By Wynne Parry
John Lambris, PhD, discovered a molecule called compstatin in 1996. In the last few years, a related molecule was approved by the FDA as a drug to treat two medical conditions.
An ancient arm of the immune system called complement comprises approximately 50 components. Like rows of falling dominoes, interactions among these proteins cascade along three pathways, enabling it to attack microbes and promote inflammation, among other things. But, like the rest of the immune system, complement can sometimes contribute to, rather than prevent, disease.
Understanding and modifying these complex molecular interactions is the realm of basic biomedical research that unfolds over decades in labs like that of John Lambris, PhD, on Penn Medicine’s campus just steps away from the hospitals where patients receive care. Basic research and medical treatments may seem like separate worlds—but, given time and focused effort, they do converge.
Within the last three years, a molecule Lambris and his colleagues discovered through their research on complement has twice been approved as a drug that is available for patients. This journey of an idea from a Penn Medicine lab to a patient’s medicine cabinet is one that leaders are now tracking through a formal process. The aim is to better quantify the real-world impact of Penn’s research on patients worldwide.
From molecule to medicine
When Lambris, the Dr. Ralph and Sallie Weaver Professor of Research Medicine in the Perelman School of Medicine, and his colleagues first set out to halt problematic complement activity in the 1990s, they focused on a single component, C3, situated at the convergence of the system’s three pathways. They then screened millions of molecules to see which could break the chain by blocking C3 and, potentially, open the door to new therapies for autoimmune and other inflammatory conditions.
“C3 is a huge protein, and you expect to get many compounds,” Lambris said. “We got only one and it had these unique properties to bind to a specific spot on C3 and inhibit complement activation.”
They reported their discovery, which they called compstatin, in 1996. Since then, that single molecule has led to many others. Lambris and his collaborators have continued refining compstatin and its successors and patenting their discoveries, creating versions that bind ever more tightly to C3, show enhanced inhibitory activity, and last ever longer in the body.
In parallel, Lambris’ discoveries have continued on the path into clinical practice. In 2021, the FDA granted approval to the pharmaceutical company Apellis Pharmaceuticals to manufacture and market pegcetacoplan, a modified C3 inhibitor, to treat a rare blood disorder, paroxysmal nocturnal hemoglobinuria (PNH). Two years later, the agency approved the same compound to treat a prevalent eye condition called geographic atrophy, an advanced form of age-related macular degeneration. Apellis developed both therapies after licensing this C3 inhibitor from Penn, which holds Lambris’ more than 200 patents, mainly for compstatin and its relatives.
Tracking innovation, one approval at a time
In 2023, Penn Medicine’s Office of Clinical Research (OCR) began formally tracking FDA approvals that result, in a substantial way, from the work of the institution’s faculty.
This type of tracking is a new way of thinking about research contributions from an academic institution. In part, that’s because the FDA issues its approvals to the company making a drug or device, for a specific indication, and as more evidence is presented, the agency can add approval for more indications. Pharmaceutical, biotechnology, and medical device companies tend to get the spotlight when the FDA approves a new treatment or indication. But, quite often, it would not have happened without academic research.
Faculty contributions that “count” for Penn’s tracking can occur at any point on the development continuum, from experiments in the lab on through the clinical trials that demonstrate safety and effectiveness. The wave of such approvals reflects both a shift toward therapies derived from basic studies of disease mechanisms and Penn’s commitment to clearing the path from discovery to commercialization for potentially transformative products.
A crowd at Penn Medicine gathered to celebrate the first FDA approval of a CAR T cell therapy in 2017.
The count originated in Penn Medicine’s Abramson Cancer Center after Robert Vonderheide, MD, DPhil, became director in 2017. That same year, CART19, a personalized immune cell therapy developed by Carl June, MD, and his team at Penn, received the FDA’s approval to treat acute lymphoblastic leukemia—the first in a string of approvals to Novartis for treating several cancers with this form of CAR T cell therapy.
Vonderheide decided to formally count the FDA approvals for other work originating in the cancer center to include in the cancer center’s annual reports on its impacts to the National Cancer Institute.
Now Penn has expanded that count to other fields.
The initiative is looking back to the point, around 2013, when Penn made the strategic decision to support the translation of its faculty’s discoveries.
“Given our unbelievable success following our shift in emphasis, we want to fully reflect our faculty’s engagement in drug and device development,” said Emma Meagher, MD, senior vice dean of clinical and translational research.
As a widely respected academic institution, Penn is well positioned to share stories of how publicly funded research can generate potentially life-changing or lifesaving new products. But this opportunity comes with a responsibility to evaluate these cases according to consistent criteria, according to Meagher.
“We are upholding our ethical responsibility to appropriately represent the work we are doing,” she says.
The complexities of counting
As of late March 2024, the initial release of a comprehensive list contained approvals for 29 indications.
The goal is not to take credit for the product owned by a company that receives the FDA approval directly. Instead, it is to carefully vet and recognize contributions of Penn faculty deemed crucial to arriving at that approval. These may include originating intellectual property, designing the proof-of-concept preclinical or clinical trial, or leading the phase 3 clinical trial, including being senior author on the publication.
Biologics, especially those in oncology, dominate Penn Medicine’s current count of FDA approvals; however, OCR is also tracking device-related approvals, whether for new inventions or new uses of existing ones. The current list includes one such example: a new technique developed by Gregory Weinstein, MD, a professor of Otorhinolaryngology, for using a surgical robot to remove malignant tumors in the pharynx and larynx.
An approval may also qualify for Penn Medicine’s official list if a faculty member developed a new indication or method of use that led to an FDA label change. Twelve of the 29 indications on the current Penn list are new indications for existing products.
Penn Medicine faculty are able to submit information about FDA-approved drugs and devices toward which their research contributed, to a new annual OCR-run survey and other mechanisms for consideration. A pair of committees—one focused on cancer, and one for all other conditions—then carefully evaluates the role the Penn scientists played in the development process for each drug or device suggested for inclusion. In some cases, like Lambris’, the decision is straightforward—because of patents or licensing agreements documented by the Penn Center for Innovation (PCI).
Other cases require more careful consideration. These contributions are typically substantiated by journal publications.
“We need to read the papers, we need to talk to the physicians, we need to clearly understand more of what they've done before we claim it as Penn’s,” said Deanna Condit-DiDonato, OCR’s director of regulatory services, who manages the annual survey, collates responses, and gathers additional details needed to complete the vetting process.
An imperfect drug brings new hope
Fred Kaplan, MD
The decision to count a new therapy called palovarotene is an example of one that took more investigation. In August 2023, it became the first drug approved to treat an extremely rare and debilitating disorder, fibrodysplasia ossificans progressiva (FOP). In affected children, painful, tumor-like lumps grow within skeletal muscles and connective tissue, slowly transforming them into bone. By around age 30, most patients are completely immobilized, locked into a sitting or standing position, according to Frederick Kaplan, MD, the Isaac and Rose Nassau Professor of Orthopaedic Molecular Medicine in Orthopaedic Surgery, who has treated patients with this disorder from around the world, since 1984.
Penn has long been a focal point for FOP treatment and research. After he began treating FOP patients, Kaplan recruited Eileen Shore, PhD, the Cali-Weldon Professor in FOP Research, to study the molecular origins of the disease, and, together, they discovered the genetic mutation responsible, confirming at last FOP’s status as a genetic condition.
Maurizio Pacifici, PhD, now director of orthopaedic research at Children’s Hospital of Philadelphia, did foundational research while he was at Thomas Jefferson University using synthetic retinoids including palovarotene, based on the role of retinoids in fetal bone development. A 2011 paper describing his team’s research in Nature Medicine caught the eye of a biotech entrepreneur, who formed a company, Clementia, to develop the drug for FOP. When international clinical trials began, Mona Al Mukaddam, MD, MS, an associate professor of Clinical Medicine, ran Penn’s study, and Kaplan oversaw sites in eleven countries.
The prospects for an approval looked dim at times. The FDA put the phase three trial on hold twice, including once when it became clear that palovarotene caused children’s growth to drop off. In the end, whole body CT scans indicated that palovarotene decreased aberrant bone formation by about 50 percent and, with support from patients, the FDA approved its use in adults, girls age 8 years and older, and boys age 10 years and older.
To evaluate Penn’s claim on this approval, Condit-DiDonato first checked in with PCI and confirmed that no one at Penn had any intellectual property related to this drug. Instead, Clementia had licensed the drug from its patent holder, Roche. Ultimately, the committee determined that the palovarotene approval qualified based on Kaplan’s leadership of the overall initiative for over a decade in combination with his and Al Mukaddam’s contribution to the trial protocols, as well as Kaplan’s role as global principal investigator, codified by his status as senior author of a paper describing the phase three trial.
Many more treatments to come
Going forward, Condit-DiDonato plans to send out annual reminders to faculty to complete the online survey. In addition, department chairs will be prompted to highlight the efforts of their faculty in FDA approvals as part of their annual departmental reports, according to Meagher.
New FOP treatments and more advanced C3 inhibitors may one day join the count. Shore and others continue to investigate the mechanisms underlying FOP. Meanwhile other studies are testing new strategies against it, including two oral medications now in clinical trials at Penn.
“Palovarotene is not the end all, be all drug for FOP, but it's a very good start,” Kaplan said. (In a separate line of investigation into FOP, Kaplan and colleagues have recently reported findings based on an unusual patient who has the FOP genetic mutation, but virtually no symptoms.)
Meanwhile, Amyndas Pharmaceuticals has licensed more recent versions of compstatin and is now investigating their potential against disorders that include severe periodontitis, certain rare diseases, ophthalmic and neurological conditions, kidney disease, and transplant rejection. Lambris, meanwhile, continues refining his inhibitors.
“Science does not stop,” he said.
Explore more about Penn Medicine’s medical discoveries leading to FDA approvals
Making what’s next in medicine: Why research at Penn powers many FDA-approved treatments: Since 2017, the FDA has approved more than two dozen new therapies with roots at Penn Medicine—almost half of which are first-in-class for their indications. Becoming a hub for drug research and development took a lot more than luck.
The path from innovation to implementation: Penn’s infrastructure in both supporting clinical research and forging commercial partnerships smooths the way from idea to approval.
Putting biomedical research advances within reach: Treatments and vaccines are only useful in the hands of the people who need them.
Why new cancer treatment discoveries are proliferating. The approval of CAR T cell therapy ushered in a new era for cancer treatment.
Penn Medicine’s FDA approvals in cancer care: A comprehensive description of the research behind each of the FDA approvals in cancer care on Penn’s list is available here.