New York, New York, – January 16, 2024  Washington University in St. Louis and Deerfield Management (“Deerfield”), a healthcare investment firm, today announced the launch of VeritaScience, a new private R&D collaboration designed to advance the discovery, clinical development and commercialization of promising therapeutic and diagnostic candidates with potential to benefit human health. 

To support projects that originate from the collaboration, Deerfield has committed up to $130 million over the next 10 years, along with functional expertise, through a newly formed company. Washington University’s investigators will have the opportunity to work with Deerfield’s internal team, which has expertise across the drug development continuum from discovery through commercialization. VeritaScience is named to honor Washington University’s motto “Per Veritatem Vis,” which means “Strength Through Truth” in Latin.

The VeritaScience collaboration complements the university’s existing efforts in drug development and its innovative culture. Project proposals can be designed around any disease indication. Washington University’s investigators will submit project proposals to VeritaScience and its scientific review team, which is led by Deerfield experts and guided by the university’s Office of Technology Management and Washington University School of Medicine’s (“WashU Medicine”) business development team. Accepted drug discovery projects will receive a development plan aimed at achieving Investigational New Drug readiness and may be eligible for additional funding and support for the creation of separate, start-up companies.

Washington University is known worldwide for its innovative research programs in the medical sciences, aimed at improving human health. The university currently is ranked #7 in National Institutes of Health (NIH) funding among U.S. universities, with $633 million received in the 2023 federal fiscal year. This includes nearly $584 million in funding for research initiatives at WashU Medicine, which currently is ranked #2 in NIH funding among U.S. medical schools.

“The exciting collaboration with Deerfield Management to create VeritaScience represents yet another major approach to leveraging the research capabilities of Washington University,” said David H. Perlmutter, MD, the George and Carol Bauer Endowed Dean of Washington University School of Medicine, executive vice chancellor for medical affairs, and the Spencer T. and Ann W. Olin Distinguished Professor. “Deerfield has extensive experience in academic-industry partnerships, and this agreement allows us to further advance the ‘virtuous cycle of academic medicine’ and our commitment to translating ever more of the landscape-altering discoveries happening in our labs into tools and therapies that will concretely improve human health and alleviate suffering.”

The VeritaScience collaboration is an example of Deerfield’s engagement with research institutions. Currently, Deerfield’s network includes nearly 30 leading research institutions and medical centers, which aims to bring the healthcare ecosystem together to collaborate and learn from each other. Together with its research partners, Deerfield has provided funding and expertise to create spin-off companies that support key avenues from concept to spin-out of novel therapeutic discoveries.

“Throughout the process of forming VeritaScience, what has stood out to our team at Deerfield is the forward-thinking and innovation-focused Washington University culture,” said James Flynn, managing partner of Deerfield. “We intend to equip the researchers of selected projects with flexible capital, expertise, and operational support to help them realize their discoveries’ potential.”

ABOUT WASHINGTON UNIVERSITY

Washington University in St. Louis is counted among the world’s leaders in teaching, research, patient care and service to society. The university draws students and faculty to St. Louis from more than 100 countries and all 50 states, the District of Columbia, Guam, Puerto Rico and the Virgin Islands. The total student body is approximately 14,000 undergraduate, graduate and professional students. Washington University has been affiliated with 25 Nobel laureates, many of whom did a significant portion of their award-winning work at the university. The university offers more than 90 programs and almost 1,500 courses leading to bachelor’s, master’s and doctoral degrees in a broad spectrum of traditional and interdisciplinary fields, with additional opportunities for minor concentrations and individualized programs.

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty. Its National Institutes of Health (NIH) research funding portfolio is the second largest among U.S. medical schools, has grown more than 40% in the last six years and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,800 faculty physicians practicing at over 65 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare.

ABOUT DEERFIELD MANAGEMENT

Deerfield is an investment management firm committed to advancing healthcare through investment, information and philanthropy. The Firm works across the healthcare ecosystem to connect people, capital, ideas and technology in bold, collaborative and inclusive ways. For more information, please visit www.deerfield.com.

Media Contact:

Anthony Karamourtopoulos

[email protected]

Diane Duke Williams

[email protected]

(New York, NY, April 6, 2020)—Deerfield Management Company, L.P. today announced the closing of the Deerfield Healthcare Innovations Fund ll, L.P., which will invest in advancements in science that may lead to important therapeutic interventions and back new technologies and infrastructure to improve the way healthcare is delivered to patients.

“Now more than ever, these unprecedented times underscore the importance of supporting the critical work of our nation’s scientists and healthcare systems,” said James E. Flynn, managing partner of Deerfield. “Our uniquely supportive model allows us to provide leverage to innovative companies and accelerate the benefit to patients.”

The Healthcare Innovations Fund II will collaborate with more than 15 leading academic institutions to seed novel scientific research. The Fund also has access to innovative medtech incubators created in partnership with two medical device industry leaders.

The Cure, the recently announced innovation campus located at 345 Park Avenue South, will become the central location of Deerfield where much of the work of the Healthcare Innovation Fund II will take place. Many of the early-stage companies will utilize the Cure’s wet and dry labs, engineering, computing and shared resource spaces.

The companies will also benefit from on-site programming, including the Fellows Program, Break into the Boardroom and Women in Science. Newly curated programs to be featured involve the “Cure Lounge,” a thought leadership and executive club, and other educational and certification initiatives.

The Deerfield Healthcare Innovations Fund ll is supported by the entire Deerfield infrastructure. 

Deerfield has been investing in and supporting the healthcare industry for more than 25 years, and partner companies benefit from its organizational capabilities.

Today, Deerfield has more than 130 experienced healthcare-focused professionals with specialized knowledge in medicine, life sciences, drug and medical device development, healthcare markets, public policy, value-based care, financial instruments, tax, accounting, operations, corporate strategy, market access research, marketing, biostatistics and sector dynamics, all of which can be leveraged by its partners.

Together, Deerfield team members fully fund and manage the Deerfield Foundation, which to date has committed or invested over $49 million to global organizations seeking to improve the delivery of healthcare, with a focus on underserved children. The Deerfield Foundation recently committed approximately 10 percent of its 2020 fiscal budget toward COVID-19 emergency funding to organizations in need of urgent resources in order to provide care to their communities.

About Deerfield Management 

Deerfield is a healthcare investment management firm committed to advancing healthcare through investment, information and philanthropy.

Contact:

Media
Deerfield Management
Karen Heidelberger, 212-692-7140
[email protected]

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(King of Prussia, PA, and New York, NY, January 22, 2020)—The Discovery Labs and Deerfield Management Company have formed The Center for Breakthrough Medicines, a Contract Development and Manufacturing Organization (CDMO) and specialty investment company, to alleviate the critical lack of capacity that is preventing patients from accessing critically needed cell and gene therapies. The CDMO is occupying over 40 percent of The Discovery Labs’ 1.6 million square foot biotech, healthcare and life sciences campus in King of Prussia, PA.

The CDMO provides preclinical through commercial manufacturing of cell and gene therapies and component raw materials. It offers process development, plasmid DNA, viral vectors, cell banking, cell processing, and support testing capabilities all under one roof. The immense $1.1 billion facility will provide instant capacity as the largest known single source for accelerating the delivery and affordability of lifesaving and life-changing therapies from the bench to the patient’s bedside.

The Company has initiated a substantial hiring effort targeting the best and brightest of the life sciences community including, experts in CGMP manufacturing. The Company expects to hire over 2,000 team members within the next 30 months.

The CDMO has retained Nucleus Careers, a cloud-based specialty life sciences human capital recruiting and retention management expert, to buildout the entire team. Nucleus has proprietary recruiting and retention software designed for large scale human capital buildouts of high growth companies.

In addition to developing the world’s largest single-point cell and gene therapy manufacturing facility, The Discovery Labs is establishing THE COLONY which will provide custom built discovery labs, breakthrough funding, sponsored research agreements, housing and relocation for the world’s leading iconic experts in cell and gene therapy.

THE COLONY will seek to work hand in hand with scientists from both academic and pharmaceutical institutions to unlock and expedite groundbreaking therapies.

Marco A. Chacón, Ph.D., Founder of Paragon Bioservices and Chairman of The Discovery Labs states, “musicians, artists, members of religious communities and great thinkers throughout time have formed colonies where freedom of thought and expression combined with unlimited dreams and potential have resulted in the world’s greatest accomplishments. The United States of America is a perfect example.” Dr. Chacón went on to say, “the goal of THE COLONY is to unshackle the potential of the world’s greatest scientific minds.”

The ability for the industry’s greatest scientists to cohabitate, collaborate, cooperate, and communicate via technology and in person will create an exponential therapeutic “X FACTOR.” THE COLONY seeks to unlock institutional barriers prohibiting the world’s greatest scientists from moving at a pace necessary in today’s ever-changing therapeutic revolution. THE COLONY will partner with the institutions where the scientists currently work by providing equity, license fees, and revenue sharing.

“The Center for Breakthrough Medicines will be serving companies from the earliest stages through commercialization. Its exceptional scale and offering will quickly relieve the production bottleneck for advanced therapies by reducing the time, complexity, and cost of commercializing vitally needed gene and cell therapies,” noted Audrey Greenberg, Board Member and Executive Managing Director for The Discovery Labs.

The addition of this end-to-end manufacturing capability is expected to significantly enhance the offerings of The Discovery Labs in an area that has become one of the largest life sciences hubs in the world. Renovations are underway to construct a total of 86 plasmid, viral vector production, universal cell processing, CGMP testing, process development and cell banking suites. The viral vector and cell processing suites will be fully compliant with both U.S. Food and Drug Administration and European Medicines Agency standards. All suites will offer the flexibility to meet client-specific workflows and will be able to adapt quickly to meet demand. The Company is in the process of reserving capacity now for late 2020.

“Today brilliant scientists are advancing an unprecedented number of gene and cell therapy drug candidates. The real tragedy, however, is a scarcity of manufacturing know-how, which is complex and expensive,” said Alex Karnal, Partner and Managing Director of Deerfield Management and a Board Member of the Discovery Labs. “With its visionary business model, it is hoped that The Center for Breakthrough Medicines will help realize the promise of cell and gene therapies in time to treat the many patients who need them.”

The Discovery Labs provides a central campus where the world’s greatest scientists can collaborate on new therapeutic discoveries to eradicate diseases affecting small and large segments of the global population. The Center for Breakthrough Medicines will work with these leaders, life sciences companies, large pharmaceutical companies, and academic and government institutions.

This new manufacturing capability is a transformational addition to The Discovery Labs market offering and dovetails with The Discovery Labs biotech incubator, Unite IQ. Unite IQ offers immediate space to emerging life sciences companies and scientists giving them the ability to grow from startup to enterprise company on one campus. The incubator and accelerator space at Unite IQ provides a comprehensive home for startups with every resource needed to initiate business operations. Unite IQ tenants are expected to utilize the discovery, development, testing, and manufacturing capabilities of the Center for Breakthrough Medicines with seamless forward integration of processes and analytics, and seamless tech transfer from research lab to large scale production

The Emerging Field of Cell and Gene Therapy in Pennsylvania

The demand for clinical and commercial manufacturing capacity is acute and expected to remain that way. The current shortfall in manufacturing for cell and gene therapies is severely underserved with few approved products. There are currently approximately 1,100 advanced therapies in the pipeline pending FDA approval. This will greatly increase highly skilled manufacturing demand. Dr. Peter Marks, Director of the FDA Center for Biologics Evaluation and Research, states, “what keeps me up at night is will we be able to manufacture these on a scale that will allow us to bring the benefit of these therapies to patients?” He further added that “if we can help see cost of goods and ability to manufacture reproducibly improve, I think that’ll be a big thing.” All of this adds up to a supply constrained market that The Center for Breakthrough Medicines aims to help address.

With the potential to treat and even cure disabling, and deadly diseases, gene and cell therapies are ushering in a new era of medicine. These therapies may eventually be able to cure genetic conditions, such as cystic fibrosis, hemophilia A, and a range of cancers. The Philadelphia area has become the epicenter for the flourishing field of gene and cell therapy. Research from CBRE currently ranks the market among the top biotech clusters for medical research and health services. The cluster has become known worldwide as “Cellicon Valley” for its leadership in research and development of this rapidly evolving field. The Discovery Lab’s suburban Philadelphia location offers a talent rich environment due to the area’s preponderance of large pharmaceutical companies and the Philadelphia region’s position boasting the top 10 universities and primary school systems in nation.

Over the past three years, multiple Philadelphia companies have received approvals for major breakthroughs in cell and gene therapy. In 2017, the U.S. FDA approved the first-ever CAR-T cell therapy, Novartis’s Kymriah, which originated at the University of Pennsylvania. Shortly thereafter, the FDA gave landmark approval for the first-ever gene therapy to treat a genetic blindness condition to Spark Therapeutics, a start-up founded by researchers at Children’s Hospital of Philadelphia. These discoveries and others in the pipeline are attracting billions of dollars of venture capital. The Greater Philadelphia Region set a recent record in venture capital financing.

The Discovery Labs Center for Breakthrough Medicines joins more than 25 healthcare, life sciences and tech-enabled companies that already call The Discovery Labs King of Prussia home.

Contact Audrey Greenberg at [email protected] for more information about development services, manufacturing capacity, incubator space or leasing information at the property.

About The Discovery Labs

Part of MLP Ventures, The Discovery Labs is a global provider of world-class cGMP manufacturing, turnkey laboratory solutions, critical materials and office space that support therapeutic products and services to the biotechnology and pharmaceutical industry so that groundbreaking medicines get to the patients that need them. The location in eastern King of Prussia is a prototype for a global rollout of The Discovery Labs, providing Big Pharma, emerging life sciences, consumer and technology companies flexible, end-to-end technical real estate and business infrastructure for the customer’s entire lifecycle from discovery to delivery, including manufacturing capacity. It is the first fully integrated environment that merges technology and life sciences under one roof to drive innovation.

About Deerfield Management

Deerfield is a healthcare investment management firm committed to advancing healthcare through investment, information and philanthropy.

Media Contact:
Tony DeFazio, DeFazio Communications
(o) 484-534-3306 (c) 484-410-1354
[email protected]

Karen Heidelberger, Deerfield Management Company
212-551-1600
[email protected]

NEW YORK, NY, September 26, 2019—In a major move, Deerfield Management Company, L.P.  is investing $635 million to create a transformative life sciences campus in New York City, designed to integrate the capabilities of innovators from academia, government, industry and the not-for-profit sectors to tackle unmet needs in healthcare. Deerfield additionally announced that it intends to commit more than $2 billion in research and seed funding by 2030 to develop much-needed new and innovative medicines and treatment solutions.  Deerfield expects this world-class infrastructure and funding to contribute to the prevention, cure or management of dozens of still deadly and debilitating diseases.  

As the foundation of this bold undertaking, Deerfield has acquired the 345 Park Avenue South property, which boasts more than 300,000 square feet. The site, designated a NYCLifeSci campus, will bring together scientists, entrepreneurs and leading organizations from around the world to work shoulder-to-shoulder to conceive of and develop new treatments and better ways to prevent and defeat disease. The campus will provide turnkey laboratories, and engineering and computing space, as well as other amenities and supportive services.  

“We are proud to be part of a community of people in New York who strive to save and extend lives. Creating an environment in which innovative thinking, ground-breaking advances in scientific discovery and where the development of new paradigms of patient care will occur every day is tremendously exciting,” said James Flynn, Managing Partner of Deerfield.  

“We are thrilled that our partnership with Deerfield will not only create quality jobs for New Yorkers but will also help provide a home for emerging companies to develop breakthrough scientific discoveries. New York City already has the best research institutions in the world. By investing in this Life Sciences campus to bring new lab space and programming for healthcare and early-stage biotech companies, we can strengthen the City’s position as a global leader in life sciences,” said NYCEDC President & CEO James Patchett.

The $540 million in financing for the acquisition and renovation of this world-class facility was led by Blackstone Real Estate, which has been a strong supporter of life sciences.  

Nadeem Meghji, Senior Managing Director, Head of Real Estate Americas at Blackstone said, “We are thrilled to finance this important project, which will advance life sciences research in New York City. With our investment in BioMed Realty, and elsewhere across our businesses, life sciences is among our highest priority investment sectors. We look forward to continuing to support the growing demand for research and innovation.”

The building construction and programming is being backed by the New York City Economic Development Corporation and Industrial Development Agency. It is expected to be in move-in ready condition for Deerfield and other innovators in healthcare by early 2021.

Due to obstacles, including a lack of capital and siloed approaches, promising new therapies and improvements in care management frequently fail to make it to patients. In addition to leveraging the value of public and private organizations in developing solutions, the Deerfield innovation campus will pursue all forms of technology, including digital, medical device and biotherapeutic approaches.  

“Many leaders have come together to build this incredible ecosystem, capable of accelerating the fight against disease. This campus should create the ideal backdrop to advance innovation,” said Alex Karnal, Partner and Portfolio Manager at Deerfield. “We are grateful to our partners, including the New York City Economic Development Corporation and Blackstone, as without them, this ambitious project might not have been possible.”

Having proven its ability to mobilize innovators in this space, MATTER, a healthcare focused incubator, in collaboration with Deerfield, will be supporting startups of all stages within the innovation campus.  MATTER has developed extensive specialized programs to train C-suite executives in the early stages of their career and to introduce young companies to established organizations for mentorship, collaboration and potential acquisition.  Combined with Deerfield’s operating support capabilities which extends to legal, finance, information technology, human resources, and market research, among other skillsets, companies formed within the campus will have unparalleled access to capabilities of the highest quality at low cost.

“Deerfield’s expertise and resources, combined with MATTER’s capabilities and experience, will create a healthcare and life sciences campus unlike any other,” said MATTER CEO Steven Collens. “We are thrilled to be a part of this endeavor to help entrepreneurs and innovators develop technologies and solutions that will improve the healthcare experience.”

Along with new educational programming being developed—and to complement the services provided by MATTER—Deerfield also announced that it will be growing its existing Deerfield LifeSci NYC Fellows and Break into the Boardroom programs. Deerfield additionally introduced a new initiative, Women in Science, focused on training women on how to commercialize their potentially lifesaving discoveries and create companies. The investment company has a rich history of developing and leading programs supporting diversity.

About Deerfield

Deerfield is an investment management firm committed to advancing healthcare through investment, information and philanthropy.

For more information, please visit www.deerfield.com

Contacts

Deerfield Management Company
Karen Heidelberger, 212-551-1600
[email protected]

In clinical trials especially those events-driven trials, it is often of great interest to predict the timing of pre-specified landmark event accurately in order to prepare for the interim or final analyses. Both parametric and non-parametric approaches have been proposed in the literature to estimate the underlying survival functions which is the key to the prediction of future event times. However, the existing approaches are neither not applicable to double-blind clinical trials or assuming smooth survival functions which might not hold in real clinical settings. In this talk, a hybrid parametric and non-parametric approach is proposed to predict event times in double-blind clinical trials with time-to-event outcomes. A greedy algorithm is first developed to detect change points in survival functions. The survival function before the last change point is estimated non-parametrically and the tail distribution beyond the last change point is estimated parametrically. Numerical results show that the proposed approach provides accurate predictions for future event times.

The entire paradigm of therapeutic and medical device development in the modern era is predicated on demonstrating safety and efficacy within parameters deemed appropriate by regulators like the Food and Drug Administration (FDA) and European Medicines Agency (EMA). This is proven in a series of clinical trials, known as Phase I to Phase IV studies, with each phase generally expected to demonstrate additional levels of data. This requirement for evidence generation via clinical trials contributes to the event driven nature of biopharma/medtech, creating somewhat predictable time points when sponsors can demonstrate added value in their programs with successful studies. The significance of a positive study to a share price or company valuation has had the unfortunate side effect of leading some sponsors to be less than 100% transparent in reporting the read-outs of trials, lest a hint of negative findings taint the remaining dataset. Below we lay out the archetypal road map of clinical trials and ways to be savvy to interpreting these.

General structure of clinical development programs

Phase I trials, sometimes known as first-in-man studies, are primarily meant to show the safety and pharmacokinetic profile (the onset, duration, and intensity of effect) of a novel therapeutic. These studies are traditionally done in healthy volunteers, and are typically not able to demonstrate efficacy. In areas like oncology, however, there may be phase I studies in actual patients that can look for preliminary signs of efficacy as well.

Phase II trials are conventionally dose-finding studies, and will test different dose levels, ideally to find the right therapeutic window of the drug, with the best combination of efficacy and safety. This can be done by taking an initial group of patients and slowly titrating up the dose of the drug over time until they experience adverse events, or by creating specified trial cohorts at different dose levels. Phase II results should importantly inform if it is even worthwhile to pursue Phase III, the costliest phase of development, or otherwise scrap a program. Once the best doses are selected from Phase II, sponsors then move on to Phase III.

The gold standard of Phase III trials is randomized, controlled, and double-blinded studies. Randomized means that patients who are enrolled in the study are divided, in a completely random fashion by someone other than the treating physician, into different arms or cohorts of the study. Controlled means that there is a comparator to the drug of interest. Comparators could be a placebo, a specific drug or regimen, or “best alternative care,” which may be any one of a series of different options determined at the physician’s discretion. The latter would be more common in studies where patients have already had multiple previous treatments. The double blinded nature of the study means that neither patient nor physician know what the dose of the administered drug (or placebo). This avoids introducing bias into the study. In the case of medical devices where a surgical procedure is required, trial protocols may call for “sham” procedures to maintain the blinded nature of the study. With any luck, a Phase III trial or trials will demonstrate the appropriate levels of safety and efficacy that allow the sponsor to submit for regulatory approval. There may be multiple Phase II and Phase III trials in a given development program, depending on the therapeutic area. Any one negative trial could kill an entire development program.

Sometimes, sponsors may have less than perfect data packages that they submit for regulatory approval. When there may be lingering questions about certain aspects of the drug or device, especially around things like long term safety, regulators may still approve the application, contingent on the completion of Phase IV or post-marketing studies, to make sure the worst fears are not borne out in use among larger populations. Also of note, trials are often conducted in “perfect” patients, who often look clinically very different from patients treated in real world settings that may have other co-morbidities, and be generally less healthy than trial patients. This makes the collection of longer term evidence more pressing, as either the number of severity of adverse events may vary in a real-world population compared to the trial population.

Understanding the general formats of data read outs

Sponsors have many outlets along the course of development to convey the results of trials to patients, health care providers, and investors. These range from something as simple as a press release, through poster and podium presentations at medical congresses, up to peer-reviewed publications in academic journals. Moving along that spectrum, there is increasingly more granular data, ideally shining a light on not only the good, but also the bad and the ugly.

The terse nature of press releases leaves them fraught with potential for ambiguity. At worst, sponsors may simply report positive efficacy trends, without noting the statistical significance as defined by a p-value, and with no mention of adverse events. The measure of efficacy can also be poorly defined; some questions a savvy reader should ask are^[1]:

• Is a positive signal from a primary endpoint or secondary endpoint? The primary endpoint is the most important hypothesis the trial sought to test.
• Was the p-value and form of statistical analysis associated with that endpoint prespecified? A prespecified statistical analysis is less vulnerable to selective p-value hacking once data has been unblinded.
• Were patients excluded from the efficacy analysis? If so, why? For example, is it just a particular subgroup or subgroups and not the entire enrolled population? Excluding patients may have the effect of only cherry picking the best-performing patients for the data analysis.

Moving up the chain, abstracts that are submitted to medical congresses as either poster or podium presentations are commonly peer-reviewed, albeit not with the same scrutiny that would come with a full journal article. These presentations typically have more details on the methods and results as compared to press releases. The public presentation of data by ether principal investigators or the scientists/clinicians driving a development program also provides at least some public venue for questions and answers.

There is a smattering of other outlets for partial data disclosure – these include corporate investor decks presented at investor conferences, so called “R&D days” hosted by companies, and sponsored satellite symposia at relevant scientific and medical conferences. These should generally be approached with the same caveats as above given the selective disclosure.

While it depends on the journal, the final publication of trial data is typically a much more robust and trustworthy source than the original press releases of the same data. Not only are there multiple authors on a given manuscript, many of whom are unlikely to be employees of the sponsor, there are also multiple peer reviewers, whom are experts in the same field and required as part the journal’s submission and editorial process. In addition, there are the journal editors themselves who are the final gatekeepers of the manuscript. In the event of particularly novel or noteworthy findings, journals may invite another key opinion leader in the same field to write an accompanying editorial to help put the findings, both good and bad, into perspective as part of the same journal issue. Often newly published articles may be open to comments from anyone interested in submitting them, which sometimes serve the purpose of poking holes in analyses or conclusions.

Full statistical plans and trial protocols may be included as appendices to the main journal article, which can be rich sources of information, but can be dense with jargon for non-experts. It is best to do a full read of not only the full manuscript but also those appendix items, and not simply rely on only the abstract or a third party summary, as these might be no better than the original press release. It is often a matter of years from the first press release to the final publication of the same data set.

Other trial designs

All of the above is based on very conventional clinical program designs, and there are some exceptions. For example, certain late stage cancers with a precision medicine biomarker, or other genetically defined rare diseases, have utilized much smaller clinical programs to gain regulatory approval, moving from a combined Phase I/II trial to a relatively small Phase III. This is due to the inability to recruit patients for large trials from a natural small pool, and in some cases, the highly targeted nature of the therapy allows for statistically significant demonstration of efficacy with a small trial size. There is also some interest in the use of basket trials to test the effect of one drug that targets a single mutation but in a variety of tumor types, or umbrella trials, that have many different arms within one trial. These designs come with different statistical considerations. Though the designs of clinical programs may vary, the platforms for presenting data are otherwise no different, and the same healthy dose of skepticism, if not more given the smaller trial sizes, should be applied to the interpretation of those results from press releases up to and including journal articles.

[1] https://www.sciencedirect.com/science/article/pii/S2451865416301132

2017 has been a landmark year that has seen the approval of two new immunotherapies known as chimeric antigen receptor T-cell (CAR-T) therapies, which are gene edited immune cells designed to recognize and attack certain cancers delivered in a one-time infusion. Much has been said about these products, and more still will be said as it is expected that these products get approvals in new indications, as well as the first-time approvals of other CAR-T products. Given the sophisticated science and novelty behind CAR-T, they are often mentioned in the same breath as gene therapy products. In some instances this may be merited, while in others it may sell CAR-T short relative to the slate of already approved gene therapies. Here, we will highlight key aspects of CAR-T, some lingering questions following these initial approvals, and points of differentiation from other gene therapy products.

Kymriah was the first CAR-T product approved in the US this year for certain acute lymphoblastic leukemias, and Yescarta was subsequently approved for certain large B-cell lymphomas. In both cases, eligible patients have already failed multiple lines of chemotherapy and even failed bone marrow transplantations (BMT) for their blood cancers. CAR-T has been shown to take patients who were otherwise nearly on death’s doorstep and given some what appear to be fairly durable remissions. The upper bound of this range is still unknown simply because trial patients continue to be followed out in real time. In the case of Kymriah, roughly half of patients in clinical trials had a previous BMT, while 8% had two or more BMTs. With standard of care, these patients would otherwise have a median survival of roughly four to seven months, versus some patients out over 14 months post CAR-T treatment and still being followed. These late line ALL patients have had a near doubling of complete responses (disease remission) of roughly 83% versus roughly 20-40% depending on standard of care chemotherapy. Other patients, while they may initially have a good response to CAR-T but subsequently relapse, have gone on to a repeat CAR-T treatment in clinical trials, or possibly BMT. However, the interim CAR-T treatment is thought to improve post-BMT prognosis for some of these patients.

Institutional Complexity

The technical skillset required to administer these therapies limits the universe of locations to a select number of specialized cancer treatment centers, typically the centers of excellence that have historically performed the more difficult BMTs. Most of these centers, who also participated in the registrational trials, issued press releases in the hours and days following the approvals of these products noting their involvement in clinical trials and plans to offer commercially, as a testament to the medical community’s excitement for them. There is also a competitive advantage for these types of centers to be proficient in the delivery of CAR-T, as more products and indications are expected to follow, as mentioned above. It will likely only be incrementally more difficult to offer additional CAR-T options as compared to the initial legwork of preparing to offer CAR-T.  This complexity is due to several factors: patients are already very sick before they arrive for treatment, and that a multi-specialty team needs to be assembled to deal with any side effects that may arise. The timing and severity of these side effects, most notably cytokine release syndrome (CRS), is somewhat variable, occurring anywhere from days to weeks post-infusion. 

Though the administration of CAR-T is a simple infusion, many centers are choosing to administer in the inpatient setting rather than outpatient, as then there is some internal control over the availability of medical or neurological intensive care unit beds if and when CRS occurs. CRS is a result of the CAR-T cells destroying the patient’s cancer burden, with that destruction causing a release of cytokines. The release of cytokines in general does not produce such a severe side effect, but rather the volume of cytokines the body needs to deal with as a result of the CAR-T doing its job so well. Some patients need to be placed into a medically induced coma depending on the severity of CRS. While a difficult side effect, it is somewhat of a catch-22 as it is a sign that the CAR-T is working appropriately. 

There is an expectation that over time, the administration will migrate outpatient as we gain a better understanding of pre-treatment parameters that may influence the likelihood of severe CRS, and patients can be triaged for in or outpatient administration as appropriate.

Other Logistical Concerns

Novartis, the maker of Kymriah, announced a price of $475,000 upon approval, leading many to speculate that this was effectively the price of a cure for any CAR-T product, in any indication. However, Novartis also said it plans to pursue indication-based pricing for Kymriah, such that future approvals for the drug in other indications, with larger or smaller patient populations, could come with lower or higher prices, accordingly. Further, the Swiss pharmaceutical  company said it has a collaboration in place with the Centers for Medicare and Medicaid Services (CMS) where CMS would only have to pay for Kymriah in patients who responded by the end of the first month after the one-time treatment.

As of yet, there are scant details on the CMS arrangement which some have criticized to be more optics than substance. There are several issues at play: that the one month outcomes point is less relevant than a three month clinical endpoint; concerns that what amounts to giving Kymriah away for free to patients who do not respond at one month would trigger anti-kickback concerns related to the Medicaid best price rule (whereby state Medicaid plans are supposed to have the least expensive drug prices compared to other government and commercial payers – so if a patient gets Kymriah for free because he/she did not respond, Medicaid patients are no longer getting the best price); and logistics of how to navigate indication-based pricing in the current infrastructure, whereby drugs are typically given a single billing code, applicable to all indications. Currently, both products are generally relegated to using unclassified billing codes, and the normal cycle and processes for new billing and procedure codes can take several years.

Subsequent press reports^[1] have noted that Novartis has said it will be able to navigate these issues under the auspices of CMS’ Center for Medicare and Medicaid Innovation (CMMI). The CAR-T specific demonstration project under CMMI will supposedly provide for subsequent distinct billing codes that are indication specific once follow-on indications are approved.  Still, details of any such arrangement have not yet been released by CMS. The small patient population for the currently approved indication, less than 600 incident cases per year, should obviate the best-price concerns given that any unique payer is unlikely to see multiple claims in the same quarter.

Some two months after Kymriah’s approval came the approval for Yescarta. Though its owner, Gilead Sciences, had paid $12 billion dollars earlier this year to acquire Kite Pharma, the original maker, it priced Yescarta at $373,000, coming in notably lower than expectations. No outcomes-based contracts have been specified for now. 

Despite the high price tags and lack of clarity on the outcomes agreement, there does seem to be some resolve from both providers and payers to push ahead, though it is early days and still slow going. A recent news article reported only 5 patients have yet been treated with Yescarta as of mid-December, citing predominantly reimbursement issues from Medicare and Medicaid as being the rate-limiting factor^[2]. Still, CAR-T treatment centers have had to assume a certain amount of financial risk just to become equipped to administer CAR-T, before even commercially treating a single patient, and there is still some willingness to take on risk with the first few patients if it means ironing out the process with different payers. 

Comparison to Gene Therapy

The early bumps for CAR-T may leave some people keen to portend a similar fate for CAR-T as compared to some of the early gene therapy approvals in Europe, though this would not do CAR-T justice. There have been two European gene therapy approvals – Glybera, manufactured by UniQure, first approved in the EU in 2012 for an ultra-rare genetic disorder called lipoprotein lipase deficiency, and Strimvelis, for a rare autoimmune deficiency, developed by GlaxoSmithKline and approved in 2016.  Neither of these products has fared well.  In fact, in October UniQure announced that it would not renew the therapy’s market authorization, and Glaxo has put Strimvelis up for sale after only a single digit number of patients were treated.

There are several factors which might determine whether or not these highly novel therapies are commercially successful.  These include price tag, number of potential patients, ability for patients to access the treatment, and the degree of unmet need the therapy addresses. In Europe, it might be easy to point to high price tags as the reason for the gene therapy failures, with list prices of $1 million and $600,000, respectively, particularly as the EU system is far less tolerant of high drug prices. However, this was countered in part by innovative approaches, such as the money back guarantee for Strimvelis if the drug lacked efficacy. But it is also clear these weren’t perfect drugs. Glybera, for instance was only tested in 27 patients and failed to demonstrate lasting effects. In contrast, the CAR-T clinical data is comparatively much more robust, and there are more than 30 treatment centers certified to administer these products at present in only the first few months post-approval.

Against that backdrop, with two US CAR-T approvals, and two European gene therapy approvals under our belts, the first gene therapy in the US was just approved – Luxturna, an ophthalmic gene therapy.

While Spark has not yet announced pricing for Luxturna, its CEO has previously said publicly that economic modeling studies would support a price tag over $1 million. An analysis done by MIT Technology Review would seem to closely corroborate that number^[3]. By plotting the incident patient populations and prices of the four approved CAR-T and gene therapy products, and knowing the incident patient population for Luxturna of fewer than 30 patients per year, it interpolated a price around $900,000, effectively coming in between Glybera and Strimvelis, but on the opposite end of the spectrum from the CAR-T products. Spark has indicated it plans to announce pricing details in January, at which point we may get better clarity on whether Luxturna’s launch will look more like that of the EU gene therapies or the US CAR-T products.

[1] https://pink.pharmaintelligence.informa.com/PS121853/CART-IndicationBased-Pricing-May-Be-Evaluated-In-Medicare-Demo

[2] https://www.bloomberg.com/news/articles/2017-12-14/cancer-patients-with-little-time-left-wait-for-gilead-s-new-drug

[3] https://www.technologyreview.com/s/609197/tracking-the-cost-of-gene-therapy/

Background

Treatment of advanced BRAF-mutant melanoma has changed dramatically in the past 3 years thanks to the approval of new immunotherapy and targeted therapy agents.

Objectives

The goal of our survey was to investigate when immunotherapy and targeted therapy are used in the management of advanced melanoma patients and whether differences exist between the types of setting.

Methods

Oncologists from academic centers, community-based centers, and private clinics were invited to participate in an online survey. Survey questions addressed the proportion of BRAF-mutant patients per treatment line, proportion of patients on targeted therapy and immunotherapy available in the United States, and reasons for prescribing each drug class.

Results

A total of 101 physicians completed the survey, of which 47 worked in a private clinic, 33 in an academic center, and 21 in a community-based center. Academic center participants tended to see more severe patients (P < .001) and had more patients in second-line treatment than participants from other setting types. In addition, academic center physicians had more patients in clinical trials (P < .001), and they prescribed the ipilimumab and nivolumab combination more frequently. In terms of sequencing, all participants used targeted therapy for severe or rapidly progressing patients and immunotherapy for those who were less severe or slowly progressing.

Conclusions

The findings illustrate the differences in treatment approach per type of setting, with patients in academic centers more likely to receive recently approved products or to be enrolled in clinical trials than those in community-based settings.

The log-rank test is frequently used to detect a potential treatment effect in randomized clinical trials with time-to-event endpoints. It is asymptotically the most powerful test under the proportional hazards setting, but it has been shown to markedly lose power when the proportional hazards assumption is violated.

Phase 2 clinical trials are of vital importance in the drug development process as they usually gather preliminary evidence of efficacy of potentially new therapies and support the go/no-go decision for Phase 3 pivotal trials. Topline results of Phase 2 trials are typically first disclosed through press releases so that key stakeholders (patients and their advocacy groups, physicians, clinical trials practitioners, investors, etc.) can have timely access to a high level summary of the important findings. The sponsors of the trials often will save more detailed findings for future medical conference presentations and/or peer-reviewed journal publications, and as a result there may be an extended period of time where only the topline results are available on which stakeholders can rely. It is therefore critical for trial sponsors to release objective findings and avoid selective disclosure of favorable results.