 and a multi-month appeal process. At the time of the latest decision, PTC CEO Matthew Klein said the developments "will result in the withdrawal" of Translarna in Europe. In deciding against renewing the drug's authorization, Europe's Committee for Medicinal Products for Human Use looked at Translarna’s data from the placebo-controlled Study 041, plus other trials. In Study 041, the PTC drug failed to meet statistical significance on its primary endpoint in a selected patient subgroup, but it did turn in "nominally statistically significant results on several key endpoints," the company argued. The study's primary endpoint looked at changes from baseline in a six-minute walking distance test. Even as PTC stood behind the medicine, the European Medicines Agency stated bluntly that the study "failed to confirm Translarna's effectiveness." After the Study 041 results dropped, the FDA told the company that the new trial doesn't provide enough evidence of benefit to support a resubmission, according to a PTC quarterly filing from last year. In response, PTC said it would request a meeting with the agency "to review the “totality of data collected to date." On a recent conference call, Klein said the company had a meeting scheduled for this month with the agency. Besides the Translarna development, PTC on Tuesday said it has submitted a biologics license application for Upstaza to treat aromatic L-amino acid decarboxylase deficiency to the FDA. 

- BLA submitted to FDA for Upstaza™ for the treatment of AADC deficiency - - NDA to be submitted mid-year for Translarna™ based on FDA feedback - SOUTH PLAINFIELD, N.J., March 19, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) today announced the submission of a BLA to the U.S. FDA for Upstaza™ (eladocagene exuparvovec), a gene therapy for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. In addition, based on recent feedback from the FDA, PTC plans to re-submit an NDA for Translarna™ (ataluren) for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). PTC expects to make the NDA resubmission by mid-year. "We are excited to bring Upstaza one step closer to children in the United States with the highly mortal and fatal disease of AADC deficiency. The data collected to date continue to demonstrate the transformative clinical benefits the gene therapy provides to patients," said Matthew B. Klein, M.D., Chief Executive Officer of PTC Therapeutics. "In addition, we look forward to the Translarna NDA resubmission this summer. We know U.S. patients and families have been waiting for an approved therapy that specially targets nmDMD." In addition, the sepiapterin MAA for PKU remains on schedule for submission to the EMA by the end of this month. About Upstaza™ (eladocagene exuparvovec) Upstaza is a one-time gene replacement therapy indicated for the treatment of patients aged 18 months and older with a clinical, molecular, and genetically confirmed diagnosis of aromatic L–amino acid decarboxylase (AADC) deficiency with a severe phenotype. It is a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy, containing the human DDC gene.1 It is designed to correct the underlying genetic defect, by delivering a functioning DDC gene directly into the putamen, increasing the AADC enzyme and restoring dopamine production.2,3 The efficacy and safety profile of Upstaza has been demonstrated across clinical trials and compassionate use programs.1 The first patient was dosed in 2010. In clinical trials, Upstaza demonstrated transformational neurological improvements. The most common side effects were initial insomnia, irritability and dyskinesia. Administration of Upstaza occurs through a stereotactic surgical procedure, a minimally invasive neurosurgical procedure used for the treatment of a number of pediatric and adult neurological disorders. The Upstaza administration procedure is performed by a qualified neurosurgeon in centers specialized in stereotactic neurosurgery. Upstaza has received marketing authorization in Europe, Great Britain and Israel. About aromatic L-amino acid decarboxylase (AADC) deficiency AADC deficiency is a fatal, rare genetic disorder that typically causes severe disability and suffering from the first months of life, affecting every aspect of life – physical, mental and behavioral. The suffering of children with AADC deficiency may be exacerbated by: episodes of distressing seizure-like oculogyric crises causing the eyes to roll up in the head, frequent vomiting, behavioral problems, and difficulty sleeping. The lives of affected children are severely impacted and shortened. Ongoing physical, occupational and speech therapy, and interventions, including surgery, also are often required to manage potentially life-threatening complications such as infections, severe feeding and breathing problems. About Translarna™ (ataluren) Translarna (ataluren), discovered and developed by PTC Therapeutics, is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as dystrophin in Duchenne. Translarna, the tradename of ataluren, is licensed in multiple countries for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD) in ambulatory patients aged 2 years and older. Ataluren is an investigational new drug in the United States. About Duchenne Muscular Dystrophy (Duchenne) Primarily affecting males, Duchenne is a rare and fatal genetic disorder that results in progressive muscle weakness from early childhood and leads to premature death in the mid-20's due to heart and respiratory failure. It is a progressive muscle disorder caused by the lack of functional dystrophin protein. Dystrophin is critical to the structural stability of all muscles, including skeletal, diaphragm, and heart muscles. Patients with Duchenne can lose the ability to walk (loss of ambulation) as early as 10 years old, followed by loss of the use of their arms. Duchenne patients subsequently experience life-threatening lung complications, requiring the need for ventilation support, and heart complications in their late teens and 20s. About PTC Therapeutics, Inc. PTC is a global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders. PTC's ability to innovate to identify new therapies and to globally commercialize products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines. PTC's mission is to provide access to best-in-class treatments for patients who have little to no treatment options. PTC's strategy is to leverage its strong scientific and clinical expertise and global commercial infrastructure to bring therapies to patients. PTC believes this allows it to maximize value for all its stakeholders. To learn more about PTC, please visit us at and follow us on Facebook, Instagram, LinkedIn and Twitter at @PTCBio. For More Information: Investors: Kylie O'Keefe +1 (908) 300-0691 [email protected] Media: Jeanine Clemente +1 (908) 912-9406 [email protected] Forward-Looking Statement This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. All statements contained in this release, other than statements of historic fact, are forward-looking statements, including statements regarding: the future expectations, plans and prospects for PTC, including with respect to the expected timing of regulatory submissions and responses, commercialization and other matters with respect to its products and product candidates; PTC's strategy, future operations, future financial position, future revenues, projected costs; the extent, timing and financial aspects of our strategic pipeline prioritization and reductions in workforce; and the objectives of management. Other forward-looking statements may be identified by the words, "guidance", "plan," "anticipate," "believe," "estimate," "expect," "intend," "may," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions. PTC's actual results, performance or achievements could differ materially from those expressed or implied by forward-looking statements it makes as a result of a variety of risks and uncertainties, including those related to: the outcome of pricing, coverage and reimbursement negotiations with third party payors for PTC's products or product candidates that PTC commercializes or may commercialize in the future; PTC's ability to use the results of Study 041, a randomized, 18-month, placebo-controlled clinical trial of Translarna for the treatment of nmDMD followed by an 18-month open-label extension, and from its international drug registry study to support a marketing approval for Translarna for the treatment of nmDMD in the United States; whether investigators agree with PTC's interpretation of the results of clinical trials and the totality of clinical data from our trials in Translarna; expectations with respect to Upstaza, including any regulatory submissions and potential approvals, commercialization, manufacturing capabilities, the potential achievement of development, regulatory and sales milestones and contingent payments that PTC may be obligated to make; significant business effects, including the effects of industry, market, economic, political or regulatory conditions; changes in tax and other laws, regulations, rates and policies; the eligible patient base and commercial potential of PTC's products and product candidates; PTC's scientific approach and general development progress; and the factors discussed in the "Risk Factors" section of PTC's most recent Annual Report on Form 10-K, as well as any updates to these risk factors filed from time to time in PTC's other filings with the SEC. You are urged to carefully consider all such factors. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. There are no guarantees that any product will receive or maintain regulatory approval in any territory, or prove to be commercially successful, including Translarna and Upstaza. The forward-looking statements contained herein represent PTC's views only as of the date of this press release and PTC does not undertake or plan to update or revise any such forward-looking statements to reflect actual results or changes in plans, prospects, assumptions, estimates or projections, or other circumstances occurring after the date of this press release except as required by law. Acronyms: BLA: Biologics License Application DMD: Duchenne Muscular Dystrophy EMA: European Medicines Agency FDA: U.S. Food and Drug Administration MAA: Marketing Authorization Application NDA: New Drug Application PKU: Phenylketonuria References: Tai CH, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022;30(2):509-518. Chien et al. AGIL-AADC gene therapy results in sustained improvements in motor and developmental milestones through 5 years in children with AADC deficiency. Poster presented at the 48th Annual Meeting of the Child Neurology Society, Charlotte, NC, USA, Oct 23-26, 2019. Chien YH, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. 2017;1(4):265-273. SOURCE PTC Therapeutics, Inc.