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The approval of Vyndaqel®/Vyndamax™ is paving the way for an expanding landscape of approved and investigational treatments for transthyretin amyloid diseases.

F-Prime is dedicated to advancing pioneering science and technologies that redefine patient care and treatment. Since 2002, F-Prime has facilitated the regulatory approval and commercialization of 33 products and drugs. In this series, Pioneering Progress, we showcase success stories behind the approval of drugs and products from our portfolio companies.

Understanding Transthyretin Amyloidosis, a Rare and Fatal Disease

Transthyretin amyloidosis (ATTR amyloidosis) is a rare, progressive, and fatal disease caused by the accumulation of misfolded proteins, known as amyloid, in the peripheral nervous system, heart, and other organs. This occurs when transthyretin (TTR)—a protein that transports the thyroid hormone thyroxine and retinol—misfolds and forms amyloid deposits. Normally, TTR exists as a tetramer, a stable cluster of four identical protein units. However, with aging or inherited mutations, these units separate and misfold, resulting in the formation of harmful amyloid fibrils, which are insoluble and resistant to degradation. ATTR amyloidosis manifests in several forms, with the two most common types being ATTR amyloidosis polyneuropathy (ATTR-PN), which affects the nerves, and ATTR cardiomyopathy (ATTR-CM), which impacts the heart.

ATTR-PN, which is estimated to affect 10,000-40,000 patients globally, leads to amyloid fibril-based damage to nerves, resulting in muscle weakness, loss of sensation, tingling, numbness, pain, and digestive track issues.^{1, 2, 3} Without prompt intervention, ATTR-PN is typically fatal within 10 years and, until recently, the only effective treatment was liver transplantation.²

ATTR-CM, on the other hand, is characterized by amyloid fibril accumulation in the heart tissue and results in symptoms resembling that of other heart conditions such as heart failure, further complicating diagnosis.³ While ATTR-CM was once considered very rare due to the diagnostic difficulty, recent improvements in diagnostic techniques have significantly increased incidence estimates, now with 5,000-7,000 new cases identified annually in the US alone⁴. Historically, individuals with ATTR-CM faced a poor prognosis, often experiencing severe health complications and a high risk of death within two to six years of diagnosis.⁵

With limited treatment options that target the root cause of ATTR amyloidosis, F-Prime saw a tremendous opportunity to bring new therapies to patients and transform how these diseases are treated and understood.

Advancing the Fight Against ATTR Amyloidosis

 The understanding of ATTR amyloidosis took a major step forward with the work of Portuguese physician and leading ATTR amyloidosis researcher Teresa Coelho, Ph.D., who linked mutations in the TTR gene to the development of amyloid disease. Her research identified key disease-causing mutations, such as V30M and V122I, and uncovered a secondary mutation that interestingly led to TTR tetramer stabilization and better patient outcomes. Building on these findings, Jeff Kelly, Ph.D., a chemist at Scripps Research Institute and co-founder of FoldRx, proposed a new treatment approach—a small molecule drug designed to stabilize TTR and prevent misfolding.

By screening known drugs and applying structure-based drug design, Kelly’s team discovered Vyndaqel/Vyndamax, a small molecule drug that binds to TTR. By keeping the protein in its stable tetramer form, this approach helps prevent TTR from breaking apart, misfolding, and forming harmful amyloid deposits. With a unique molecule and promising early data, Kelly co-founded FoldRx in 2003 together with Susan Lindquist, Ph.D., former director of the Whitehead Institute for Biomedical Research.

“FoldRx came to us with a strong foundation of peer-reviewed scientific research supporting its hypothesis and a simple but innovative approach for addressing ATTR amyloidosis that offered curative potential,” said Stephen Knight, M.D., President and Senior Managing Partner at F-Prime. “Their solution made FoldRx an ideal investment opportunity that closely aligned with F-Prime’s goal to fund companies with transformative potential. Together, we were able to lay the foundation for Vyndaqel/Vyndamax’s eventual approval and bring forward a much-needed therapy for this life-threatening disease.”

Under the leadership of CEO Richard Labaudiniere, Ph.D., FoldRx initiated clinical development of Vyndaqel/Vyndamax, starting with a Phase 0 study to better characterize the typical ATTR-PN patient natural history—which at the time was entirely unknown—and continuing through completion of a Phase 2 study.

Based on encouraging data from the Phase 2 study, Pfizer acquired FoldRx and Vyndaqel/Vyndamax received European marketing approval in 2010 as the first therapy to treat ATTR-PN. Following additional clinical studies, Vyndaqel/Vyndamax was approved by the US FDA for the treatment of ATTR-CM in 2019.

From Breakthrough to Progress

The approval of Vyndaqel/Vyndamax as a first-in-class treatment for ATTR-PN and ATTR-CM set the stage for an influx of new drugs that address the diseases through various modalities. This growing list includes approved siRNA-based treatments Onpattro® (patisiran) and Amvuttra® (vutisiran), antisense oligonucleotide medicines WAINUA™ (eplontersen) and Tegsedi® (inotersen), small molecule drug Attruby™ (acoramidis), and an investigational CRISPR/Cas9-based approach, NTLA-2001.

Vyndaqel/Vyndamax highlights F-Prime’s role in advancing innovative treatments that transform patient care. Its success has helped drive progress in the field, paving the way for more life-saving treatment options for patients. This journey—from groundbreaking research to a first-in-class therapy—demonstrates the power of scientific innovation and strategic investment in changing the course of rare, fatal diseases.

References:

1. Schmidt HH, Waddington-Cruz M, Botteman MF, et al. Estimating the global prevalence of transthyretin familial amyloid polyneuropathy. Muscle Nerve. 2018;57(5):829-837. doi:10.1002/mus.26034
2. González-Duarte A, Conceição I, Amass L, Botteman MF, Carter JA, Stewart M. Impact of Non-Cardiac Clinicopathologic Characteristics on Survival in Transthyretin Amyloid Polyneuropathy. Neurol Ther. 2020;9(1):135-149. doi:10.1007/s40120-020-00183-7
3. Pfizer. Understanding This Rare Disease Called ATTR Amyloidosis. Accessed January 22, 2025.
4. Jain A, Zahra F. Transthyretin Amyloid Cardiomyopathy (ATTR-CM). StatPearls. 2023.
5. Rozenbaum MH, Garcia A, Grima D, et al. Health impact of tafamidis in transthyretin amyloid cardiomyopathy patients: an analysis from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and the open-label long-term extension studies. Eur Heart J Qual Care Clin Outcomes. 2022;8(5):529-538. doi:10.1093/ehjqcco/qcab031
6. Castaño A, Drachman BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015;20(2):163-178. doi:10.1007/s10741-014-9462-7

Orchard Therapeutics’ Lenmeldy™ is a first of its kind treatment for an ultra-rare pediatric hereditary disorder.

F-Prime is dedicated to advancing pioneering science and technologies that redefine patient care. Since 2002, F-Prime has facilitated the regulatory approval and commercialization of 33 products and drugs. In our series, Pioneering Progress, we will be showcasing the success stories behind the approval of drugs and products from our portfolio companies.

A Devastating Childhood Disease

Metachromatic leukodystrophy (MLD) is an ultra-rare hereditary disorder caused by mutations in the ARSA gene which render the body unable to break down certain lipids inside cells. This results in progressive destruction of a fatty protective layer on the outside of nerve cells called myelin, leading to impairment of an individual’s movement, severe neurological decline, and ultimately death.

MLD is estimated to affect 1 in 40,000 to 1 in 160,000 live births worldwide¹. The disease most commonly manifests in infants and young children, though it can present later in life. Symptoms vary depending on the age of onset but typically include muscle weakness, difficulty walking, loss of motor skills, cognitive decline, seizures, and loss of vision and hearing.

Historically, there has been no way of stopping the disease’s progression and treatment options have been limited to symptom management and supportive care.

New Hope for MLD Patients

Recognizing the potential for bone marrow gene therapy to transform how patients with ultra-rare diseases such as MLD are treated, F-Prime partnered with Bobby Gaspar, M.D., Ph.D., a world-renowned physician and Professor of Pediatrics and Immunology at University College London’s Great Ormond Street Institute of Child Health. Working with Bobby and his global network of academic collaborators, F-Prime formed a new company called Orchard Therapeutics.

Using the combined expertise and resources of F-Prime, Bobby and his collaborators Orchard assembled a portfolio of gene therapies that act on the bone marrow of patients. In 2018, Lenmeldy™ entered the spotlight when Orchard acquired the gene therapy programs of GSK, as the big pharma pivoted away from rare disease.

“As a leading expert in bone marrow gene therapy for severe inherited disease, Bobby brought deep technical and clinical know-how to fuel Orchard’s R&D. F-Prime supplemented his expertise with a company creation engine,” said Alex Pasteur, Ph.D., Partner at F-Prime. “We were a thought partner to Bobby throughout the founding of Orchard, and we helped him to acquire the Lenmeldy program from GSK.”

Throughout its development, Lenmeldy consistently generated promising clinical data, which earned the project lead program status within Orchard’s pipeline. Due to the rarity of MLD, it was essential to educate regulators and other stakeholders about the natural history of the disease, difference clinical methods for assessing symptoms, and Orchard’s new approach.

Upon reaching market approval in Europe in 2020 (as Libmeldy™) and in the U.S. in 2024 (as Lenmeldy™), the therapy became the first-in-class disease-modifying treatment for MLD patients. At the time of approval, the product had the most extensive follow-up data for any gene therapy in the U.S., demonstrating the treatment’s long-term safety and efficacy.

The approval of Lenmeldy was based on studies involving 37 children who received a single dose of the gene therapy². Remarkably, 100% of children with pre-symptomatic late infantile (PSLI) MLD who were treated with Lenmeldy were alive at six years old, while only 58% of children in the natural history group survived to that age. At five years of age, 71% of children treated with Lenmeldy were able to walk independently, and 85% exhibited normal language and performance IQ scores – outcomes that had not previously been observed in MLD children. Additionally, a slowing of motor and cognitive decline was observed in children with pre-symptomatic early juvenile (PSEJ) and early-symptomatic early juvenile (ESEJ) MLD.

Stakeholder education remains a priority for Orchard post approval of Lenmeldy, with the focus shifting from regulators to physicians and payers. To ensure that the full patient population benefits from Lenmeldy’s curative potential, it has been important for Orchard to accelerate adoption by rolling out standardized diagnosis and newborn screening programs.

Empowering Change with Strategic Investment

We extend our appreciation to Bobby, his collaborators and the entire Orchard team for their efforts throughout the journey of Lenmeldy, which marks a groundbreaking advancement in the treatment of MLD. The success of Lenmeldy not only transforms the outlook for MLD families but also demonstrates the potential for bone-marrow gene therapy to address other severe inherited neurometabolic diseases.

“Our partnership with Bobby – who has spent 10 years at Orchard immersed in company creation, clinical development, regulatory engagement and business development – continues with Bobby joining F-Prime as Venture Partner, ready to help F-Prime build another company with an innovative approach and a mission to help patients in life-altering ways,” said Pasteur.

F-Prime is committed to building transformative companies by supporting the next generation of innovators as they tackle the toughest challenges in healthcare. The success of Lenmeldy serves as an inspirational example, offering hope to MLD families and fueling continued efforts toward future breakthrough treatments for rare diseases.

 

1. Chang, SC., Bergamasco, A., Bonnin, M. et al. A systematic review on the birth prevalence of metachromatic leukodystrophy. Orphanet J Rare Dis 19, 80 (2024). https://doi.org/10.1186/s13023-024-03044-w
2. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystrophy