Specific enzyme deficiency (disorder)

Takeda Pharmaceutical is stocking up its rare disease drug pipeline, reaching a deal for global rights to a Protagonist Therapeutics drug in late-stage development for the treatment of the rare blood disorder polycythemia vera. Under deal terms announced Thursday, Takeda is paying $300 million up front to share in the development of the drug, rusfertide. Newark, California-based Protagonist remains responsible for completing the ongoing Phase 3 test and submitting the drug for FDA review. If it’s approved, Takeda will lead commercialization of the drug. Polycythemia vera is an overproduction of blood cells. It’s caused by a mutation in the stem cells of the bone marrow, where red blood cells are produced. In addition to the higher red blood cell count, patients experience iron deficiency. The disorder raises the risk of cardiovascular events, such as heart attack and stroke. One common treatment for polycythemia vera is phlebotomy, frequent withdrawals of blood that decreases blood volume and reduces the levels of excess blood cells. Rusfertide is a peptide from Protagonist’s peptide technology platform. The company said the drug’s exact mechanism of action is not known, but it’s thought to regulate iron homeostasis and control the absorption, storage, and distribution of iron in the body. In an open-label Phase 2 clinical trial enrolling 70 participants, Protagonist reported that the once-weekly injectable drug controlled red blood cell levels and eliminated the need for phlebotomies, achieving the main study goal. Longer-term data presented in December during the annual meeting of the American Society of Hematology showed the drug continued to show durable effects through two-and-a-half years. A 250-patient, placebo-controlled Phase 3 study is underway with the same main goal as the mid-stage test. Protagonist expects to complete enrollment in the current quarter. In this 32-week study, rusfertide or a placebo will be added to a patient’s current polycythemia vera therapy. In an investor presentation, Protagonist said it expects to have 32-week data in the first quarter of next year, potentially setting the stage for an FDA submission in the fourth quarter of 2025. If rusfertide reaches the market, the deal calls for Takeda and Protagonist to split profits equally. Protagonist has an option to share in the marketing of the drug in the U.S. The biotech also has the right to opt-out of the profit share provision of the deal. Doing so would put Protagonist in line for opt-out payments and enhanced milestone and royalty payments. If Protagonist exercises either option, Takeda will still retain full rights to rusfertide outside of the U.S. According to a Protagonist regulatory filing, exercising the full opt-out right would put the company in line for up to $975 million in payments. For Takeda, rusfertide fits with the pharma giant’s strategy of acquiring late-stage assets in rare diseases, Julie Kim, president, U.S. business unit and U.S. country head, Takeda, said in a prepared statement. It also fits with other assets in the pharma giant’s hematology portfolio. This past November, the FDA approved Takeda’s Adzynma, a treatment for congenital thrombotic thrombocytopenic purpura, a rare inherited enzyme deficiency that leads to blood clotting problems. Protagonist does not yet have any FDA-approved products. President and CEO Dinesh Patel said the Takeda deal allows his company to focus on completing rusfertide’s Phase 3 study while leveraging Takeda’s global commercialization capabilities to immediately start pre-commercial work. “As we progress towards a fully integrated pharmaceutical company, this deal mitigates the inherent execution risks of a first-time commercial launch, optimizes the timing and enhances the scope for peak potential sales of rusfertide, while still allowing us to actively participate in the commercial experience and economics with a 50:50 profit split in the U.S. market,” Patel said. PharmaEssentia claimed the first FDA approval of a polycythemia vera therapy in 2021. This injectable drug, named Besremi, is an engineered version of interferon alpha. It’s believed to activate a signaling cascade that reduces production of red blood cells. Others developing potential treatments for the disease include Silence Therapeutics with a drug that employs RNA interference, and Ionis Pharmaceuticals, whose drug candidate is an antisense oligonucleotide.

The Progeria Research Foundation Marks Significant Achievement as Zokinvy™ (lonafarnib) Receives Japanese Approval for the Treatment of Progeria and Processing-Deficient Progeroid Laminopathies PEABODY, Mass., Jan. 20, 2024 /PRNewswire/ -- The Progeria Research Foundation (PRF) today announced a new milestone with the approval of Zokinvy™ (lonafarnib) by the Japanese Ministry of Health, Labor and Welfare (MHLW), for the treatment of Progeria and processing-deficient Progeroid Laminopathies (PL). Progeria is an ultra-rare, fatal pediatric "rapid-aging" disease. PRF, a pioneer in the rare disease research foundation space, has led Zokinvy clinical trial research since 2007. Eiger BioPharmaceuticals (Eiger) and PRF began a partnership in 2018 to bring this drug to market. Approval from the U.S. Food and Drug Administration (FDA) for Zokinvy was granted in November, 2020 and the European Medicines Administration (EMA) in July, 2022. Zokinvy is a farnesyltransferase inhibitor (FTI) that has shown survival benefit in children with Progeria. Data based on information from the PRF International Patient Registry and clinical trials co-coordinated by PRF and Boston Children's Hospital (BCH) demonstrated that in patients with Progeria, Zokinvy reduced the incidence of mortality by 72% and increased average survival time by an average of 30% (4.3 years). Without Zokinvy treatment, children with Progeria die of heart disease at an average age of 14.5 years. Prevalence data from PRF's International Patient Registry indicate an expected 6 children with Progeria are living in Japan today. "We're thrilled by this wonderful news," said Audrey Gordon, President and Executive Director of The Progeria Research Foundation. "On the heels of the 2020 FDA approval and the 2022 EMA approval for Zokinvy, now children and young adults with Progeria and PL in Japan will be able to access this life-extending, heart-strengthening treatment through the convenience of a prescription." "Since co-founding The Progeria Research Foundation in 1999, we have poured our hearts and souls into the most promising research toward treatments and the cure for every child with Progeria," said Leslie Gordon, MD, PhD, PRF Medical Director and Zokinvy Clinical Trial Investigator. "After more than a decade of Zokinvy research funded by PRF and co-conducted by PRF and BCH, Zokinvy's authorization in Japan is a win for the worldwide Progeria community. Thank you to the courageous children, their families, and our many expert Progeria research teams and pharmaceutical partners who made this key milestone possible." Over the course of its 24-year existence, PRF has made tremendous strides toward its mission to discover the cause, treatments and cure for Progeria. In partnership with the National Institutes of Health (NIH), PRF was the driving force behind the 2003 Progeria gene discovery. PRF holds bi-annual scientific workshops, funds research grants breaking new ground in areas such as RNA therapeutics and Genetic Base Editing, and funds clinical drug trials. PRF's core patient-focused programs include the Progeria International Patient Registry, Medical & Research Database, Cell & Tissue Bank, Diagnostics Testing Program, and a Clinical Care Handbook for families and physicians. "After conducting 16 years of Progeria clinical trials at Boston Children's Hospital, this milestone demonstrates the positive impact of a dedicated research team, rigorous testing, and the steadfast bravery of the wonderful children and their families," said Dr. Monica Kleinman, Principal Investigator for the Progeria clinical trials at Boston Children's Hospital. "Being a part of this achievement for these children is not only professionally rewarding but also a testament to the transformative potential of scientific advancement in Progeria research." About Progeria Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), and PL are ultra-rare, multisystemic, premature aging diseases that accelerate mortality in young patients due to accumulation of cellular progerin in HGPS or an abnormal lamin A protein in PL. Progeria is caused by a genetic mutation in the LMNA ("lamin A") gene, and results in a disease-causing abnormal protein called progerin. There are approximately 400-450 children worldwide with Progeria. Thanks to PRF-funded research, we now know that progerin is produced in all of us as we age, but at a much lower rate than in children with Progeria. Due to this discovery of the biological connection between Progeria, heart disease and aging, finding the cure for one of the rarest diseases on earth could provide keys for treating millions of adults with heart disease and stroke associated with the natural aging process, as well as help the entire aging population. About The Progeria Research Foundation The Progeria Research Foundation (PRF) was established in 1999 by the family of Sam Berns, a child with Progeria. Within four years of its founding, the PRF Genetics Consortium discovered the Progeria gene, a collaboration led by Dr. Francis Collins, Acting Science Advisor to the President of the United States and former Director of the National Institutes of Health (NIH). PRF has funded and co-coordinated all Zokinvy-associated clinical trials for Progeria and Progeroid Laminopathies, conducted at Boston Children's Hospital, and supports scientists who conduct Progeria research worldwide. PRF's International Patient Registry includes over 370 children with Progeria in 70 countries. PRF is the only non-profit organization solely dedicated to finding treatments and the cure for Progeria and its aging-related conditions, including heart disease. The organization fills a void, putting these children and Progeria at the forefront of scientific efforts. For more information and to support PRF's mission, please visit . SOURCE Progeria Research Foundation

Sanofi is walking away from a deal to license an experimental Maze Therapeutics drug for a rare enzyme deficiency after the Federal Trade Commission challenged the transaction as anti-competitive. The French pharmaceutical giant already markets Lumizyme and Nexviazyme for the disorder, called Pompe disease. Until this year, they were the only available Pompe treatments. In an administrative complaint filed Monday, the anti-trust regulator said Sanofi’s deal for Maze’s drug candidate amounts to a large company trying to eliminate a smaller competitor. Both Sanofi and Maze disagree with the FTC’s position. South San Francisco-based Maze said it is reviewing its legal and business options. Sanofi isn’t waiting. The pharma giant said the FTC action will be a delay and it concluded contesting it would not be in the best interest of patients. Consequently, Sanofi will terminate the licensing agreement. Pompe is caused by mutations to the gene that codes for acid alpha glucosidase (GAA), an enzyme needed for breaking down glycogen in muscles. As a result, glycogen, a form of glucose, accumulates in skeletal, lung, and cardiac muscle tissue. Glycogen buildup leads to progressively worsening muscle weakness and respiratory problems that become fatal. Like many inherited enzyme deficiencies, treatment for Pompe is enzyme replacement therapy. Sanofi’s Lumizyme (marketed in Europe as Myozyme) was the first Pompe product, offering patients an engineered version of GAA. The annual cost of treatment is more than $750,000. Sanofi’s Nexviazyme (Nexviadyme in Europe) is also an engineered version of GAA, but designed in a way to improve the enzyme’s ability to clear glycogen. Nexviazyme was approved by the FDA in 2021 and by the European Commission last year. Maze drug candidate MZE001 takes a different approach to Pompe. Rather than replacing GAA, the Maze drug aims to impede glycogen production. MZE001 blocks glycogen synthase, an enzyme important in making glycogen. The drug is a small molecule that would be less expensive to manufacture than Sanofi’s engineered enzymes. It’s also formulated as a twice-daily pill that is much more convenient for patients than receiving regular infusions. When the licensing agreement for MZE001 was announced in May—$150 million up front and up to $600 million in milestone payments—Maze had encouraging Phase 1 data showing the drug was well tolerated and it also led reduction in glycogen levels across all of the tested doses. Both Sanofi and Maze said the deal placed the small molecules in the hands of a global company with the resources and Pompe experience to advance its development. The FTC disagrees. “This is a case about a monopolist seeking to eliminate a nascent threat to its monopoly,” the agency said in the complaint. Many key details of the 17-page complaint are redacted, but the publicly viewable portions portray a pharmaceutical giant concluding its own products would not be competitive with the oral dose formulation of the Maze drug candidate. They also suggest that the licensing agreement was intended to keep the molecule from getting in the hands of rival pharma companies. The complaint goes on to state that by eliminating the competitive threat of MZE001, the deal contributes to Sanofi’s monopoly in Pompe, violating the anti-monopoly provisions of Section 2 of the Sherman Act. Revenue for the Sanofi Pompe franchise increased 7.3% year over year topping €1 billion in 2022, according to the company’s annual report. Sanofi attributes that growth to Nexviazyme’s launch in U.S., Europe, and Japan. However, 2022 sales of Lumizyme/Myozyme are from the prior year due to eligible Pompe patients switching to Nexviazyme. Pompe patients do have a new treatment option available from Amicus Therapeutics. In September, the FDA approved Amicus’s Pombiliti, an engineered version of GAA. That therapy is taken with Opfolda, a small molecule that Amicus designed to improves muscle cell uptake of Pombiliti. But the new Amicus products are not direct competitors to Sanofi’s Pompe therapies. The FDA’s approval o the combination therapy covers the treatment of Pompe patients who are not improving with the Sanofi therapies. The FTC complaint notes that Amicus’s therapy currently has little to no market share, posing little price competition to the Sanofi products. “Because Amicus Therapeutics’ two-component [enzyme replacement therapy] was only approved as a second-line therapy (for patients not improving on Sanofi’s therapies), Sanofi has little to no incentive to decrease its list prices or offer significant discounts or rebates on Lumizyme and Nexviazyme, which remain the only FDA-approved treatments for newly diagnosed patients starting treatment for Pompe disease,” the FTC said. The regulator set a May 15, 2024 date for an evidentiary hearing—a little more than one year after Sanofi and Maze announced the licensing agreement. Sanofi’s assertion that protracted litigation will not help Pompe patients has some merit. The Maze molecule has been ready for Phase 2 testing and further clinical development is in limbo as long as the case is ongoing. With Sanofi bowing out of development of MZE001, privately held Maze will need to figure out how to finance development of that molecule and others in its pipeline. The initial deal called for Sanofi to pay Maze $130 million up front and make a $20 million equity investment in the biotech when it completes an initial public offering, the FTC complaint revealed. Regardless of whether Sanofi invests in Maze or not, the market remains mostly closed for biotech IPOs.