Ipilimumab, a Great University Startup Tale

It’s not everyday that a university startup drug gets FDA approval, especially when that drug is an immunotherapy. 

Dr. James Allison, the current head of immunology at the Memorial Sloan-Kettering Cancer Center, made a seminal discovery that led to the creation of Yervoy, also known as ipilimumab, in the 1990s while he was a professor at UC Berkeley.  Dr. Allison is the discoverer of CTLA-4, an immunoglobin that is expressed on the surface of T helper cells and transmits an inhibitory signal to T cells.  This discovery led Dr. Allison and his team at UC Berkeley to hypothesize that creating a molecule to block CTLA4 could potentially release the brakes on immune system inactivation and in turn decrease immune system tolerance against tumors.  Tumors have numerous crafty mechanisms for evading the human immune system, and blocking CTLA4 (what Dr. Allison dubbed the “CTLA4 Blockade”) could act like an ignition key, stimulating the immune system to mount an attack on the tumor. 

New drugs aren’t launched overnight.  The history of Yervoy meanders through four different technology owners and over 13 years of development once the technology was licensed from Berkeley.  I thought it might be cool to give a brief accounting of the drug’s history (with a little help from Drug R&D).

In 1998, NexStar announces that the University of California at Berkeley has granted the company an exclusive option to license the intellectual property rights to a novel therapeutic technology aimed at fighting cancer and infectious diseases (CTLA4 Blockade). 

NexStar in itself is a rather interesting story and a university startup (University of Colorado). The company was founded by Larry Gold and Craig Tuerk, who had discovered that nucleic acids could bind to any protein and therefore potentially bind to and intercept proteins that cause disease.  To rapidly identify inhibitory nucleic acids (aptamers), Gold and Tuerk developed an aptamer screening technology called SELEX (Systematic Evolution of Ligands by Exponential Enrichment).  NexStar licensed the CTLA4 technology and began to screen for inhibitory aptamers against the target.

In June 1999, Gilead acquired Nexstar.

In August 1999, Medarex obtained an exclusive sublicense from Gilead Sciences, which gave Medarex access to the CTLA-4 blockade intellectual property rights. Gilead Sciences had previously acquired a sublicensable licence from UC Berkeley, through its merger with NeXstar Pharmaceuticals. The sublicense allowed Medarex to further develop fully human antibodies that inhibit CTLA-4, including ipilimumab, which was created using Medarex’s proprietary HuMAb-Mouse technology. Under the terms of the sublicensing agreement, Medarex also had an option to develop non-antibody agents that block CTLA-4. Both Gilead Sciences and UC Berkeley were to receive a royalty split based on future product sales and UC Berkeley was also to receive milestone payments.

In December 1999, IDM became Medarex’s first partner in a program investigating the use of CTLA-4 blockade technology to increase the efficacy of cancer vaccines.  Back then Medarex was a startup biotech that was linking partnership deals for its HuMAb-Mouse technology left and right to generate non-dilutive capital.  At the same time, IDM was developing a proprietary immunostimulant called Dentritophages.  After co-culture in vitro with fragments of the patient’s tumor cells, Dendritophages process and present specific tumor antigens on their cell surface. Once reinjected, Dendritophages may initiate a powerful immune response, helping the patient reject the tumor and prevent tumor recurrence.  Taken together, researchers hoped that the Medarex CTLA-4 antibody and IDM Dentritophages, when used together, could potentiate a strong and durable immune response against tumors. 

In June 2002, Medarex entered into a joint development and supply agreement with IDM (later IDM Pharma). Under the agreement, ipilimumab and various Cell Drug™ combinations were to be investigated.   The IDM partnership for the ipilimumab program was later dropped as Medarex sought to develop only the antibody and not the combination.

In May 2003, Cell Genesys and Medarex entered into a research and development collaboration to evaluate combination therapy with Cell Genesys’ GVAX^® prostate cancer vaccine and ipilimumab. A phase I trial was completed for this combination therapy and under terms of the agreement, both companies shared the cost of the trial equally. However, Cell Genesys discontinued all clinical development activities in June 2009 as part of its restructuring plan.

In January 2005, Medarex and BMS entered into a worldwide collaboration to develop and commercialize ipilimumab and MDX 1379. BMS and Medarex were to share profits and the costs of developing the compounds in the US and EU based on a pre-agreed percentage allocation. BMS was to receive an exclusive license to territories outside the US and pay royalties to Medarex. Medarex received an initial cash payment of $US50 million and up to $US480 million in regulatory and sales-related milestone payments.

In September 2009, Medarex was acquired by BMS for $2.4 billion and became a wholly owned subsidiary of BMS.

On March 25, 2011 ipilumamab was approved as a therapy to treat metastatic melanoma.  In Phase III trials, Ipilumamb improved survival in skin-cancer patients who had prior therapy to an average of 10 months, versus nearly 6.5 months in people treated with an experimental vaccine believed to have limited effectiveness.  Analysts now predict ipilimumab will have yearly sales of more than $1 billion by 2017.

The ipilimumab story is a great tale of the meandering path a drug typically takes before it gets to market.  It is incredible to think that the basic science research performed at a university almost twenty years ago would lead to a blockbuster drug that can help extend the lives of melanoma patients who have no where else to turn.

Congrats to UC Berkeley, Sloan Kettering, and of course, Dr. James Allison!

Antibody-Drug Conjugates

Over the next few entries I will dive into the world of antibody-drug conjugates or ADCs.  An ADC is an antibody that has been conjugated (bound) to a cell-killing drug by a chemical linker.  Most ADCs in development are directed against solid tumors, and to a lesser extent to hematological cancers.  This is an area of personal interest as well as being highly relevant to my work at Osage as some of the hottest ADC startups – Ambrx, Allozyne, Redwood Biosciences – are all university spinouts.  My first entry will be a rough overview on ADCs followed by more specific blog posts about startup activity in the space, drug development challenges, promising ADCs in late stage development, and maybe even an entry on some ADCs that have failed in the clinic.

The concept of ADCs has been around for the last 30 years, but it was really within the last five or so years that drug development interest in the space has really accelerated.  The reasons for the increased enthusiasm for ADCs are multifold.  First, healthcare reform granted biologics 12 years of exclusivity, even if the patent has expired.  This incentivizes pharma companies to develop antibodies and also encourages them to develop ADCs and other strategies to extend the brand life of marketed biologics.  Second, many first generation antibodies are starting to see higher rates of relapse than previously anticipated.  By linking first generation antibodies with cell-killing agents, pharma companies could keep relapsed patients within their brand family.  Finally, scientists have uncovered many new and exciting targets that provide ideal candidates for ADCs.

Antibodies bind to ligands with incredible specificity and it is this functionality that researchers seek to exploit in developing ADCs.  When antibodies bind to specific membrane-bound targets they often get rapidly internalized into the cell.  In developing ADCs, scientists try to link various payloads to antibodies in hopes that the antibodies will more efficiently traffic those payloads into specific cells.  Conceptually this seems pretty simple, but in practice, it is quite hard to efficiently get a conjugated antibody into a cell in high enough quantities to produce a therapeutic effect.

Linking an antibody to another molecule, large or small, is quite a feat of chemical engineering.  Because antibodies are large molecules that provide numerous locations to attach a linker, choosing the right location for the linker can have profound effects on the antibody’s ability to stably carry the toxic agent, bind to its ligand, and get internalized.

Once the linker location is locked down, researchers can then go about choosing the optimal cell-killing agent to conjugate to the antibody.  Most cell-killing agents are chemotherapies that were originally designed for systemic administration and not selective insertion into cells.  Standard assumptions about the properties of chemotherapies often break down in the context of ADCs which forces researchers to tinker with various antibody-chemotherapy combinations until they find a suitable combination.  Such tinkering takes considerable time and money, with little assurance of clinical predictability (ADC could be way more or less toxic than predicted) after all of the hard work. 

Antibodies are great because they are large molecules that persist in the blood stream for a much longer time than their smaller peptide counterparts.  This strength becomes a weakness in the context of ADCs.  As the ADCs travel around the body the chemical linker must keep the antibody bound to the cell-killing agent.  As the ADC gets knocked around the body, the chances of the cell-killing agent breaking off increases greatly making off target cell-killing a significant risk factor.    

While there are significant drug development challenges associated with ADCs, the ability to selectively kill cancer cells continues to intrigue big pharma and encourage the development of novel ADCs.

Personalized Cancer Therapy

Personalized therapy is the wave of the future for drug development.  Unfortunately, personalized therapy has been considered as such for the last 20 years. Individualizing therapeutic regimes is a tantalizing thought, but one that has yielded few tangible results due to the overall complexity of the human body.  

Personalized therapy has garnered the most attention in the oncology world.  Tumors are thought to be patient-specific – that is, each patient accumulates various mutations that lead to disease presentation.  By identifying and mapping mutations across a wide swath of tumors via next-gen DNA sequencing, cancer geneticists believed that they can identify certain tumor profiles that would make tumors most susceptible to certain types of therapy.  In practice, geneticists learned that tumors had a greater diversity of mutations and gene expression profiles that were far more complex than anticipated, making it significantly more challenging to identify putative cancer causing mutations that could lead to aberrant gene expression. 

Tumor profiling has not been a complete disaster as it has yielded some very important diagnostic tests such as the BRCA and HER2 tests.  However, those tests are relatively simple as they only measure the expression level of one gene.

Why hasn’t there been more progress over the last 20 years? 

Unlike normal cells, tumors are typically a mix-mosh of several different types of abnormal cells and some normal cells.  Screening tumor cells for mutations requires quite a bit more skill and time compared to normal cells.  Normal cells require roughly 40x sequencing coverage to ensure the fidelity of the sequence read.  Because cancer cells are so heterogeneous, they require more like 500-1,000x coverage to figure out the various sequences for the different types of cells.  While the price of DNA sequencing has dropped dramatically, it is still super expensive when you have to do 10-25 times the amount of sequencing runs for cancer cells as opposed to normal cells.  Also, it takes some serious software and computing power to align all of those sequences!

As scientists have accumulated more and more sequencing data, their appreciation for the complexity of mutations in tumors has grown.  In the past, people assumed that 4-6 mutations drove a cancer.  Now, geneticists estimate that 10-15+ mutations are needed for tumorignesis.  If 15 mutations are involved in a tumor, it is super hard to figure out which one or two are the really important ones. 

As an aside, that also makes you wonder about the rationale for monoclonal antibodies in cancer.  Maybe it is time people gear up for polyclonals…

Lastly, sequencing requires a really nice biopsy needs to be taken.  No two biopsies are the same, so one could argue that there is a need to take several to fully capture the cellular diversity of a tumor.  That is not so easy when the tumor has latched onto the lung or pancreas, or is too small to see. 

I am a big fan of the power of personalized therapy, but leery of investing the space.  This whole blog entry basically only covered analysis of mutations that drive cancer in genes that are being expressed as quantified by sequencing.  What about epigenetic modifications, non-coding RNAs, or other regulatory elements that are overlooked when doing sequencing analysis?  In time, I believe that someone will figure out a more holistic way of analyzing tumors so that patient-specific therapy decisions can be made.  

University Startups Focused on Personalized Therapy

Foundation Medical: Developing a comprehensive solution that enables physicians to personalize cancer treatment for their patients. By harnessing emerging technologies to develop unparalleled tests that identify and interpret an ever-growing set of actionable genomic and other molecular alterations, Foundation is enabling personalized cancer medicine. Technology licensed from MIT.

Precision Therapeutics: Precision’s first commercial test, ChemoFx®, is a proprietary drug response marker which measures an individual’s malignant tumor response to a range of standard therapeutic alternatives under consideration by a physician with the goal of optimizing patient outcomes. Technology licensed from the University of Pittsburgh.

Therasis: The Company’s proprietary technology, the Therasis Filter™, represents a paradigm shift in the ability to discover therapeutic targets, their chemical inhibitors, and associated biomarkers. This platform integrates world-class expertise in high throughput screening, systems biology, cancer genetics and clinical research. Technology licensed from Columbia University.

Predictive Biosciences: A Multiple Biomarker Approach to Bladder Cancer Detection.  The test utilizes both protein biomarkers and molecular DNA analysis optimized to provide both sensitivity and specificity. Technology licensed from Children’s Hospital Boston.

Imuneering Corp.: Immuneering helps pharmaceutical companies develop immunology-based therapies for cancer, neurodegeneration, and autoimmunity. The company utilizes proprietary engineering techniques to quantitatively model the physical processes occurring at the cellular and molecular level in a given disease, and determine how particular medicines will impact those processes.  Technology licensed from MIT.

On-Q-Ity: On-Q-ity’s proprietary technologies provide more frequent and effective monitoring of cancer progression by proactively measuring tumor biology and intelligently adjusting therapy as necessary throughout a patient’s treatment lifecycle. By combining DNA repair biomarkers with the company’s ability to capture and analyze circulating tumor cells (CTCs), On-Q-Ity can provide a complete view of an individual patient’s pending treatment options and allows for more patient-friendly monitoring of the treatment’s progress. Technology licensed from Massachusetts General Hospital and MIT.